Development of LIME-NZ: a generic tool for prompt estimation of economic impacts of disease for New Zealand livestock.

AIMS: To develop a simple and robust generic tool to measure the impacts of livestock diseases on New Zealand dairy, beef and sheep farms using enterprise gross margin models. METHODS: The most recent (2018-2020) livestock production benchmarking data was extracted from industry-led economic surveys. Gross margin models were built for each enterprise type, accounting for 11 dairy farm types and 16 farm types for beef and sheep. Disease parameters, including changes in mortality, reproduction performance, milk yield, price of animals and culling rate, as well as additional expenses for veterinary intervention, were applied to the infected compartment of the herd/flock using the assumed annual within-herd disease incidence. Farm-level disease impacts were estimated as the difference in annual profit between the baseline and infected farm. The baseline gross margin models were validated against the industry data. The disease impact models were validated using a recently published study on bovine viral diarrhoea (BVD). The impact assessment tool, LIME-NZ, was developed using the statistical software R and implemented in the web-based R package Shiny. The input parameters can be varied interactively to obtain a range of disease impacts for uncertain disease parameters. RESULTS: The baseline gross margin models demonstrated reasonable accuracy with a mean percentage error of <14% when compared with the industry reports. The estimated annual impacts of BVD were comparable to those reported in the BVD study, NZ$38.5-140.4 thousand and $0.9-32.6 thousand per farm per year for dairy and beef enterprises, respectively. CONCLUSIONS: LIME-NZ can be used to rapidly obtain the likely economic impacts of diseases that are endemic, recently introduced or at increased risk of introduction in the New Zealand context. This will aid communication and decision-making among government agencies and the livestock industry, including veterinarians and livestock producers, about the management of diseases, until refined information becomes available to improve decision-making.

Point Absorber Limits to Future Gravitational-Wave Detectors.

High-quality optical resonant cavities require low optical loss, typically on the scale of parts per million. However, unintended micron-scale contaminants on the resonator mirrors that absorb the light circulating in the cavity can deform the surface thermoelastically and thus increase losses by scattering light out of the resonant mode. The point absorber effect is a limiting factor in some high-power cavity experiments, for example, the Advanced LIGO gravitational-wave detector. In this Letter, we present a general approach to the point absorber effect from first principles and simulate its contribution to the increased scattering. The achievable circulating power in current and future gravitational-wave detectors is calculated statistically given different point absorber configurations. Our formulation is further confirmed experimentally in comparison with the scattered power in the arm cavity of Advanced LIGO measured by in situ photodiodes. The understanding presented here provides an important tool in the global effort to design future gravitational-wave detectors that support high optical power and thus reduce quantum noise.

Salbutamol use in relation to maintenance bronchodilator efficacy in COPD: a prospective subgroup analysis of the EMAX trial.

BACKGROUND: Short-acting ß2-agonist (SABA) bronchodilators help alleviate symptoms in chronic obstructive pulmonary disease (COPD) and may be a useful marker of symptom severity. This analysis investigated whether SABA use impacts treatment differences between maintenance dual- and mono-bronchodilators in patients with COPD. METHODS: The Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids 1:1:1 to once-daily umeclidinium/vilanterol 62.5/25 µg, once-daily umeclidinium 62.5 µg or twice-daily salmeterol 50 µg for 24 weeks. Pre-specified subgroup analyses stratified patients by median baseline SABA use (low, < 1.5 puffs/day; high, ≥1.5 puffs/day) to examine change from baseline in trough forced expiratory volume in 1 s (FEV1), change in symptoms (Transition Dyspnoea Index [TDI], Evaluating Respiratory Symptoms-COPD [E-RS]), daily SABA use and exacerbation risk. A post hoc analysis used fractional polynomial modelling with continuous transformations of baseline SABA use covariates. RESULTS: At baseline, patients in the high SABA use subgroup (mean: 3.91 puffs/day, n = 1212) had more severe airflow limitation, were more symptomatic and had worse health status versus patients in the low SABA use subgroup (0.39 puffs/day, n = 1206). Patients treated with umeclidinium/vilanterol versus umeclidinium demonstrated statistically significant improvements in trough FEV1 at Week 24 in both SABA subgroups (59-74 mL; p < 0.001); however, only low SABA users demonstrated significant improvements in TDI (high: 0.27 [p = 0.241]; low: 0.49 [p = 0.025]) and E-RS (high: 0.48 [p = 0.138]; low: 0.60 [p = 0.034]) scores. By contrast, significant reductions in mean SABA puffs/day with umeclidinium/vilanterol versus umeclidinium were observed only in high SABA users (high: - 0.56 [p < 0.001]; low: - 0.10 [p = 0.132]). Similar findings were observed when comparing umeclidinium/vilanterol and salmeterol. Fractional polynomial modelling showed baseline SABA use ≥4 puffs/day resulted in smaller incremental symptom improvements with umeclidinium/vilanterol versus umeclidinium compared with baseline SABA use < 4 puffs/day. CONCLUSIONS: In high SABA users, there may be a smaller difference in treatment response between dual- and mono-bronchodilator therapy; the reasons for this require further investigation. SABA use may be a confounding factor in bronchodilator trials and in high SABA users; changes in SABA use may be considered a robust symptom outcome. FUNDING: GlaxoSmithKline (study number 201749 [NCT03034915]).

Invited review: A systematic literature review and meta-analysis of mortality and culling in dairy cattle.

Dairy industries and individual farmers are concerned about mortality and culling of dairy animals. This is because the timing and fates of animals that exit dairy farms have important animal welfare and economic consequences that reflect the conditions under which they are farmed and the efficiency of their production systems. Reports from a few countries have indicated increased incidence of mortality, and occasionally culling, of dairy animals in recent decades, and these changes have been associated with intensification of production systems. Dairy industries and farmers need benchmarks for culling and mortality against which they can compare themselves, as well as improved understanding of the extent of any change and of any associated factors. We reasoned that a systematic literature review and meta-analysis of scientific articles published between 1989 and 2014 would allow us to determine whether these reports were universal, to quantify any change over time, and to investigate whether production systems or study factors were associated with culling and mortality. From 3,275 articles retrieved from databases and manual searching of cited articles, 118 articles were appraised independently by 2 assessors, and 51 articles representing 54 studies were determined to be eligible for review and meta-analysis. We estimated that both the annual incidence risk (IR) and incidence density of mortality of cows had increased significantly from 0.02 per cow and 2.32 per 100 cow-years, to 0.04 per cow and 3.75 per 100 cow-years, an increase per decade of 0.02 per cow and 1.42 per 100 cow-years, respectively. We also estimated that the annual IR of culling attributed to low production had declined significantly from 0.07 to 0.05 and that the IR of perinatal, but not neonatal, mortality had increased significantly from 0.04 to 0.06 per decade. We found no evidence of change in overall annual IR of culling of cows over time or any association between study design factors and the IR or incidence density of culling or mortality. These findings provide benchmarks for describing culling and mortality, and should encourage farmers and researchers in countries with modern dairy industries to discover and implement management strategies to reduce the animal welfare and economic costs associated with these changes.

Efficacy of controlled-release capsules containing monensin for the prevention of subclinical ketosis in pasture-fed dairy cows.

AIMS: To determine the effectiveness of intra-rumenal controlled release capsules (CRC) containing 32 g of monensin administered pre-calving to reduce the cumulative incidence of subclinical ketosis (SCK) in mainly pasture-fed dairy cows. METHODS: Cows (n=837) due to calve in the first 6 weeks of the spring calving period were enrolled from four commercial herds in the Waikato region of New Zealand in a blinded, randomised, negative-controlled field trial. Three weeks before the start of the calving period cows were randomly allocated to receive either no treatment (control) or a single CRC containing monensin and then blood sampled on two occasions, 7 days apart within 12 days following calving for measurement of concentrations of beta hydroxybutyrate (BHBA) in blood. Cows were diagnosed with SCK if the concentration of BHBA in blood in either of these samples was ≥1.2 mmol/L. RESULTS: Fewer treated cows were diagnosed with SCK within 12 days post-calving than control cows (144/340 (42.4%) vs. 192/336 (57.1%); p<0.001). There was no interaction between treatment group and age, breed or herd of origin. From the final multivariable model it was estimated that treatment with CRC containing monensin reduced the absolute cumulative incidence of SCK by 17.9 (95% CI=9.2-25.8)% compared to no treatment. CONCLUSIONS: Treatment with a CRC containing monensin>10 days prior to calving reduced the cumulative incidence of SCK of pasture-based dairy cows in commercial dairy herds within 12 days post-calving. CLINICAL RELEVANCE: Administration pre-calving of an intra-rumenal bolus containing monensin can be considered as one of a range of management options for the control of SCK in early lactation.

Subclinical ketosis in post-partum dairy cows fed a predominantly pasture-based diet: defining cut-points for diagnosis using concentrations of beta-hydroxybutyrate in blood and determining prevalence.

AIMS: Firstly, to define, in dairy cows in the first 5 weeks post-calving fed a predominantly pasture-based diet, cut-points of concentrations of beta-hydroxybutyrate (BHBA) in blood, above which there were associations with purulent vaginal discharge (PVD), reduced pregnancy rates (PR) and decreased milk production, in order to better define subclinical ketosis (SCK) in such cattle; and secondly, to determine the prevalence, incidence and risk factors for SCK. METHODS: An observational field study was conducted in 565 cows from 15 spring-calving and predominantly pasture-fed dairy herds in two regions of New Zealand during the 2010- 2011 dairy season. Within each herd, a cohort of randomly selected cows (approximately 40 per herd) was blood sampled to determine concentrations of BHBA on six occasions at weekly intervals starting within 5 days of calving. The key outcome variables were the presence/absence of PVD at 5 weeks post-calving, PR after 6 weeks (6-week PR) and after the completion of the breeding season (final PR), and mean daily milk solids production. RESULTS: Two cut-points for defining SCK were identified: firstly concentration of BHBA in blood≥1.2 mmol/L within 5 days post-calving, which was associated with an increased diagnosis of PVD (24 vs. 8%); and secondly concentration of BHBA in blood≥1.2 mmol/L at any stage within 5 weeks post-calving, which was associated with decreased 6-week PR (78 vs. 85%). The mean herd-level incidence of SCK within 5 weeks post-calving was 68 (min 12; max 100)% and large variations existed between herds in peak prevalence of SCK and the interval post-calving at which such peaks occurred. Cows>8 years of age and cows losing body condition were at increased risk of SCK within 5 weeks of calving. CONCLUSIONS: Cows with concentration of BHBA in blood≥1.2 mmol/L in early lactation had a higher risk of PVD and lower 6-week PR. Cow and herd-level prevalence of SCK varied widely in early lactation. CLINICAL RELEVANCE: Subclinical ketosis is common and is significantly associated with reproductive performance in mainly pasture-fed New Zealand dairy cattle. Controlling SCK may therefore result in improvements in herd reproductive performance. However considerable variation exists among herds in the incidence of SCK and in the timing of peak prevalence which means that herd-specific monitoring programmes are required to define herd SCK status accurately.

Randomised controlled trials demonstrate efficacy of a novel internal teat sealant to prevent new intramammary infections in dairy cows and heifers.

AIMS: The main aim was to investigate the effectiveness of a novel internal teat sealant (ITS) formulation containing bismuth subnitrate and the antiseptic chlorhexidine, in adult cows (Trial A) and nulliparous heifers (Trial B), to reduce the incidence of new intramammary infection (IMI) between treatment and calving and reduce the prevalence of IMI within 6 days following calving. METHODS: In Trial A dairy cows (n=326) without history of clinical mastitis and with a maximum composite milk somatic cell count <200,000 cells/mL during the current lactation were enrolled from three spring-calving mainly pasture-based herds immediately following the final milking. In Trial B all heifers (n=166) were enrolled from two herds approximately 3 weeks before the start of calving. Glands were randomly assigned to controls or treatment with ITS, and mammary secretion samples were taken from all glands prior to treatment, and on two occasions 0-4 and 3-6 days post-calving to determine the incidence of new IMI and the prevalence of IMI immediately post-calving. Additionally, cows in Trial A were monitored for cases of clinical mastitis (CM) in the non-lactating period and animals in both trials were monitored for cases of CM within 30 days of calving. RESULTS: The ITS reduced the estimated incidence of new IMI with both major and any pathogens compared to control glands in cows (6.2 vs. 14.2% and 14.7 vs. 32.8%, respectively) and in heifers (3.0 vs. 13.1% and 13.4 vs. 25.3%, respectively) (p<0.001). The ITS reduced the estimated prevalence of a major or any pathogen compared to untreated controls at both 0-4 and 3-6 days post-calving, in both cows and heifers. Additionally, the ITS reduced the incidence of CM in the non-lactating period in cows (-1.0%, p=0.01) and in the 30 days following calving in heifers (-2.0%, p=0.06), and tended to reduce the estimated incidence of CM in cows post-calving (-1.7%, p=0.10). CONCLUSIONS: The novel ITS reduced the incidence of new IMI, and the prevalence of IMI at calving in both adult cows and heifers, and reduced the incidence of CM in the non-lactating period of cows and in the first 30 days after calving in heifers. CLINICAL RELEVANCE: The results of these trials demonstrate the efficacy of a novel ITS for the control of mastitis in likely uninfected dairy cows over the non-lactating period and in heifers in late pregnancy.

Prevalence of subclinical ketosis in mainly pasture-grazed dairy cows in New Zealand in early lactation.

AIMS: The main aim of this study was to describe the prevalence of primary subclinical ketosis (SCK) in mainly pasture-grazed dairy cows in three dairy-farming regions of New Zealand 7-12, and 35-40 days post-calving. A second aim was to investigate herd- and cow-level factors associated with the prevalence of SCK. METHODS: A cross-sectional longitudinal prevalence survey was undertaken in 1,620 dairy cows from 57 herds. A random sample of cows without disease in the prior 30 days were enrolled at one farm visit within 5 days of calving, and blood samples were collected 7 and 28 days later (7-12 and 35-40 days post-calving) for measurement of beta-hydroxy butyrate (BHBA) concentrations using an electronic cow-side meter. SCK was defined as blood BHBA concentration ≥1.4 mmol/L. RESULTS: Mean cow-level prevalence of SCK varied with interval post-calving (16.8 and 3.2% at 7-12 days and 35-40 days post-calving, respectively) and age (13.0 and 13.1% of 2-year olds and ≥8-year olds, respectively, compared to 7.2% of 3-4-year-old cows). Mean herd-level prevalence of SCK was 14.3 (min 0, max 60.0)% and 2.6 (min 0, max 24.4)% at 7-12 days and 35-40 days post-calving, respectively, and was greater in Southland (13.3%) than Waikato and Canterbury herds (6.9 and 4.7%, respectively). CONCLUSIONS: This is the first population-based report of the prevalence of SCK in New Zealand dairy herds and demonstrates that age and interval post-calving are important risk factors determining prevalence; and that there is wide variation in prevalence between herds. CLINICAL RELEVANCE: Subclinical ketosis may be unrecognised but common in many New Zealand dairy cows in the first 2 weeks of lactation.

The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting ß2-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD.

Evaluation of three synchrony programs for pasture-based dairy heifers.

The objective was to evaluate the efficacy and economic benefits of three synchrony programs in 1137 heifers from 10 pasture-based dairy herds. Heifers were randomly assigned to one of three treatments within each herd on Day -13 (Day 0 = start of the breeding program). They were treated with: (1) PGF(2α) on Days -13 and -2, with AI after detection of estrus between Days 0 and 3 (Double PG); (2) GnRH, PGF(2α), and GnRH on Days -9, -2, and 0, respectively, with placement of an intravaginal progesterone (P4)-releasing device between Days -9 and -2, and set time AI on Day 1 (GPG + P4); or (3) same as the GPG + P4 group but with the set time AI on Day 0 (Cosynch + P4). Plasma P4 concentrations were determined on Days -20 and -13 to determine pubertal status. The Cosynch + P4 treatment had a higher (P < 0.05) conception rate to AI (57% vs. 47% vs. 48% for Cosynch + P4, GPG + P4, and Double PG, respectively), 21-day in-calf rate (76% vs. 72% vs. 63% for Cosynch + P4, GPG + P4, and Double PG), and a shorter median interval from the start of the breeding program to conception (0, 14, and 19 days for Cosynch + P4, GPG + P4, and Double PG). Heifers that had reached puberty before breeding, compared with those that had not, had higher (P < 0.05) in-calf rates to AI (53% vs. 47%) at 21 days (74% vs. 64%) and at 42 days (91% vs. 84%). Pubertal status was associated with herd, breed, age, and body condition score at the start of mating (P < 0.05). A partial budget model demonstrated that, compared with the Double PG program, there was an economic benefit from the Cosynch + P4 (mean, NZ$25.73; 95% confidence interval, 2.99-50.69), but not the GPG + P4 program (mean, NZ$-0.65; 95% confidence interval, -21.87 to 21.58). We concluded that the Cosynch + P4 program resulted in the highest fertility and economic benefit of the three programs evaluated, and that reproductive response was affected by pubertal status.

Determination of foetal sex in pregnancies at risk of haemophilia: a qualitative study exploring the clinical practices and attitudes of health professionals in the United Kingdom.

In pregnancies at risk of haemophilia, foetal sex determination is used to plan perinatal management and to guide the offer of invasive testing in pregnancies with a male foetus. Traditionally ultrasound from 12 weeks gestation has been used, but recently options for early foetal sex determination have increased following the introduction of non-invasive prenatal diagnosis (NIPD) using cell free foetal DNA in maternal plasma. This study was conducted to identify clinical practices and examine health professional attitudes regarding NIPD for foetal sex determination. A qualitative approach using one-to-one semi structured interviews was used to enable an in-depth exploration of current practice, introduction and use of NIPD and benefits and disadvantages of offering NIPD. Interviews were conducted with consultant haematologists (N = 7), specialist haemophilia nurses (N = 7), genetic counsellors (N = 6), consultants in clinical genetics (N = 5), specialist midwives (N = 2) and obstetricians (N = 5) from 24 services across the United Kingdom (UK). Key differences in how NIPD for foetal sexing is utilized throughout the UK were identified. Some services routinely offered NIPD to all carriers of haemophilia or to all carriers of severe haemophilia, others discussed the value of NIPD with all or primarily offered NIPD as a first step to invasive testing. This study informs our understanding of how NIPD is being utilized and provides unique insights into current practice. The identification of variation between services in how prenatal testing options are offered has implications for future policy and guidelines for prenatal care.

Relationships between endometritis and metabolic state during the transition period in pasture-grazed dairy cows.

The primary objective of this study was to identify relationships between endometritis and metabolic state during the calving transition and early lactation periods. A subset of mixed age and breed dairy cows (n=78) from a seasonal, pasture-grazed herd of 389 cows was examined. The selected cows were grouped as having endometritis at d 42 postpartum or being unaffected by endometritis. Endometritis was defined as >6% (upper quartile) of uterine nucleated cells being polymorphonuclear cells (H-PMN; n=38); unaffected by endometritis was defined as ≤1% of nucleated cells being polymorphonuclear (L-PMN; n=40). Milk yield was determined at each milking, and milk composition (fat and protein) was determined at 2-wk intervals. Blood samples collected on d -14, 0 (d of calving), 4, 7, 14, 28, and 42 were analyzed for indicators of energy status (nonesterified fatty acids, glucose, and urea), liver function (albumin, globulin, glutamate dehydrogenase, and aspartate aminotransferase), inflammation (haptoglobin), and mineral status (Ca and Mg). Samples collected weekly from d 21 to 63 or 70 were analyzed for progesterone content. The postpartum anovulatory interval was defined to end on the first day postpartum that plasma progesterone concentration was ≥1 ng/mL. A greater percentage of H-PMN cows failed to ovulate before d 63 or 70 (34%) compared with L-PMN cows (10%), although the proportions of cows ovulating within either polymorphonuclear group was similar through d 56 postpartum. Plasma concentrations of albumin and the albumin:globulin ratio were consistently lower in H-PMN cows. Plasma Mg was lower, whereas glutamate dehydrogenase and aspartate aminotransferase were higher, in H-PMN cows during early lactation compared with L-PMN cows. Circulating metabolites indicative of energy status (nonesterified fatty acids, glucose, and urea) were not different between polymorphonuclear groups. Among 3- to 5-yr-old cows, daily milk yield for the first 42 d after calving was lower for H-PMN cows than for L-PMN cows. Among cows >5 yr old, protein percentage was lower in H-PMN cows compared with L-PMN cows. In summary, endometritis at 42 d postpartum in the herd studied was associated with an increased likelihood of remaining anovulatory. These cows had lower albumin concentrations throughout the calving transition period, perhaps indicating impaired liver function, with lower plasma Mg and evidence of hepatocellular damage in early lactation. Similar profiles of nonesterified fatty acids and glucose indicated that energy status was not a risk factor for endometritis.

A longitudinal study of reproductive performance and management of 82 dairy herds in the Waikato region with differing policies on the routine use of induction of parturition.

AIMS: To describe the reproductive performance and management practices over three lactations in dairy herds that had different policies on the routine use of induction of parturition; to describe any change in outcomes in herds that ceased inductions during the study period; and to investigate other herd-level factors associated with reproductive performance. METHODS: From 2002 to 2004 inclusive, a longitudinal study was undertaken in 82 herds in the Waikato region of New Zealand. The main outcome variables were the percentage of cows pregnant after 8 weeks of mating (8-week in-calf rate) and the percentage of cows not pregnant at the end of mating (final empty rate). Data were obtained from pregnancy diagnosis records from a veterinary practice and from an electronic database, and a questionnaire. Herds were classified as either not using inductions in the three lactations (Nil; n=14), ceased inductions in the second or third lactation (Transitional; n=12), or continuing to induce (Continuing; n=56). RESULTS: Nil herds had a higher 8-week in-calf rate (p=0.01) than Transitional or Continuing herds (83%, 78% and 79%, respectively). The final empty rate in Nil and Transitional herds was similar (10.2% and 9.9%), tended to be greater in Nil than in Continuing herds (10.2% vs 9.0%; p=0.06) and was greater in Transitional than in Continuing herds (9.9% vs 9.0%; p=0.04), respectively. Multivariable modelling found that 8-week in-calf rates were additionally associated with year of lactation, interval from the planned start of calving (PSC) to the median calving date, duration of artificial insemination, and 21-day submission rate; and that final empty rates were associated with year of lactation, predominant breed, percentage of the herd calving within 40 days of the planned start of mating (PSM), the total duration of mating, and the 21-day submission rate, but not the herd induction policy. A change to ceasing routine use of induction tended to be associated (p=0.07) with a 2.5% increase in the final empty rate in the lactation of change. CONCLUSIONS: The reproductive performance of herds was associated with induction policy, in addition to other factors. Herds that ceased induction had a greater 8-week in-calf rate but a greater final empty rate than those that continued. The higher empty rate in Nil herds was partly due to their shorter duration of mating. CLINICAL RELEVANCE: Herdowners and their advisors planning to cease routine use of induction should plan for an increase in the final empty rate in both the lactation of change and in the longer term, and undertake measures to mitigate against this effect.

A review of prevention and control of heifer mastitis via non-antibiotic strategies.

Clinical and subclinical mastitis is a significant problem in primiparous dairy cattle (heifers) with a higher prevalence and incidence in heifers than cows, especially early in lactation. Differences in management (e.g. nutrition, pasturing, no use of dry cow therapy) as well as differences in physiological status (e.g. continuing growth in heifers) are likely contribute to the observed differences between heifers and cows. These differences may result in the requirement for different approaches for mastitis management in heifers than for cows. Mastitis is a multifactorial disease, hence control requires an understanding of the risk factors before effective interventions can be defined. Control strategies are aimed at reducing the incidence of new intramammary infections and eliminating existing infections. Potential strategies can include improved environmental and animal hygiene, application of internal and external teat sealants, prepartum application of teat antiseptics, prepartum milking and control of horn fly in environments where it acts as vector. Other less well-proven strategies to control heifer mastitis include management of heifers as a physically separate group from older cows and not feeding mastitic milk to calves. It is concluded that several well-proven strategies are available to manage heifer mastitis. However, further research is likely to improve understanding of heifer mastitis and lead to novel managerial approaches to mastitis control in this age group.

Effect of application of an external teat sealant and/or oral treatment with a monensin capsule pre-calving on the prevalence and incidence of subclinical and clinical mastitis in dairy heifers.

AIM: To assess the effect of applying an external teat sealant or a slow-release intraruminal monensin capsule pre-calving on the prevalence and incidence of subclinical or clinical mastitis in dairy heifers post-calving. METHODS: The studies were undertaken in 13 herds. In two herds application of an external teat sealant was compared with a negative control; in nine herds treatment with monensin was compared with controls, and in two herds treatments were applied in a 2 x 2 factorial design. Heifers were randomly assigned within herd to be treated with a slow-release intraruminal device containing 32 g monensin (n=383), or left as untreated controls (n=389), approximately 30 days before the start of the spring calving period; or to be treated with a latex external teat sealant (n=206) when calving was impending, or be left as untreated controls (n=205). Milk samples were collected from each gland between 0 and 5 days after calving and from any gland diagnosed with clinical mastitis. The effect of the treatments on the prevalence of intramammary infection (IMI), i.e. subclinical mastitis, and clinical mastitis were initially analysed at the univariate level, with associated variables (p<0.2) being used in construction of multivariable models. RESULTS: The prevalence of IMI was 18.4% at the gland level, and coagulase-negative staphylococci followed by Streptococcus uberis were the most common isolates. Treatment with an external teat sealant reduced the prevalence, compared with controls, of any IMI (12.1 (SE 1.7)% vs 16.5 (SE 2.1)%, respectively; p=0.05) or IMI caused by a major pathogen (3.8 (SE 0.8)% vs 6.0 (SE 1.1)%, respectively; p=0.05). Monensin treatment did not affect the prevalence of any IMI (p=0.68) or IMI due to a major pathogen (p=0.11). The cumulative incidence of clinical mastitis was 14.2%. Neither monensin treatment (p=0.47) nor application of an external teat sealant (p=0.71) altered the risk of clinical mastitis. There was no interaction between the monensin and external teat sealant in the two herds where the treatments were applied in a 2 x 2 factorial design. CONCLUSIONS: Application of an external teat sealant resulted in a lower prevalence of any IMI and of an IMI caused by a major pathogen. Despite monensin reducing the mobilisation of body tissue and the risk of subclinical ketosis, it had no effect on the prevalence or incidence of IMI or clinical mastitis. CLINICAL RELEVANCE: Application of an external teat sealant is an option for reducing the prevalence of IMI in pasture fed dairy heifers.

Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy.

The ability to predict complete pathologic response or sensitivity to radiation before treatment would have a significant impact on the selection of patients for preoperative radiotherapy or chemo-radiation therapy schedules. The aim of this study was to determine the value of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), p53, Bcl-2 and apoptosis protease-activating factor-1 (APAF-1) as predictors of complete pathologic tumour regression in patients undergoing preoperative radiotherapy for advanced rectal cancer. Pretreatment tumour biopsies from predominantly cT3 patients undergoing a preoperative high-dose-rate brachytherapy protocol were immunostained for EGFR, VEGF, p53, Bcl-2 and APAF-1. Immunoreactivity was evaluated by three pathologists. Cut-off scores for tumour marker positivity were obtained by receiver-operating characteristic (ROC) curve analysis. The association of marker expression with complete pathologic response was analysed in univariate and multivariable analysis. Multi-marker phenotypes of the independent protein markers were evaluated. In multivariable analysis, loss of VEGF (P-value=0.009; odds ratio (OR) (95% CI)=0.24 (0.08-0.69)) and positive EGFR (P-value=0.01; OR (95% CI)=3.82 (1.37-10.6)) both demonstrated independent predictive value for complete pathologic response. The odds of complete response were 12.8 for the multi-marker combination of VEGF-negative and EGFR-positive tumours. Of the 34 EGFR-negative- and VEGF-positive cases, 32 (94.1%) had no complete pathologic response. The combined analysis of VEGF and EGFR is predictive of complete pathologic response in patients undergoing preoperative radiotherapy. In addition, the findings of this study have identified a subgroup of simultaneous EGFR-negative and VEGF-positive patients who are highly resistant to radiotherapy and should perhaps be considered candidates for innovative neoadjuvant combined modalities.

Quarter-level analysis of subclinical and clinical mastitis in primiparous heifers following the use of a teat sealant or an injectable antibiotic, or both, precalving.

This study investigated the effect of infusion of a bismuth subnitrate teat canal sealant or an injectable antibiotic, or both, in heifers on the cure of existing intramammary infection (IMI), incidence of new IMI, prevalence of postcalving IMI, and incidence of clinical mastitis in the first 2 wk postcalving at the quarter level. Heifers (n = 1,067) in 30 seasonally calving, pasture-fed dairy herds were randomly assigned at the heifer level to 1 of 4 treatments (no treatment; 3 intramuscular injections of 5 g of tylosin antibiotic at 24-h intervals; infusion of a teat sealant into all 4 quarters; 3 intramuscular injections of 5 g of tylosin antibiotic and infusion of teat sealant into all 4 quarters). Mammary gland secretion samples were collected from each quarter of every heifer before treatment. Heifers within a herd were enrolled on one calendar day, 27 d (on average) before the planned start of the seasonal calving period. Duplicate milk samples were collected from each gland within 5 d after calving for bacterial culture and from glands the herdowners diagnosed as having clinical mastitis. The relative risk of effect of treatment on the incidence of cure, incidence of new IMI, prevalence of postcalving IMI, and incidence of clinical mastitis were calculated at the gland level using multivariate logistic regression analyses. Neither infusion of a teat sealant nor treatment with the injectable antibiotic increased the cure of precalving IMI. Infusion of the teat sealant reduced the risk of new IMI with any pathogen by 74%, reduced the prevalence of postcalving IMI by 65%, reduced the risk of new infection with Streptococcus uberis by 70% in quarters with an IMI precalving, and reduced the incidence of clinical mastitis from which a pathogen was isolated by 70% in quarters with an IMI precalving. Parenteral antibiotic treatment had no effect on any of these outcomes. In conclusion, use of an internal teat-canal sealant in heifers reduced the postcalving IMI prevalence and the incidence of pathogen-associated clinical mastitis postcalving by decreasing the incidence of new infections over this high-risk peripartum period, and may be a useful tool for reducing the risk of mastitis in heifers.

Management of dairy heifers and its relationships with the incidence of clinical mastitis.

AIM: To describe aspects of management of dairy heifers before calving and determine risk factors for clinical mastitis postpartum in heifers, at the herd level, under pasture-based management systems in the Waikato and Taranaki regions of New Zealand. METHODS: Dairy herdowners (n=578) provided information via a prospective survey about their practices for rearing heifers and management of mastitis. A proportion of herdowners (n=250) subsequently provided data on the cases of clinical mastitis in their herds, including the date, cow identification, age and quarter affected from cases occurring in the 4 months after the planned start of calving (PSC) in the subsequent lactation. The relationship between management factors and the proportion of heifers diagnosed with clinical mastitis within a herd was examined using bivariate and multivariate analyses. RESULTS: The herd average percentage of heifers with clinical mastitis was 13.6 (95% confidence interval (CI)=12.3-14.9)%, and multiparous cows with clinical mastitis was 9.0 (95% CI=8.2-9.8)% in the first 4 months of lactation. There were positive relationships between the proportion of heifers with clinical mastitis and average milk production per cow (kg milksolids/ lactation; p<0.001), number of cows milked per labour unit (p=0.003), stocking rate (<> 3.30 cows/ha; p=0.002), and incidence of clinical mastitis in multiparous cows (%/120 days; p<0.04), in the final multivariate model. The proportion of heifers with clinical mastitis per herd was lower in herds that milked their lactating cows in multiple groups (p=0.02). CONCLUSIONS: The risk of clinical mastitis in heifers was significantly associated with management practices. It may be possible to reduce the incidence of clinical mastitis in heifers by modification of management practices at the herd level, and further studies are required to investigate this.

Epidemiology of mastitis in pasture-grazed peripartum dairy heifers and its effects on productivity.

An observational field study was conducted on 708 heifers in 30 spring-calving dairy herds in the Waikato region of New Zealand. The aim of the study was to describe patterns and effects of intramammary infection (IMI) and clinical mastitis (CM) in the peripartum period. Mammary secretion samples for bacteriological testing were taken from all quarters approximately 3 wk before the planned start of the calving period and within 5 d following calving, in addition to quarters diagnosed with CM within 14 d of calving. Precalving IMI was diagnosed in 18.5% of quarters, and of these, coagulase-negative staphylococci were the predominant isolate (13.5% of quarters). Streptococcus uberis prevalence increased 4-fold to 10.0% of quarters on the day of calving compared with the precalving period. Prevalence of all pathogens decreased rapidly following calving. Clinical mastitis cases were predominantly associated with Strep. uberis (64%). The daily hazard of diagnosis was higher in heifers than in cows (0.06 vs. 0.02/d on d 1 postcalving, respectively), but was not different by d 5 (0.005 vs. 0.002, respectively) of lactation. Intramammary infection with a major pathogen was associated with an increased risk of removal from the herd (15 vs. 10% for infected and noninfected heifers, respectively) and somatic cell count >200,000 cells/mL at subsequent herd tests (15 vs. 8%), but neither CM nor IMI were associated with reduced milk yield or milk solids production. Results suggest that bacterial species involved and the pattern of IMI prevalence in pasture-grazed peripartum heifers differ from those in other production systems. Further, mastitis control programs need to target major environmental pathogens causing precalving IMI, because new infections are likely before the onset of lactation, whereas existing detection and control measures are generally implemented after calving. Novel control programs that reduce new infections due to Strep. uberis immediately before calving are required to reduce the incidence of CM in pasture-grazed dairy heifers.