The impact of stress and anesthesia on animal models of infectious disease.

Stress and general anesthesia have an impact on the functional response of the organism due to the detrimental effects on cardiovascular, immunological, and metabolic function, which could limit the organism's response to an infectious event. Animal studies have formed an essential step in understanding and mitigating infectious diseases, as the complexities of physiology and immunity cannot yet be replicated in vivo. Using animals in research continues to come under increasing societal scrutiny, and it is therefore crucial that the welfare of animals used in disease research is optimized to meet both societal expectations and improve scientific outcomes. Everyday management and procedures in animal studies are known to cause stress, which can not only cause poorer welfare outcomes, but also introduces variables in disease studies. Whilst general anesthesia is necessary at times to reduce stress and enhance animal welfare in disease research, evidence of physiological and immunological disruption caused by general anesthesia is increasing. To better understand and quantify the effects of stress and anesthesia on disease study and welfare outcomes, utilizing the most appropriate animal monitoring strategies is imperative. This article aims to analyze recent scientific evidence about the impact of stress and anesthesia as uncontrolled variables, as well as reviewing monitoring strategies and technologies in animal models during infectious diseases.

Evaluation of the MilA ELISA for the diagnosis of herd infection with Mycoplasma bovis using bulk tank milk and estimation of the prevalence of M. bovis in Australia.

Infection with Mycoplasma bovis has been identified as a growing threat in dairy industries worldwide and there is an urgent need for an inexpensive and accurate herd-level screening tool to identify herds that have been exposed to M. bovis. This study aimed to evaluate the use of the MilA ELISA for testing bulk tank milk (BTM) samples for antibodies against M. bovis and estimate a suitable cut-off and diagnostic sensitivity (DSe) and specificity (DSp) for this assay. An optimal cut-off was then applied for investigating the geographical and seasonal distribution of infection with M. bovis in Australia. A total of 5554 BTM samples from 2683 dairy herds were collected during March, August and December 2017. BTM samples were tested in the MilA ELISA and a cut-off of 29 antibody units (AU) was estimated to be optimal using Bayesian latent class analysis which makes no assumption about the true disease status of herds under investigation. At this cut-off, the DSe and DSp were estimated to be 96.6% (95% highest probability density [HPD] interval: 87.0, 99.8) and 94.2% (95% HPD: 89.9, 97.4), respectively. The diagnostic specifications were found to vary markedly with stage of the production cycle, suggesting that targeted sampling was needed to maximize accuracy. We also found distinct differences in the apparent prevalence of M. bovis in different dairying regions, as well as seasonal variation. The highest apparent prevalence of M. bovis was observed in samples collected in March and an overall drop in the proportion of positive herds was seen from March to December. Overall, this study provides insights into the dynamics of BTM antibodies against M. bovis in Australian dairy herds and how the MilA ELISA can be applied for bulk tank milk testing.

Can calf age be estimated using a combination of serum gamma-glutamyl transferase, total protein and immunoglobulin G?

Our aim was to test a novel method for estimating the age of young calves, using serum γ-glutamyl transferase (GGT) activity, total protein concentration and immunoglobulin G (IgG) concentration. Blood samples were taken from 59 dairy calves at 2, 4, 6, 8, 10, 12, and 14 days of age, and serum GGT activity, total protein concentration, and IgG concentration were measured. Bayesian regression models were used to estimate the association of GGT, total protein, and IgG, with calf age. A multivariate hierarchical regression model was then created, and the model's reliability in estimating the age of simulated subjects was assessed. The univariate models showed a strong within-calf relationship between age and GGT (conditional R2 (cR2) = 0.93), and age and total protein (cR2 = 0.75), while the relationship between calf age and IgG was less consistent (cR2 = 0.63). There was a high degree of variation between calves for these parameters, particularly for the relationship between age and total protein (marginal R2 (mR2) 0.02), and age and IgG (mR2 0.01); somewhat less between-calf variation was seen for GGT (mR2 0.30). For the final multivariate model, we tested the model reliability by simulating new subjects. The credible intervals for estimates of calf age generated from the model were wide, indicating poor reliability. We concluded that single measurements of serum GGT activity, total protein concentrations and IgG concentrations cannot be used to reliably estimate the age of young calves to within 1-2 days.

Blood parameters of young calves at abattoirs are related to distance transported and farm of origin.

Nonreplacement dairy calves, or bobby calves, are fasted and transported to abattoirs from as young as 5 d of age in Australia. The aims of this cross-sectional observational study were (1) to assess the welfare status, as measured by blood parameters, of bobby calves in the commercial supply chain after transport and lairage, and (2) to assess whether distance and duration of transport are risk factors for poor bobby calf welfare, as measured by blood parameters. We hypothesized that bobby calves transported greater distances would be more likely to show evidence of compromised welfare, as measured by blood indicators of hydration, energy status, and muscle fatigue or damage. We also hypothesized that there would be a large amount of variability in indicators of energy status between calves from different farms. We analyzed blood samples collected at slaughter over a spring and an autumn calving period from 4,484 Australian bobby calves aged approximately 5 to 14 d old from 3 different states, after transport, fasting, and lairage. Packed cell volume (PCV), plasma glucose, and serum urea, total protein, ß-hydroxybutyrate (BHB), and creatine kinase (CK) were measured. Radio frequency identification ear tag data were used to estimate the distance that the calves were transported and to identify the farm of origin. Data were analyzed using linear mixed models, except for BHB, which was analyzed using a Goodman-Kruskal gamma test due to left censoring of the data. Twelve percent of calves showed evidence of anemia (PCV less than 0.23 L/L), and 11% had urea concentrations consistent with dehydration (urea more than 7.7 mmol/L). Thirty-six percent of calves had CK activity above normal resting values, and 1% of calves had CK >2,000 U/L, indicating muscle fatigue or damage. Distance transported had significant effects on all blood variables except urea and BHB. With increasing distance transported, calves were more likely to show evidence of a negative energy balance (low plasma glucose) or dehydration (high PCV or total protein). The estimated effect of distance overall was small, but for calves transported more than 500 km, plasma glucose concentration declined more per kilometer. The calves' farm of origin accounted for a reasonable amount of the random variation between calves for plasma glucose (20%). Our results suggest that longer transport distances may increase the risk of poor calf welfare (dehydration, negative energy balance) after transport, and on-farm calf management (e.g., nutrition, timing of feeding before transport) may affect transported calves' energy status; improving this area could result in better energy availability during fasting.

The Impact of Bushfire Smoke on Cattle-A Review.

In 2019-2020, a particularly bad bushfire season in Australia resulted in cattle being exposed to prolonged periods of smoke haze and reduced air quality. Bushfire smoke contains many harmful pollutants, and impacts on regions far from the fire front, with smoke haze persisting for weeks. Particulate matter (PM) is one of the major components of bushfire smoke known to have a negative impact on human health. However, little has been reported about the potential effects that bushfire smoke has on cattle exposed to smoke haze for extended periods. We explored the current literature to investigate evidence for likely effects on cattle from prolonged exposure to smoke generated from bushfires in Australia. We conducted a search for papers related to the impacts of smoke on cattle. Initial searching returned no relevant articles through either CAB Direct or PubMed databases, whilst Google Scholar provided a small number of results. The search was then expanded to look at two sub-questions: the type of pollution that is found in bushfire smoke, and the reported effects of both humans and cattle being exposed to these types of pollutants. The primary mechanism for damage due to bushfire smoke is due to small airborne particulate matter (PM). Although evidence demonstrates that PM from bushfire smoke has a measurable impact on both human mortality and cardiorespiratory morbidities, there is little evidence regarding the impact of chronic bushfire smoke exposure in cattle. We hypothesize that cattle are not severely affected by chronic exposure to smoke haze, as evidenced by the lack of reports. This may be because cattle do not tend to suffer from the co-morbidities that, in the human population, seem to be made worse by smoke and pollution. Further, small changes to background mortality rates or transient morbidity may also go unreported.

Biochemistry and hematology reference intervals for neonatal dairy calves aged 5-12 days.

BACKGROUND: Comprehensive hematology and biochemistry RIs are currently lacking in the literature for young dairy calves based on sample sizes more than 120. Young dairy calves are at a relatively high risk of poor health and welfare outcomes. They have a high risk of morbidity and mortality in the first 2 weeks of life, and many are transported and fasted during this time. For example, non-replacement calves in Australia and New Zealand are usually 5-12 days old when transported to abattoirs, meaning that calves of this age group are potentially at risk of both health and welfare compromise. Given these factors, sound, comprehensive, age-specific biochemical and hematologic RIs are needed for both veterinary clinical practice and to inform research on calf health and welfare. OBJECTIVES: The aim of this study was to generate age-specific hematology and biochemistry RIs for dairy calves aged 5-12 days. METHODS: We collected blood samples from 141 fasted, healthy dairy calves on 10 Australian farms. Reference Value Advisor software was used to calculate nonparametric RIs for multiple biochemistry and hematology variables. RESULTS: RIs for a panel of hematology and biochemistry variables in dairy calves aged 5-12 days old were derived. CONCLUSIONS: These RIs will be useful for clinical veterinary practice, as well as for research on dairy calf health and welfare.

Invited review: The welfare of young calves transported by road.

The transport of young calves is a welfare concern. Young calves aged ≤3 mo are particularly vulnerable to compromised welfare, and are at a relatively high risk of morbidity and mortality compared with adult cattle. Calves face several potential challenges to welfare during and after transport, including food and water deprivation, disease, injury, and stress from handling, social mixing, and new environments. The key risk factors identified for poor calf welfare associated with transport include long transport and fasting durations, young age at transport, poor colostral immunity, timing within the calving season, lack of bedding in trucks, and high stocking density. Maximizing calf welfare thus requires a multifaceted approach, such as minimizing transport and fasting durations, transporting at an appropriate stocking density with comfortable bedding, only transporting calves that are healthy and fit, and optimizing pre-transport calf management. More research is needed to understand the effect of transport on the mental or affective state of calves.

Treatment effects may remain the same even when trial participants differed from the target population.

OBJECTIVES: Randomized controlled trials (RCTs) have been criticized for lacking external validity. We assessed whether a trial in people with type I diabetes mellitus mirrored the wider population and applied sample-weighting methods to assess the impact of differences on our trial's findings. STUDY DESIGN AND SETTING: The Relative Effectiveness of Pumps over MDI and Structured Education trial was nested within a large UK cohort capturing demographic, clinical, and quality of life data for people with type I diabetes mellitus undergoing structured diabetes-specific education. We first assessed whether our RCT participants were comparable with this cohort using propensity score modeling. After this, we reweighted the trial population to better match the wider cohort and re-estimated the treatment effect. RESULTS: Trial participants differed from the cohort in regard to sex, weight, HbA1c, and also quality of life and satisfaction with current treatment. Nevertheless, the treatment effects derived from alternative model weightings were similar to that of the original RCT. CONCLUSION: Our RCT participants differed in composition to the wider population, but the original findings were unaffected by sampling adjustments. We encourage investigators take steps to address criticisms of generalizability but doing so is problematic; external data, even if available, may contain limited information and analyses can be susceptible to model misspecification.

Blood collection from dairy calves at exsanguination post-slaughter yields similar biochemical and packed cell volume measurements compared with in vivo collection during lairage.

Blood collection at exsanguination is a method of collecting samples at abattoirs which itself has no effect on animal welfare, compared with collection prior to stunning. However, there is the potential for artefact to affect measurements. It was hypothesised that, for most blood analytes measured, the differences between lairage and exsanguination measurements would be minimal, except for creatine kinase, which was expected be higher in exsanguination samples. Fifty-nine male dairy calves approximately 5-10 days old were sampled prior to slaughter, and again during exsanguination after stunning. Each sample was analysed for packed cell volume, serum urea, beta-hydroxybutyrate, gamma-glutamyl transferase, total protein, glucose and creatine kinase concentrations. Exsanguination and lairage blood results were compared using a paired t-test. There were no significant differences between the measurements taken at exsanguination compared with lairage for packed cell volume, urea and beta-hydroxybutyrate. Glucose concentrations were higher in exsanguination samples, and total protein concentrations were lower, but for both of these analytes the differences were clinically small. Gamma-glutamyl transferase activity was lower in exsanguination samples compared with lairage samples. Creatine kinase activity was higher in exsanguination samples. It was concluded that collecting blood at exsanguination is a valid method for collecting samples for measurement of packed cell volume, urea, and beta-hydroxybutyrate in calves. Glucose and total protein can also yield useful measurements in these samples, though care needs to be taken with interpretation given the minor differences between exsanguination and lairage measurements. Exsanguination samples may be unsuitable for creatine kinase and gamma-glutamyl transferase measurement.

Adverse vacuolation in multiple tissues in cynomolgus monkeys following repeat-dose administration of a PEGylated protein.

PEGylation is considered a safe mechanism to enhance the pharmacokinetics (PK) and pharmacodynamics (PD) of biotherapeutics. Previous studies using PEGylation as a PK enhancement tool have reported benign PEG-related vacuolation in multiple tissues. This paper establishes a threshold for PEG burden beyond which there are alterations in tissue architecture that could potentially lead to dysfunction. As part of the nonclinical safety assessment of Compound A, a 12 kDa protein conjugated to a 40 kDa branched PEG molecule, monkeys were dosed subcutaneously twice weekly for 3 months at protein doses resulting in weekly PEG doses of 8, 24, 120, or 160 mg/kg. Consistent with previous reports with PEGylated biomolecules, Compound A administration resulted in intracellular vacuoles attributed to the PEG moiety in macrophages in numerous tissues and epithelial cells in the choroid plexus and kidney. Vacuolation occurred at all doses with dose-dependent severity and no evidence of recovery up to 2 months after dosing cessation. The vacuolation was considered nonadverse at PEG doses ≤120 mg/kg/week. However, at 160 mg/kg/week PEG, the vacuolation in choroid plexus, pituitary gland, kidney, and choroid of the eye was considered adverse due to significant alterations of tissue architecture that raised concern for the possibility of compromised tissue function. To our knowledge, this is the first report of potentially adverse cellular consequences of PEG accumulation in tissues other than kidney. Furthermore, the lack of reversibility of vacuolation coupled with the lack of a biomarker for intracellular PEG accumulation highlights a potential risk that should be weighed against the benefits of PK/PD enhancement for long-term administration of PEGylated compounds at high doses.

PAID-11: A brief measure of diabetes distress validated in adults with type 1 diabetes.

OBJECTIVE: The Problem Areas In Diabetes (PAID) questionnaire is widely used to assess emotional distress related to living with diabetes, although it is lengthy for routine clinical use. Our aim was to determine whether the original 20-item PAID questionnaire can be abbreviated, whilst maintaining its reliability, validity and utility. METHODS: We analysed data from the UK DAFNE (Dose Adjustment For Normal Eating) education programme for adults with Type 1 diabetes. Data were analysed at baseline (n = 1547) and 1-year post intervention (n = 846). Exploratory factor analysis (EFA) with principal axis factoring method was used to examine PAID responses within a random half of the baseline data (n = 746). Then, two confirmatory factor analyses (CFA) were conducted using the remaining baseline (n = 801) and 1-year data. Reliability, predictive validity, convergent validity and responsiveness were also examined. RESULTS: Based on the EFA results, which were corroborated by CFA, an 11-item PAID questionnaire was identified with a cut-off score of 18 indicating severe diabetes distress. In the current sample, this brief version had high internal consistency (Cronbach's α = 0.93). Predictive validity was demonstrated with the PAID-11 identifying severe diabetes distress from the original 20-item measure, with 95% sensitivity and 96% specificity. Convergent validity was demonstrated by strong positive correlations with HADS anxiety and depressive symptoms (average r = 0.65 and r = 0.55, respectively), while divergent validity was shown with weaker correlations with EQ5D health status (average r = 0.37). CONCLUSIONS: Based on present results, PAID-11 appears to be a valid and reliable measure, which seems suitable for use as a brief tool for the detection of diabetes distress in adults with type 1 diabetes. Importantly, this tool may reduce participant burden in multi-measure studies. However, further studies are urgently needed to determine the validity and utility of PAID-11 beyond the UK DAFNE population.

The major membrane nuclease MnuA degrades neutrophil extracellular traps induced by Mycoplasma bovis.

Mycoplasma bovis has been increasingly recognised worldwide as an economically important pathogen of cattle, causing a range of diseases, including pneumonia, mastitis, polyarthritis and otitis media. It is believed that M. bovis utilises a range of cell surface proteins, including nucleases, to evade the host immune response and survive. However, despite the importance of neutrophils in controlling pathogenic bacteria, the interaction between these cells and M. bovis is not well-characterised. In addition to phagocytosis, neutrophils combat pathogens through the release of neutrophil extracellular traps (NETs), which are composed of their nuclear and granular components, including DNA. Here we investigated the effect of the major membrane nuclease MnuA of M. bovis, which in vitro is responsible for the majority of the nuclease activity of M. bovis, on NET formation. We quantified NET formation by bovine neutrophils 4 h after stimulation with wild-type M. bovis, an mnuA mutant and a mnuA-pIRR45 complemented mnuA mutant. NETs were detected following stimulation of neutrophils with the mnuA mutant but not after exposure to either the wild-type or the mnuA-pIRR45 complemented mutant, and NETs were degraded in the presence of even low concentrations of wild type M. bovis. Surprisingly, there was no increase in levels of intracellular reactive oxygen species (ROS) production in neutrophils stimulated with M. bovis, even though these neutrophils produced NETs. These results clearly demonstrate that M. bovis can induce NET formation in bovine neutrophils, but that the major membrane nuclease MnuA is able to rapidly degrade NETs, and thus is likely to play a significant role in virulence. In addition, M. bovis appears to induce NETs even though ROS production seems to be suppressed.

The Performance of Three Immune Assays to Assess the Serological Status of Cattle Experimentally Exposed to Mycoplasma bovis.

Mycoplasma bovis is associated with several clinical syndromes of cattle. Currently, limited information is available on the sensitivity (Se) and specificity (Sp) of serological assays used for the detection of M. bovis-specific antibodies. Consequently, it is difficult to critically evaluate the outcomes of studies that use these assays. Therefore, the current study used bovine sera sourced from M. bovis exposure studies from three countries to estimate the Se and Sp of two commercial M. bovis enzyme-linked immunosorbent assays (ELISA), BIO K302 and BIO K260, and Western blotting. Western blotting had the highest Se estimate of 74% (95% confidence interval (CI): 16-98%), compared to the BIO K302: 47% (95% CI: 10-87%) and BIO K260: 28% (95% CI: 1-92%). However, for Sp, the BIO K302: 96% (95% CI: 87-99%) and the BIO K260: 100% (95% CI: 93-100%) out-performed Western blotting: 88% (95% CI: 56-98%). Western blotting was the best assay for detecting seroconversion, correctly identifying 61% (95% CI: 29-86%) of exposed animals compared to 35% for BIO K302 (95% CI: 21-54%) and 8% for BIO K260 (95% CI: 0-87%). While none of the methods assessed had high Se and Sp, the availability of these estimates will aid in the interpretation of studies that use these assays. The results of this study highlight the difficulties encountered when using serology to detect exposure to M. bovis in cattle.

Reproduction of respiratory mycoplasmosis in calves by exposure to an aerosolised culture of Mycoplasma bovis.

Mycoplasma bovis is an important pathogen of cattle, causing pneumonia, arthritis and otitis media in young calves, and mastitis in lactating cows, resulting in increased morbidity and, in some instances, mortality. The objective of this study was to evaluate the survival of a M. bovis isolate following nebulisation and to establish whether respiratory disease similar to that seen in the field could be induced in calves by exposing them to an aerosolised culture of M. bovis. A group of eight M. bovis-free calves 14-28days old were exposed to an aerosolised culture of a field isolate of M. bovis that had originally been recovered from a joint lesion in a calf. Three weeks after aerosol exposure necropsies were conducted on all calves. Lung lesions were seen in 7 of 8 calves exposed to the aerosol of M. bovis, whilst calves exposed to the culture medium alone did not develop lesions. Two calves in the infected group had detectable concentrations of serum antibody against M. bovis on day 7 post infection and 4 calves had detectable concentrations of serum antibody against M. bovis on day 21 post infection when tested by MilA IgG ELISA. M. bovis was reisolated from the upper trachea of 6 of the 8 infected calves. The infection method described here appeared to induce lung lesions typical of naturally occurring disease associated with infection with M. bovis and should be applicable to testing the safety and efficacy of attenuated vaccine candidates to control disease caused by this pathogen.

Exercise Metabolism in Nonobese Patients with Type 2 Diabetes Following the Acute Restoration of Normoglycaemia.

This study investigated how acute restoration of normoglycaemia affected energy metabolism during exercise in nonobese patients with type 2 diabetes. Six subjects (mean ± SEM) aged 56.2 ± 2.7 years, with a BMI of 24.5 ± 1.5 kg/m2 and a VO2 peak of 28.7 ml/kg/min, attended the lab on two randomised occasions for a four-hour resting infusion of insulin or saline, followed by 30 minutes cycling at 50% VO2 peak. During the 4 h resting infusion, there was a greater (P < 0.0001) reduction in blood glucose in insulin treatment (INS) (from 11.2 ± 0.6 to 5.6 ± 0.1 mmol/l) than in saline treatment/control (CON) (from 11.5 ± 0.7 to 8.5 ± 0.6 mmol/l). This was associated with a lower (P < 0.05) resting metabolic rate in INS (3.87 ± 0.17) than in CON (4.39 ± 0.30 kJ/min). During subsequent exercise, blood glucose increased significantly in INS from 5.6 ± 0.1 at 0 min to 6.3 ± 0.3 mmol/l at 30 min (P < 0.01), which was accompanied by a lower blood lactate response (P < 0.05). Oxygen uptake, rates of substrate utilization, heart rate, and ratings of perceived exertion were not different between trials. Insulin-induced normoglycaemia increased blood glucose during subsequent exercise without altering overall substrate utilization.

A cluster randomised trial, cost-effectiveness analysis and psychosocial evaluation of insulin pump therapy compared with multiple injections during flexible intensive insulin therapy for type 1 diabetes: the REPOSE Trial.

BACKGROUND: Insulin is generally administered to people with type 1 diabetes mellitus (T1DM) using multiple daily injections (MDIs), but can also be delivered using infusion pumps. In the UK, pumps are recommended for patients with the greatest need and adult use is less than in comparable countries. Previous trials have been small, of short duration and have failed to control for training in insulin adjustment. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of pump therapy compared with MDI for adults with T1DM, with both groups receiving equivalent structured training in flexible insulin therapy. DESIGN: Pragmatic, multicentre, open-label, parallel-group cluster randomised controlled trial, including economic and psychosocial evaluations. After participants were assigned a group training course, courses were randomly allocated in pairs to either pump or MDI. SETTING: Eight secondary care diabetes centres in the UK. PARTICIPANTS: Adults with T1DM for > 12 months, willing to undertake intensive insulin therapy, with no preference for pump or MDI, or a clinical indication for pumps. INTERVENTIONS: Pump or MDI structured training in flexible insulin therapy, followed up for 2 years. MDI participants used insulin analogues. Pump participants used a Medtronic Paradigm® VeoTM (Medtronic, Watford, UK) with insulin aspart (NovoRapid, Novo Nordisk, Gatwick, UK). MAIN OUTCOME MEASURES: Primary outcome - change in glycated haemoglobin (HbA1c) at 2 years in participants whose baseline HbA1c was ≥ 7.5% (58 mmol/mol). Key secondary outcome - proportion of participants with HbA1c ≤ 7.5% at 2 years. Other outcomes at 6, 12 and 24 months - moderate and severe hypoglycaemia; insulin dose; body weight; proteinuria; diabetic ketoacidosis; quality of life (QoL); fear of hypoglycaemia; treatment satisfaction; emotional well-being; qualitative interviews with participants and staff (2 weeks), and participants (6 months); and ICERs in trial and modelled estimates of cost-effectiveness. RESULTS: We randomised 46 courses comprising 317 participants: 267 attended a Dose Adjustment For Normal Eating course (132 pump; 135 MDI); 260 were included in the intention-to-treat analysis, of which 235 (119 pump; 116 MDI) had baseline HbA1c of ≥ 7.5%. HbA1c and severe hypoglycaemia improved in both groups. The drop in HbA1c% at 2 years was 0.85 on pump and 0.42 on MDI. The mean difference (MD) in HbA1c change at 2 years, at which the baseline HbA1c was ≥ 7.5%, was -0.24% [95% confidence interval (CI) -0.53% to 0.05%] in favour of the pump (p = 0.098). The per-protocol analysis showed a MD in change of -0.36% (95% CI -0.64% to -0.07%) favouring pumps (p = 0.015). Pumps were not cost-effective in the base case and all of the sensitivity analyses. The pump group had greater improvement in diabetes-specific QoL diet restrictions, daily hassle plus treatment satisfaction, statistically significant at 12 and 24 months and supported by qualitative interviews. LIMITATION: Blinding of pump therapy was not possible, although an objective primary outcome was used. CONCLUSION: Adding pump therapy to structured training in flexible insulin therapy did not significantly enhance glycaemic control or psychosocial outcomes in adults with T1DM. RESEARCH PRIORITY: To understand why few patients achieve a HbA1c of < 7.5%, particularly as glycaemic control is worse in the UK than in other European countries. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61215213. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 20. See the NIHR Journals Library website for further project information.

Expectations of Graduate Communication Skills in Professional Veterinary Practice.

Good communication skills are an important entry-level attribute of graduates of professional degrees. The inclusion of communication training within the curriculum can be problematic, particularly in programs with a high content load, such as veterinary science. This study examined the differences between the perceptions of students and qualified veterinarians with regards to the entry-level communication skills required of new graduates in clinical practice. Surveys were distributed to students in each of the four year levels of the veterinary science degree at the University of Melbourne and to recent graduates and experienced veterinarians registered in Victoria, Australia. Respondents were asked to rank the relative importance of six different skill sets: knowledge base; medical and technical skills; surgical skills; verbal communication and interpersonal skills; written communication skills; and critical thinking and problem solving. They were then asked to rate the importance of specific communication skills for new graduate veterinarians. Veterinarians and students ranked verbal communication and interpersonal skills as the most important skill set for an entry-level veterinarian. Veterinarians considered many new graduates to be deficient in these skills. Students often felt they lacked confidence in this area. This has important implications for veterinary educators in terms of managing the expectations of students and improving the delivery of communication skills courses within the veterinary curriculum.

The Impact of Diabetes-Related Complications on Preference-Based Measures of Health-Related Quality of Life in Adults with Type I Diabetes.

INTRODUCTION: This study estimates health-related quality of life (HRQoL) or utility decrements associated with type 1 diabetes mellitus (T1DM) using data from a UK research program on the Dose Adjustment For Normal Eating (DAFNE) education program. METHODS: A wide range of data was collected from 2341 individuals who undertook a DAFNE course in 2009-2012, at baseline and for 2 subsequent years. We use fixed- and random-effects linear models to generate utility estimates for T1DM using different instruments: EQ-5D, SF-6D, and EQ-VAS. We show models with and without controls for HbA1c and depression, which may be endogenous (if, for example, there is reverse causality in operation). RESULTS: We find strong evidence of an unobserved individual effect, suggesting the superiority of the fixed-effects model. Depression shows the greatest decrement across all the models in the preferred fixed-effects model. The fixed-effects EQ-5D model also finds a significant decrement from retinopathy, body mass index, and HbA1c (%). Estimating a decrement using the fixed-effects model is not possible for some conditions where there are few new cases. In the random-effects model, diabetic foot disease shows substantial utility decrements, yet these are not significant in the fixed-effects models. CONCLUSION: Utility decrements have been calculated for a wide variety of health states in T1DM that can be used in economic analyses. However, despite the large data set, the low incidence of several complications leads to uncertainty in calculating the utility weights. Depression and diabetic foot disease result in a substantial loss in HRQoL for patients with T1DM. HbA1c (%) appears to have an independent negative impact on HRQoL, although concerns remain regarding the potential endogeneity of this variable.

Diabetes and pregnancy.

An increasing number of women who are pregnant have diabetes, whether gestational or pre-existing. Diabetes in pregnancy is associated with a number of adverse outcomes including birth trauma, neonatal hypoglycaemia, macrosomia and pre-eclampsia. Those with pre-existing diabetes have the additional risks which include congenital defects and increased perinatal mortality. This paper summarises the complications of diabetes in pregnancy and highlights some of the recent controversy surrounding the diagnosis of gestational diabetes.