Expert UK consensus on the definition of high risk of recurrence in HER2-negative early breast cancer: A modified Delphi panel.

BACKGROUND: There is currently no standardised definition for patients at high risk of recurrence of human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC; stages 1-3) after surgery. This modified Delphi panel aimed to establish expert UK consensus on this definition, separately considering hormone receptor (HR)-positive and triple-negative (TN) patients. METHODS: Over three consecutive rounds, results were collected from 29, 24 and 22 UK senior breast cancer oncologists and surgeons, respectively. The first round aimed to determine key risk factors in each patient subgroup; subsequent rounds aimed to establish appropriate risk thresholds. Consensus was pre-defined as ≥70% of respondents. RESULTS: Expert consensus was achieved on need to assess age, tumour size, tumour grade, number of positive lymph nodes, inflammatory breast cancer and risk prediction tools in all HER2-negative patients. There was additional agreement on use of tumour profiling tests and biomarkers in HR-positive patients, and pathologic complete response (pCR) status in TN patients. Thresholds for high recurrence risk were subsequently agreed. In HR-positive patients, these included age <35 years, tumour size >5 cm (as independent risk factors); tumour grade 3 (independently and combined with other high-risk factors); number of positive nodes ≥4 (independently) and ≥1 (combined). For TN patients, the following thresholds reached consensus, both independently and in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive nodes ≥1. CONCLUSIONS: The results may be a valuable reference point to guide recurrence risk assessment and decision-making after surgery in the HER2-negative eBC population.

Light microscopic observations of the ruminal papillae of cattle on diets with divergent forage to cereal ratios.

High levels of supplementation with cereal increases production rates in cattle but can increase incidence of disease, ranging from mild indigestion to acute ruminal acidosis and death. Therefore, there is motivation to determine biological markers which can be used to identify whether animals have been, or are being fed, sufficient or excessive cereals. This study aimed to describe light microscopic findings from animals being fed diverse dietary cereal proportions and to test the performance of a novel rumen epithelial scoring system. Rumen wall tissue samples were obtained from the abattoir from 195 cattle from 11 Scottish farms and processed for histological examination. Light microscopic examination was used to characterise ruminal epithelial response to dietary challenge. Secondary objectives included describing the distribution of immune-related cells in bovine ruminal epithelium and assessing the use of a modified Elastin Martius Scarlet Blue stain (EMSB) for histological examination of the rumen epithelium. Cells staining positive for cluster of differentiation 3 were distributed mainly in the lower layers of the stratum basale and were found in higher densities in animals offered lower cereal proportion diets. Cells staining positive for major histocompatibility complex class 2 (MHCII) were most common in perivascular locations and in the junction between the lower stratum basale and the propria-submucosa. The density of MHCII positive staining cells was higher in animals on lower cereal diets. The level of supplementation with cereal was also associated with the thickness of the stratum corneum (SCT) and stratum granulosum (SGT), the integrity of the stratum corneum and sloughing of cornified cells. There were no advantages in using EMSB stain over haematoxylin and eosin (H&E) in this scoring system. We concluded that a scoring system that included only SCT, SGT and a measure of the loss of appearance of intercellular space allowed differentiation of groups of animals according to the level of cereal supplementation.

Predicting feed intake using modelling based on feeding behaviour in finishing beef steers.

Current techniques for measuring feed intake in housed cattle are both expensive and time-consuming making them unsuitable for use on commercial farms. Estimates of individual animal intake are required for assessing production efficiency. The aim of this study was to predict individual animal intake using parameters that can be easily obtained on commercial farms including feeding behaviour, liveweight and age. In total, 80 steers were used, and each steer was allocated to one of two diets (40 per diet) which consisted of (g/kg; DM) forage to concentrate ratios of either 494:506 (MIXED) or 80:920 (CONC). Individual daily fresh weight intakes (FWI; kg/day) were recorded for each animal using 32 electronic feeders over a 56-day period, and individual DM intakes (DMI; kg/day) subsequently calculated. Individual feeding behaviour variables were calculated for each day of the measurement period from the electronic feeders and included: total number of visits to the feeder, total time spent at the feeder (TOTFEEDTIME), total time where feed was consumed (TIMEWITHFEED) and average length of time during each visit to the feeder. These feeding behaviour variables were chosen due to ease of obtaining from accelerometers. Four modelling techniques to predict individual animal intake were examined, based on (i) individual animal TOTFEEDTIME relative expressed as a proportion of the dietary group (GRP) and total GRP intake, (ii) multiple linear regression (REG) (iii) random forests (RF) and (iv) support vector regressor (SVR). Each model was used to predict CONC and MIXED diets separately, giving eight prediction models, (i) GRP_CONC, (ii) GRP_MIXED, (iii) REG_CONC, (iv) REG_MIXED, (v) RF_CONC, (vi) RF_MIXED, (vii) SVR_CONC and (viii) SVR_MIXED. Each model was tested on FWI and DMI. Model performance was assessed using repeated measures correlations (R2_RM) to capture the repeated nature of daily intakes compared with standard R2, RMSE and mean absolute error (MAE). REG, RF and SVR models predicted FWI with R2_RM = 0.1-0.36, RMSE = 1.51-2.96 kg and MAE = 1.19-2.49 kg, and DMI with R2_RM = 0.13-0.19, RMSE = 1.15-1.61 kg and MAE = 0.9-1.28 kg. The GRP models predicted FWI with R2_RM = 0.42-0.49, RMSE = 2.76-3.88 kg and MAE = 2.46-3.47 kg, and DMI with R2_RM = 0.32-0.44, RMSE = 0.32-0.44 kg, MAE = 1.55-2.22 kg. Whilst more simplistic GRP models showed higher R2_RM than regression and machine learning techniques, these models had larger errors, likely due to individual feeding patterns not being captured. Although regression and machine learning techniques produced lower errors associated with individual intakes, overall precision of prediction was too low for practical use.

The frequency and severity of capecitabine-induced hypertriglyceridaemia in routine clinical practice: a prospective study.

BACKGROUND: Capecitabine is known to rarely cause raised serum triglycerides (TG). In our centre, several patients receiving capecitabine developed raised TG levels corresponding to the 'very high risk' category for potentially serious acute pancreatitis. METHODS: A fasting blood lipid screening protocol was introduced into clinical practice for patients receiving capecitabine. Patients with TGs >5 mmol l(-1) were treated and followed up. An 18-month prospective audit was performed to establish the incidence and severity of capecitabine-induced hypertriglyceridaemia (CIHT). RESULTS: A total of 304 patients received capecitabine for colorectal cancer between January 2008 and June 2009. Of these, 212 patients (70%) were screened and 8 (3.7%) developed clinically significant hypertriglyceridaemia requiring lipid-lowering therapy. Two of the eight patients had diabetes and one had pre-existing dyslipidaemia. One suffered cerebral infarction during chemotherapy. There were no cases of acute pancreatitis. Follow-up showed that serum TGs safely and rapidly returned to normal with appropriate treatment without discontinuation of capecitabine. CONCLUSIONS: This is the first prospective study evaluating CIHT. These results suggest that it should be classed as a 'common' undesired effect of capecitabine. Despite this, the incidence does not justify routine screening in all patients. Targeted screening in those with diabetes or pre-existing hyperlipidaemia is recommended, together with adoption of a clear management policy.

Using animal-mounted sensor technology and machine learning to predict time-to-calving in beef and dairy cows.

Worldwide, there is a trend towards increased herd sizes, and the animal-to-stockman ratio is increasing within the beef and dairy sectors; thus, the time available to monitoring individual animals is reducing. The behaviour of cows is known to change in the hours prior to parturition, for example, less time ruminating and eating and increased activity level and tail-raise events. These behaviours can be monitored non-invasively using animal-mounted sensors. Thus, behavioural traits are ideal variables for the prediction of calving. This study explored the potential of two sensor technologies for their capabilities in predicting when calf expulsion should be expected. Two trials were conducted at separate locations: (i) beef cows (n = 144) and (ii) dairy cows (n = 110). Two sensors were deployed on each cow: (1) Afimilk Silent Herdsman (SHM) collars monitoring time spent ruminating (RUM), eating (EAT) and the relative activity level (ACT) of the cow, and (2) tail-mounted Axivity accelerometers to detect tail-raise events (TAIL). The exact time the calf was expelled from the cow was determined by viewing closed-circuit television camera footage. Machine learning random forest algorithms were developed to predict when calf expulsion should be expected using single-sensor variables and by integrating multiple-sensor data-streams. The performance of the models was tested using the Matthew's correlation coefficient (MCC), the area under the curve, and the sensitivity and specificity of predictions. The TAIL model was slightly better at predicting calving within a 5-h window for beef cows (MCC = 0.31) than for dairy cows (MCC = 0.29). The TAIL + RUM + EAT models were equally as good at predicting calving within a 5-h window for beef and dairy cows (MCC = 0.32 for both models). Combining data-streams from SHM and tail sensors did not substantially improve model performance over tail sensors alone; therefore, hour-by-hour algorithms for the prediction of time of calf expulsion were developed using tail sensor data. Optimal classification occurred at 2 h prior to calving for both beef (MCC = 0.29) and dairy cows (MCC = 0.25). This study showed that tail sensors alone are adequate for the prediction of parturition and that the optimal time for prediction is 2 h before expulsion of the calf.

Postmortem observations on rumen wall histology and gene expression and ruminal and caecal content of beef cattle fattened on barley-based rations.

Sub-acute ruminal acidosis (SARA) can reduce the production efficiency and impair the welfare of cattle, potentially in all production systems. The aim of this study was to characterise measurable postmortem observations from divergently managed intensive beef finishing farms with high rates of concentrate feeding. At the time of slaughter, we obtained samples from 19 to 20 animals on each of 6 beef finishing units (119 animals in total) with diverse feeding practices, which had been subjectively classified as being high risk (three farms) or low risk (three farms) for SARA on the basis of the proportions of barley, silage and straw in the ration. We measured the concentrations of histamine, lipopolysaccharide (LPS), lactate and other short-chain fatty acids (SCFAs) in ruminal fluid, LPS and SCFA in caecal fluid. We also took samples of the ventral blind sac of the rumen for histopathology, immunohistopathology and gene expression. Subjective assessments were made of the presence of lesions on the ruminal wall, the colour of the lining of the ruminal wall and the shape of the ruminal papillae. Almost all variables differed significantly and substantially among farms. Very few pathological changes were detected in any of the rumens examined. The animals on the high-risk diets had lower concentrations of SCFA and higher concentrations of lactate and LPS in the ruminal fluid. Higher LPS concentrations were found in the caecum than the rumen but were not related to the risk status of the farm. The diameters of the stratum granulosum, stratum corneum and of the vasculature of the papillae, and the expression of the gene TLR4 in the ruminal epithelium were all increased on the high-risk farms. The expression of IFN-γ and IL-1ß and the counts of cluster of differentiation 3 positive and major histocompatibility complex class two positive cells were lower on the high-risk farms. High among-farm variation and the unbalanced design inherent in this type of study in the field prevented confident assignment of variation in the dependent variables to individual dietary components; however, the CP percentage of the total mixed ration DM was the factor that was most consistently associated with the variables of interest. Despite the strong effect of farm on the measured variables, there was wide inter-animal variation.

A simple intervention improves the recording of vital signs in children presenting to the emergency department.

OBJECTIVES: Vital signs are often not documented in paediatric patients at triage. This study was conducted to find out whether the use of a small, laminated aide memoire and a short teaching session might improve this situation. METHODS: A preliminary audit of the measurement of vital signs in 106 children aged less than 6 years was carried out in a district general hospital emergency department (ED). A small card illustrating normal values for these was then distributed-this could be attached to staff identity cards. At the same time doctors and nursing staff were given a teaching session on the importance of these measures. The audit was then repeated in a further 106 children. RESULTS: There was significant improvement in recording of all vital signs with the exception of blood pressure and temperature. CONCLUSION: A low-cost card together with a short period of training offers a useful strategy to improve the rate of documentation of vital signs in children presenting to the ED.

Human breast milk immunology: a review.

Breast feeding has been shown to enhance the development of the immune system of the newborn as well as provide protection against enteric and respiratory infections. It has been suggested that implementation of breast feeding programs has the potential to save hundreds of thousands of lives worldwide. Human milk is a bodily fluid which, apart from being an excellent nutritional source for the growing infant, also contains a variety of immune components such as antibodies, growth factors, cytokines, antimicrobial compounds, and specific immune cells. These help to support the immature immune system of the newborn baby, and protect it against infectious risks during the postnatal period while its own immune system matures. This article reviews some of the factors in human breast milk that give it these important properties.

Lymphocyte dynamics, apoptosis and HIV infection.

Death of HIV-infected CD4+ cells and HIV-induced death of uninfected CD4+ cells by apoptosis have been suggested to be important factors in causing the gradual progressive decline of CD4+ cells in the blood of HIV-positive patients. Recent advances in our knowledge of the dynamics of infection and the mechanism of apoptosis are reviewed with the aid of a mathematical model.

The clinical significance of T-cell superantigens.

Superantigens are a diverse collection of molecules that share the ability to activate specific lymphocyte subsets. In animal models, many of these molecules delete T-cell populations or render them anergic. The clinical impact of superantigens is significant, but much of their pathophysiology remains unclear.

Xenotransplantation, endogenous pig retroviruses and the precautionary principle.

Xenotransplantation poses challenges to scientists, ethicists and clinicians. Recent studies of the role of endogenous retroviruses suggest that these agents could threaten the safety of porcine xenotransplantation both for the recipient of a transplant, and possibly for people who have contact with that patient. Although the risk of such complications is low, the history of recent infectious diseases suggests that the precautionary principle should be invoked.

Memory and the lifespan of human T lymphocytes.

The properties of human CD45RA and CD45R0 T cells are described. CD45R0 cells respond to recall antigens and provide help for B lymphocytes. They produce a wide variety of cytokines including IL-2, IL-4 and IFN-gamma. CD45RA T cells respond poorly to recall antigens and produce mainly IL-2. The phenotype of CD45R0 cells suggests that they may be in cycle and in vivo data shows that they have a short lifespan while CD45RA cells are long lived. The lineage relationship of the two subsets is not clear but in vivo and in vitro evidence suggests bidirectional conversion between CD45RA and CD45R0 phenotypes.

The effect of treatment on lymphokine-secreting cells in the intestinal mucosa of children with Crohn's disease.

BACKGROUND: Recent studies have shown both interleukin 2 (IL-2) and interferon gamma (IFN) to be elevated in patients with active Crohn's disease compared to ulcerative colitis or non-inflammatory bowel disease controls. However the effect of treatment on these lymphokines has not been studied. PATIENTS AND METHODS: Using a reverse haemolytic plaque assay the percentage of lymphokine-secreting cells was determined in the intestinal mucosa of children with Crohn's disease before and after 8 weeks of treatment with either enteral nutrition, cyclosporin or steroids. RESULTS: Before treatment, a high percentage of cells isolated from mucosal biopsies secreted IL-2 or interferon-gamma. Eight weeks' treatment with the immunosuppressive agents cyclosporin, or with corticosteroids, produced a significant reduction in the percentage of IL-2 secreting cells, although only for the former was there also a reduction in interferon-gamma secreting cells. Enteral nutrition however, produced a reduction in lymphokine-secreting cells equivalent to cyclosporin and produced the best histological and clinical improvement. CONCLUSION: Enteral nutrition and cyclosporin can down-regulate lymphokine secretion in the gut in Crohn's disease.

Psychopathy across cultures: North America and Scotland compared.

Differences in the prevalence and presentation of psychopathic personality disorder between North America and Scotland were evaluated. R. D. Hare's (1991) Psychopathy Checklist--Revised ratings obtained from a sample of 2,067 North American male prisoners and forensic patients were compared with ratings obtained from 246 Scottish male prisoners. Item response theory methods were used to examine differences in the performance of items and to equate the scale across settings. The items had equal relevance to the description of psychopathic personality disorder in both settings; however, the Scottish prisoners had to have higher levels of the underlying latent trait before certain characteristics became apparent. The prevalence of the disorder appears to be lower in Scotland. Explanations for the observed differences in terms of enculturation, socialization, and migration are explored.

Physiological secretion of chemokines in human breast milk.

Human breast milk has been observed to contain high concentrations of the chemotactic cytokines (chemokines) interleukin-8 (IL-8) and RANTES. Concentrations are greatest in colostrum, but are measurable in milk after several months of lactation. These chemokines are also found in the secretions of patients with galactorrhoea and in the "witch's milk" of the newborn. Chemokine levels show good correlation with the sodium levels but not with cell counts or the creamatocrit of the secreted milk. Mothers with pre-term deliveries show no statistical difference in chemokine secretion in comparison with those with term deliveries. Immunohistochemisty demonstrates IL-8 and RANTES immunoreactivity in the acinary epithelial cells of normal mammary tissue and IL-8 and RANTES were shown to be produced by cultured, human mammary epithelial cells (HMEC) after stimulation with different cytokines. These results suggest that mammary epithelial cells are the source of chemokines in human milk and that the recruitment of leukocytes in human milk is likely to be chemokine-driven.