The clinical effectiveness and cost-effectiveness of cetuximab (mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal No.150 and part review of technology appraisal No. 118): a systematic review and economic model

Colorectal cancer is the third most commonly diagnosed cancer in the UK after breast and lung cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Recently, targeted agents have become available including anti-epidermal growth factor receptor (EGFR) agents, for example cetuximab and panitumumab, and anti-vascular endothelial growth factor (VEGF) receptor agents, for example bevacizumab

Automated prediction of mastitis infection patterns in dairy herds using machine learning

© 2020, The Author(s). Mastitis in dairy cattle is extremely costly both in economic and welfare terms and is one of the most significant drivers of antimicrobial usage in dairy cattle. A critical step in the prevention of mastitis is the diagnosis of the predominant route of transmission of pathogens into either contagious (CONT) or environmental (ENV), with environmental being further subdivided as transmission during either the nonlactating “dry” period (EDP) or lactating period (EL). Using data from 1000 farms, random forest algorithms were able to replicate the complex herd level diagnoses made by specialist veterinary clinicians with a high degree of accuracy. An accuracy of 98%, positive predictive value (PPV) of 86% and negative predictive value (NPV) of 99% was achieved for the diagnosis of CONT vs ENV (with CONT as a “positive” diagnosis), and an accuracy of 78%, PPV of 76% and NPV of 81% for the diagnosis of EDP vs EL (with EDP as a “positive” diagnosis). An accurate, automated mastitis diagnosis tool has great potential to aid non-specialist veterinary clinicians to make a rapid herd level diagnosis and promptly implement appropriate control measures for an extremely damaging disease in terms of animal health, productivity, welfare and antimicrobial use

The effect of environmental temperature on average daily gain in preweaned calves: A randomized controlled trial and Bayesian analysis

Neonatal calves are relatively susceptible to heat loss, and previous research suggests that reduced environmental temperatures are associated with reduced average daily gain (ADG) during the preweaning phase. Current methods of mitigating negative effects of colder environmental conditions include the use of calf jackets and the provision of supplementary heat sources; however, previous research is limited. The aim of this study was to evaluate the effect of calf jackets and 1-kW heat lamps on the growth rates of preweaning calves and evaluate associations between environmental temperature and ADG using a Bayesian approach to incorporate both current and previous data. Seventy-nine calves from a single British dairy farm were randomly allocated at birth to 1 of the following 4 groups: no jacket and no heat lamp, heat lamp but no jacket, jacket but no heat lamp, or both heat lamp and jacket between January and April of 2021. Calves were weighed at both birth and at approximately 21 d of age. Temperature was recorded both inside and outside of the calf building, and in pens both with and without heat lamps using data loggers. To explore the effect of treatment group and environmental temperature on ADG, a fixed effects model was fitted over 1,000 bootstrap samples. The effect of environmental temperature on ADG was further explored within a Bayesian framework that used temperature and ADG data for 484 calves from 16 farms available from a previous trial as prior information. Calves housed under a 1-kW heat lamp had an increased ADG of 0.09 kg/d (95% bootstrap confidence interval: −0.02 to 0.20 kg/d), and no effect of jacket or interactions between jacket and heat lamp were found. A significant positive association was identified between the mean environmental temperature of the calf building and ADG, with a 1°C increase in temperature being associated with a 0.03 kg/d increase in ADG (95% bootstrap confidence interval: 0.01 to 0.04 kg/d). Associations between environmental temperature and ADG were further evaluated within a Bayesian framework, and posterior estimates were 0.014 kg/d of ADG per 1°C increase (95% credible interval: 0.009 to 0.021 kg/d). This study demonstrated that a 1-kW heat lamp was effective in increasing ADG in calves, and no significant effect of calf jacket on ADG was found. A significant, positive effect of increased pen temperature on calf ADG was identified in this study and was reinforced when including prior information from previous research within a Bayesian framework

Improving growth rates in preweaning calves on dairy farms: A randomized controlled trial

Previous research has identified key factors associated with improved average daily gain (ADG) in preweaning dairy calves and these factors have been combined to create a web app–based calf health plan (www.nottingham.ac.uk/herdhealthtoolkit). A randomized controlled trial was conducted to determine the effect of implementing this evidence-based calf health plan on both productivity and health outcomes for calves reared on British dairy farms. Sixty dairy farms were randomized by location (North, South, and Midlands) to either receive the plan at the beginning (INT) or after the end of the trial (CON) and recorded birth and weaning weights by weigh tape, and cases of morbidity and mortality. Calf records were returned for 3,593 calves from 45 farms (21 CON, 24 INT), with 1,760 calves from 43 farms having 2 weights recorded >40 d apart for ADG calculations, with 1,871 calves from 43 farms born >90 d before the end of the trial for morbidity and mortality calculations. Associations between both intervention group and the number of interventions in place with ADG were analyzed using linear regression models. Morbidity and mortality rates were analyzed using beta regression models. Mean ADG was 0.78 kg/d, ranging from 0.33 to 1.13 kg/d, with mean rates of 20.12% (0–96.55%), 16.40% (0–95.24%), and 4.28% (0–18.75%) for diarrhea, pneumonia, and mortality. The INT farms were undertaking a greater number of interventions (9.9) by the end of the trial than CON farms (7.6). Mean farm ADG was higher for calves on INT farms than CON farms for both male beef (MB, +0.22 kg/d) and dairy heifer (DH, +0.03 kg/d) calves. The MB calves on INT farms had significantly increased mean ADG (0.12 kg/d, 95% confidence interval: 0.02–0.22) compared with CON farms. No significant differences were observed between intervention groups for morbidity or mortality. Implementing one additional intervention from the plan, regardless of intervention group, was associated with improvements in mean ADG for DH calves of 0.01 kg/d (0.01, 0–0.03) and MB calves of 0.02 kg/d (0.00–0.04). Model predictions suggest that a farm with the highest number of interventions in place (15) compared with farms with the lowest number of interventions in place (4) would expect an improvement in growth rates from 0.65 to 0.81 kg/d for MB, from 0.73 to 0.88 kg/d for DH, a decrease in mortality rates from 10.9% to 2.8% in MB, and a decrease in diarrhea rates from 42.1% to 15.1% in DH. The calf health plan tested in this study represents a useful tool to aid veterinarians and farmers in the implementation of effective management interventions likely to improve the growth rates, health, and welfare of preweaning calves on dairy farms

Quantitative Analysis of Colostrum Bacteriology on British Dairy Farms

© Copyright © 2020 Hyde, Green, Hudson and Down. Total bacterial counts (TBC) and coliform counts (CC) were estimated for 328 colostrum samples from 56 British dairy farms. Samples collected directly from cows' teats had lower mean TBC (32,079) and CC (21) than those collected from both colostrum collection buckets (TBC: 327,879, CC: 13,294) and feeding equipment (TBC: 439,438, CC: 17,859). Mixed effects models were built using an automated backwards stepwise process in conjunction with repeated bootstrap sampling to provide robust estimates of both effect size and 95% bootstrap confidence intervals (BCI) as well as an estimate of the reproducibility of a variable effect within a target population (stability). Colostrum collected using parlor (2.06 log cfu/ml, 95% BCI: 0.35–3.71) or robot (3.38 log cfu/ml, 95% BCI: 1.29–5.80) milking systems, and samples collected from feeding equipment (2.36 log cfu/ml, 95% BCI: 0.77–5.45) were associated with higher TBC than those collected from the teat, suggesting interventions to reduce bacterial contamination should focus on the hygiene of collection and feeding equipment. The use of hot water to clean feeding equipment (−2.54 log cfu/ml, 95% BCI: −3.76 to −1.74) was associated with reductions in TBC, and the use of peracetic acid (−2.04 log cfu/ml, 95% BCI: −3.49 to −0.56) or hypochlorite (−1.60 log cfu/ml, 95% BCI: −3.01 to 0.27) to clean collection equipment was associated with reductions in TBC compared with water. Cleaning collection equipment less frequently than every use (1.75 log cfu/ml, 95% BCI: 1.30–2.49) was associated with increased TBC, the use of pre-milking teat disinfection prior to colostrum collection (−1.85 log cfu/ml, 95% BCI: −3.39 to 2.23) and the pasteurization of colostrum (−3.79 log cfu/ml, 95% BCI: −5.87 to −2.93) were associated with reduced TBC. Colostrum collection protocols should include the cleaning of colostrum collection and feeding equipment after every use with hot water as opposed to cold water, and hypochlorite or peracetic acid as opposed to water or parlor wash. Cows' teats should be prepared with a pre-milking teat disinfectant and wiped with a clean, dry paper towel prior to colostrum collection, and colostrum should be pasteurized where possible

Factors associated with daily weight gain in preweaned calves on dairy farms

The preweaning period is vital in the development of calves on dairy farms and improving daily liveweight gain (DLWG) is important to both financial and carbon efficiency; minimising rearing costs and improving first lactation milk yields. In order to improve DLWG, veterinary advisors should provide advice that has both a large effect size as well as being consistently important on the majority of farms. Whilst a variety of factors have previously been identified as influencing the DLWG of preweaned calves, it can be challenging to determine their relative importance, which is essential for optimal on-farm management decisions. Regularised regression methods such as ridge or lasso regression provide a solution by penalising variable coefficients unless there is a proportional improvement in model performance. Elastic net regression incorporates both lasso and ridge penalties and was used in this research to provide a sparse model to accommodate strongly correlated predictors and provide robust coefficient estimates. Sixty randomly selected British dairy farms were enrolled to collect weigh tape data from preweaned calves at birth and weaning, resulting in data being available for 1014 calves from 30 farms after filtering to remove poor quality data, with a mean DLWG of 0.79 kg/d (range 0.49–1.06 kg/d, SD 0.13). Farm management practices (e.g. colostrum, feeding, hygiene protocols), building dimensions, temperature/humidity and colostrum quality/bacteriology data were collected, resulting in 293 potential variables affecting farm level DLWG. Bootstrapped elastic net regression models identified 17 variables as having both a large effect size and high stability. Increasing the maximum preweaned age within the first housing group (0.001 kg/d per 1d increase, 90 % bootstrap confidence interval (BCI): 0.000−0.002), increased mean environmental temperature within the first month of life (0.012 kg/d per 1 °C increase, 90 % BCI: 0.002−0.037) and increased mean volume of milk feeding (0.012 kg/d per 1 L increase, 90 % BCI: 0.001−0.024) were associated with increased DLWG. An increase in the number of days between the cleaning out of calving pen (-0.001 kg/d per 1d increase, 90 % BCI: -0.001−0.000) and group housing pens (-0.001 kg/d per 1d increase, 90 % BCI: -0.002−0.000) were both associated with decreased DLWG. Through bootstrapped elastic net regression, a small number of stable variables have been identified as most likely to have the largest effect size on DLWG in preweaned calves. Many of these variables represent practical aspects of management with a focus around stocking demographics, milk/colostrum feeding, environmental hygiene and environmental temperature; these variables should now be tested in a randomised controlled trial to elucidate causality

The luminosities, sizes and velocity dispersions of Brightest Cluster Galaxies: Implications for formation history

The size-luminosity relation of early-type Brightest Cluster Galaxies (BCGs), R_e ~ L^0.88, is steeper than that for the bulk of the early-type galaxy population, for which R_e ~ L^0.68. In addition, although BCGs are hardly offset from the Fundamental Plane defined by the bulk of the early-type population, they show considerably smaller scatter. The larger than expected sizes of BCGs, and the increased homogeneity, are qualitatively consistent with models which seek to explain the colors of the most massive galaxies by invoking dry dissipationless mergers, since dissipation tends to reduce the sizes of galaxies, and wet mergers which result in star formation would tend to increase the scatter in luminosity at fixed size and velocity dispersion. Furthermore, BCGs define the same g-r color-magnitude relation as the bulk of the early-type population. If BCGs formed from dry mergers, then BCG progenitors must have been red for their magnitudes, suggesting that they hosted older stellar populations than typical for their luminosities. Our findings have two other consequences. First, the R_e-L relation of the early-type galaxy population as a whole (i.e., normal plus BCG) exhibits some curvature. Some of this curvature must be a consequence of the fact that an increasing fraction of the most luminous galaxies are BCGs. The second consequence is suggested by the fact that, despite following a steeper size-luminosity relation, BCGs tend to define a tight relation between dynamical mass R_e sigma^2/G and luminosity. As consequence, we find that BCGs define a shallower sigma-L relation than the bulk of the early-type galaxy population.Comment: 16 pages, 16 figures, AJ in pres

Test-treatment RCTs are susceptible to bias:a review of the methodological quality of randomized trials that evaluate diagnostic tests

Abstract Background There is a growing recognition for the need to expand our evidence base for the clinical effectiveness of diagnostic tests. Many international bodies are calling for diagnostic randomized controlled trials to provide the most rigorous evidence of impact to patient health. Although these so-called test-treatment RCTs are very challenging to undertake due to their methodological complexity, they have not been subjected to a systematic appraisal of their methodological quality. The extent to which these trials may be producing biased results therefore remains unknown. We set out to address this issue by conducting a methodological review of published test-treatment trials to determine how often they implement adequate methods to limit bias and safeguard the validity of results. Methods We ascertained all test-treatment RCTs published 2004–2007, indexed in CENTRAL, including RCTs which randomized patients to diagnostic tests and measured patient outcomes after treatment. Tests used for screening, monitoring or prognosis were excluded. We assessed adequacy of sequence generation, allocation concealment and intention-to-treat, appropriateness of primary analyses, blinding and reporting of power calculations, and extracted study characteristics including the primary outcome. Results One hundred three trials compared 105 control with 119 experimental interventions, and reported 150 primary outcomes. Randomization and allocation concealment were adequate in 57 and 37% of trials. Blinding was uncommon (patients 5%, clinicians 4%, outcome assessors 21%), as was an adequate intention-to-treat analysis (29%). Overall 101 of 103 trials (98%) were at risk of bias, as judged using standard Cochrane criteria. Conclusion Test-treatment trials are particularly susceptible to attrition and inadequate primary analyses, lack of blinding and under-powering. These weaknesses pose much greater methodological and practical challenges to conducting reliable RCT evaluations of test-treatment strategies than standard treatment interventions. We suggest a cautious approach that first examines whether a test-treatment intervention can accommodate the methodological safeguards necessary to minimize bias, and highlight that test-treatment RCTs require different methods to ensure reliability than standard treatment trials. Please see the companion paper to this article: http://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-016-0286-0

Evidence-based selection of theories for designing behaviour change interventions : using methods based on theoretical construct domains to understand clinicians' blood transfusion behaviour

Peer reviewedPostprin