A multicentred study to validate a consensus bleeding assessment tool developed by the biomedical excellence for safer transfusion collaborative for use in patients with haematological malignancy.

BACKGROUND: There continues to be uncertainty about the optimal approach to documenting bleeding data in platelet transfusion trials, with a desire to apply a common assessment tool across all trials. With this in mind, a consensus bleeding assessment tool (BAT) has been developed by the Biomedical Excellence for Safer Transfusion (BEST) collaborative, based on review of data collection forms used in published randomized trials and following content validation with a range of healthcare professionals at seven haematology centres through BEST members. This study aimed to evaluate reliability and reproducibility of the consensus BAT. METHODS: Replicated clinical assessments of bleeding were undertaken by participants with haematological malignancies recruited at four haematology centres in an international, multicentred, observational study. Concordance of repeat assessments was calculated for agreement in site and grade of bleeding observed. RESULTS: Forty patients consented to participate, and 13 trained bleeding assessors collected these data. Bleeding assessments were carried out on 113 separate days. Of all 225 bleeding assessments, 204 were compared for grade concordance, and 160 were compared for site concordance. There was very good grade concordance (83%, 95% confidence interval 74-93%) and good bleeding site concordance (69%, 95% confidence interval 57-79%) in observations of bleeding. Discordance was primarily in relation to assessing skin bleeding. CONCLUSIONS: Alongside a structured training programme, levels of concordance for a consensus BAT were high. Researchers using assessment tools for bleeding need to balance comprehensive data collection against potential loss of accuracy for some types of bleeding, such as skin findings.

Costs and quality of life associated with acute upper gastrointestinal bleeding in the UK: cohort analysis of patients in a cluster randomised trial.

OBJECTIVES: Data on costs associated with acute upper gastrointestinal bleeding (AUGIB) are scarce. We provide estimates of UK healthcare costs, indirect costs and health-related quality of life (HRQoL) for patients presenting to hospital with AUGIB. SETTING: Six UK university hospitals with >20 AUGIB admissions per month, >400 adult beds, 24 h endoscopy, and on-site access to intensive care and surgery. PARTICIPANTS: 936 patients aged ≥18 years, admitted with AUGIB, and enrolled between August 2012 and March 2013 in the TRIGGER trial of AUGIB comparing restrictive versus liberal red blood cell (RBC) transfusion thresholds. PRIMARY AND SECONDARY OUTCOME MEASURES: Healthcare resource use during hospitalisation and postdischarge up to 28  days, unpaid informal care, time away from paid employment and HRQoL using the EuroQol EQ-5D at 28  days were measured prospectively. National unit costs were used to value resource use. Initial in-hospital treatment costs were upscaled to a UK level. RESULTS: Mean initial in-hospital costs were £2458 (SE=£216) per patient. Inpatient bed days, endoscopy and RBC transfusions were key cost drivers. Postdischarge healthcare costs were £391 (£44) per patient. One-third of patients received unpaid informal care and the quarter in paid employment required time away from work. Mean HRQoL for survivors was 0.74. Annual initial inhospital treatment cost for all AUGIB cases in the UK was estimated to be £155.5 million, with exploratory analyses of the incremental costs of treating hospitalised patients developing AUGIB generating figures of between £143 million and £168 million. CONCLUSIONS: AUGIB is a large burden for UK hospitals with inpatient stay, endoscopy and RBC transfusions as the main cost drivers. It is anticipated that this work will enable quantification of the impact of cost reduction strategies in AUGIB and will inform economic analyses of novel or existing interventions for AUGIB. TRIAL REGISTRATION NUMBER: ISRCTN85757829 and NCT02105532.

Comparison of codes assessing galactic cosmic radiation exposure of aircraft crew.

The assessment of the exposure to cosmic radiation onboard aircraft is one of the preoccupations of bodies responsible for radiation protection. Cosmic particle flux is significantly higher onboard aircraft than at ground level and its intensity depends on the solar activity. The dose is usually estimated using codes validated by the experimental data. In this paper, a comparison of various codes is presented, some of them are used routinely, to assess the dose received by the aircraft crew caused by the galactic cosmic radiation. Results are provided for periods close to solar maximum and minimum and for selected flights covering major commercial routes in the world. The overall agreement between the codes, particularly for those routinely used for aircraft crew dosimetry, was better than +/-20 % from the median in all but two cases. The agreement within the codes is considered to be fully satisfactory for radiation protection purposes.

Validation of modelling the radiation exposure due to solar particle events at aircraft altitudes.

Dose assessment procedures for cosmic radiation exposure of aircraft crew have been introduced in most European countries in accordance with the corresponding European directive and national regulations. However, the radiation exposure due to solar particle events is still a matter of scientific research. Here we describe the European research project CONRAD, WP6, Subgroup-B, about the current status of available solar storm measurements and existing models for dose estimation at flight altitudes during solar particle events leading to ground level enhancement (GLE). Three models for the numerical dose estimation during GLEs are discussed. Some of the models agree with limited experimental data reasonably well. Analysis of GLEs during geomagnetically disturbed conditions is still complex and time consuming. Currently available solar particle event models can disagree with each other by an order of magnitude. Further research and verification by on-board measurements is still needed.

Comparison of the histology and immunohistochemistry of vaccination-site and non-vaccination-site sarcomas from cats in New Zealand.

AIMS: To compare the histology and immunohistochemistry of vaccination-site sarcomas (VSSs) with non-vaccination-site sarcomas (NVSSs) in cats in New Zealand. To determine whether VSSs in cats in New Zealand have similar histological and immunohistochemical features to those previously described in feline vaccine-associated sarcomas (VASs) in North American studies. METHODS: A retrospective survey of skin biopsies submitted between 2004 and 2006 was performed to identify cutaneous sarcomas from both vaccination and non-vaccination sites in cats. Vaccination sites included the interscapular, shoulder, or dorsal or lateral cervical and thoracic regions. All sarcomas were examined histologically, and smooth muscle actin and desmin were assessed immunohistochemically. Features previously described in VASs were assessed and compared. RESULTS: Sarcomas from 34 cats were identified, 10 of which occurred at vaccination sites. Compared with NVSSs, VSSs were more likely to be located in the hypodermis and have greater cellular pleomorphism, higher mitotic rates, more frequent peripheral lymphocytic aggregates and multinucleated giant cells. VSSs were also more likely than NVSSs to show partial myofibroblastic differentiation, demonstrable using immunohistochemistry. The histological and immunohistochemical features of VSSs in cats in New Zealand are consistent with those previously described in VASs in cats in North America. CONCLUSIONS: The results of this study suggest that VASs occur in cats in New Zealand. CLINICAL RELEVANCE: The occurrence of VASs in cats in New Zealand would provide further support for restriction of the vaccination of cats to the minimum necessary to protect health, and adoption of the New Zealand Veterinary Association guidelines on vaccination.

Further phenotypic delineation of subtelomeric (terminal) 4q deletion with emphasis on intracranial and reproductive anatomy.

OBJECTIVE: To describe selected morphological and developmental features associated with subtelomeric deletion at chromosome 4q. MATERIALS AND METHODS: A 21-year old female was brought for gynecologic evaluation of menorrhagia. High-resolution metaphase karyotype and subtelomere fluorescent in-situ hybridization (FISH) analysis were used for genotype determination. Pelvic anatomy was characterized via CT and laparoscopy; MR and CT were used for intracranial imaging. RESULTS: A de novo deletion [46,XX del(4)(q32)] was identified cytogenetically and confirmed as a terminal loss via subtelomere FISH. Hand/foot malformation characteristic of deletion at this segment was present. Pelvic CT and laparoscopy revealed normal uterine anatomy. Fallopian tubes appeared grossly unremarkable, and a right ovarian cyst was excised without difficulty. Bilateral broad ligament fibroadipose nodularities were noted adjacent to the uterus between round ligament and fallopian tube. Neurological exam revealed no focal defects, although brain MR identified an abnormal signal intensity at the inferior margin of the globus pallidus, consistent with old lacunar infarct and gliosis. Developmental delay was supported by an observed level of general intellectual function estimated at age seven. CONCLUSION: Terminal deletion of the long arm of chromosome 4 is a rare genetic event associated with a distinctive phenotype dependent on the size of the deletion. Chromosomal losses that span the 4q32 band include mental retardation and mild craniofacial anomalies. Here, further characterization of this disorder is offered including precise quantification of the DNA loss, information on brain morphology and pelvic anatomy. Additional studies will be required to characterize the full developmental and physiologic implications of this unusual genetic disorder.

Feasibility and usefulness of self-assessment of bleeding in patients with haematological malignancies, and the association between platelet count and bleeding.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the collection of daily prospective information about bleeding outcomes in patients with thrombocytopenia, including information obtained by patient self-assessment. MATERIALS AND METHODS: Consecutive patients with haematological malignancies were enrolled in a study of bleeding data collection during the period of thrombocytopenia. A short educational session and information sheet was designed for self-assessment. Platelet counts and all transfusions were recorded daily. Bleeding scores were translated into World Health Organization (WHO) bleeding grades. RESULTS: Nineteen patients were included in the study. Four-hundred and ten days of thrombocytopenia were eligible for assessment of bleeds. Self-assessment was feasible, as defined by the total proportion of days on which self-assessment was completed (70%, 288 thrombocytopenic days). There was 86% agreement between bleeding data collected by self-assessment and by medical examination using a structured assessment form. Examples of discrepancies included the duration of petechiae/bruises and the reporting of minor bleeding. There was no evidence for an association between patients' morning platelet count and daily WHO bleeding grade. The incidences of WHO grade 1 and grade 2 bleeding on days with platelet counts < or = 10 x 10(9)/l, 11-20 x 10(9)/l, and > 20 x 10(9)/l were similar and did not reveal higher rates of bleeding at lower counts. CONCLUSIONS: Patient self-assessment can help to support comprehensive daily prospective monitoring of bleeding, specifically facilitating data collection following hospital discharge. The discrepancies between self-assessment and medical examination highlight the need to develop a validated international assessment tool. The association among platelet count, risk of bleeding and role of prophylactic platelet transfusions needs further evaluation in larger prospective trials.

Factors affecting the monetary return from programmes for synchronising oestrus in dairy cows with gonadotrophin-releasing hormone and prostaglandin F2alpha.

Synchronisation, using a combination of gonadotrophin-releasing hormone and prostaglandin F2alpha injections, is commonly used to control the reproductive cycle of dairy cows. A simple model that could predict the monetary return from synchronisation would be a valuable tool in determining whether it would be worthwhile. This study used data from three controlled clinical trials to investigate the effects of six factors (interval between calving and synchronisation, 21-day submission rate, number of cows synchronised, average age, pregnancy rate of non-synchronised cows and season) on the return from synchronisation. The results suggests that the herd's submission and pregnancy rates, the time between calving and synchronisation, and the number of cows synchronised can all significantly affect the return from synchronisation, but only time since calving significantly affected the return in all three trials. They also suggest that there is no simple linear relationship between these factors and the return from synchronisation.

Potential prognostic and therapeutic roles for cytokines in breast cancer (Review).

Cytokines are known to have both stimulatory and inhibitory effects on breast cancer growth depending on their relative concentrations and the presence of other modulating factors in the tumour microenvironment. Certain cytokines appear to prevent an effective immune response being mounted, permitting cancer growth, whereas others promote the immune system's anti-tumour capability. Furthermore, the systemic levels of certain cytokines, e.g. IL-6 and IL-18, independently show promising correlations with disease stage and progression. With advances in methods for delivery of cytokines to a tumour site, the enhanced induction of anti-tumour immunity by targeted cytokine release is becoming a realistic option. Here, we review the role of cytokines in the immune response against breast cancer and assess their potential as prognostic indicators and/or use in immune therapy. A literature search was conducted using Medline, restricted to articles published in the English language, using combinations of the following MeSH terms: cytokines, breast cancer, immunology, immunotherapy and interleukins. Focused searches using keywords relevant to the role of cytokines in breast cancer immunology yielded >200 references.

Calculations and observations of solar particle enhancements to the radiation environment at aircraft altitudes.

Solar particle events can give greatly enhanced radiation at aircraft altitudes, but are both difficult to predict and to calculate retrospectively. This enhanced radiation can give significant dose to aircrew and greatly increase the rate of single event effects in avionics. Validation of calculations is required but only very few events have been measured in flight. The CREAM detector on Concorde detected the event of 29 September 1989 and also four periods of enhancement during the events of 19-24 October 1989. Instantaneous rates were enhanced by up to a factor ten compared with quiet-time cosmic rays, while flight-averages were enhanced by up to a factor six. Calculations are described for increases in radiation at aircraft altitudes using solar particle spectra in conjunction with Monte Carlo radiation transport codes. In order to obtain solar particle spectra with sufficient accuracy over the required energy range it is necessary to combine space data with measurements from a wide range of geomagnetically dispersed, ground-level neutron monitors. Such spectra have been obtained for 29 September 1989 and 24 October 1989 and these are used to calculate enhancements that are compared with the data from CREAM on Concorde. The effect of cut-off rigidity suppression by geomagnetic activity is shown to be significant. For the largest event on record on 23 February 1956, there are no space data but there are data from a number of ground-level cosmic-ray detectors. Predictions for all events show very steep dependencies on both latitude and altitude. At high latitude and altitude (17 km) calculated increases with respect to cosmic rays are a factor 70 and 500 respectively for 29 September 1989 and 23 February 1956. The levels of radiation for high latitude, subsonic routes are calculated, using London to Los Angeles as an example, and can exceed 1 mSv, which is significantly higher than for Concorde routes from Europe to New York. The sensitivity of the calculations to spectral fitting, geomagnetic activity and other assumptions demonstrates the requirement for widespread carriage of radiation monitors on aircraft.

Effect of spray-dried plasma and lipopolysaccharide exposure on weaned pigs: I. Effects on the immune axis of weaned pigs.

A study was conducted with 20 weaned barrows (14 d, 4.98 +/- .21 kg) to determine the effect of spray-dried plasma (SDP) on the pig's immune response to a lipopolysaccharide (LPS) challenge. After weaning, pigs were fed a diet containing 0 or 7% SDP for 7 d. On d 6 postweaning, all pigs were fitted with a jugular catheter. On d 7 postweaning, the pigs were given an i.p. injection of either saline or LPS (150 microg/kg BW) followed by a 3-h blood collection every 15 min. Following blood collection, all pigs were killed and tissue was collected for mRNA analysis. Additionally, the small intestine was collected for measurement of villus height, crypt depth, and villus height:crypt depth ratio (VCR) at three sites (25, 50, and 75% of the total length). Feeding SDP resulted in reduced (P < 0.05) mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA in the adrenal gland, spleen, hypothalamus, pituitary gland, and liver. Additionally, expression of IL-6 mRNA was reduced (P < 0.05) in the spleen and pituitary gland for pigs fed SDP. For pigs fed the diet with SDP, LPS administration did not affect (P > 0.10) cytokine mRNA expression, whereas LPS reduced expression of TNF-alpha mRNA in the spleen and IL-1beta mRNA in the adrenal gland, spleen, and thymus for pigs fed the diet without SDP. For pigs fed the diet with SDP, LPS caused serum TNF-alpha to increase 150-fold compared to a 60-fold increase for pigs fed the diet without SDP. Similarly, interferon-gamma (IFN-gamma) increased 110-fold for pigs fed the diet with SDP compared to a 16-fold increase for pigs fed the diet without SDP. For pigs fed the diet with SDP, LPS caused major villus atrophy, whereas for pigs fed the diet without SDP, LPS had no effect on intestinal morphology. These results demonstrate that the basal activation of the immune system appears to be less for pigs fed the diet with SDP compared to pigs fed the diet without SDP after weaning. Additionally, for pigs fed the diet with SDP, there appeared to be an overresponse of the immune system following LPS administration, which resulted in major damage to the mucosa of the gastrointestinal tract.

Impact of environmental temperature on response of neonatal pigs to an endotoxin challenge.

OBJECTIVE: To evaluate the effect of various environmental temperatures (ET) on the ability of neonatal pigs to cope with an endotoxin challenge. ANIMALS: 28 crossbred male pigs that were 24 hours old. PROCEDURE: At 24 hours of age, pigs were placed in environmentally controlled chambers maintained at 18 or 34 C (14 pigs/ET). Rectal temperatures (RT) were recorded at 15-minute intervals for 3 hours following an IP injection of 0.9% NaCl (7 control pigs/ET) or lipopolysaccharide (LPS; 150 microg/kg of body weight; 7 LPS-treated pigs/ET). Tissue specimens and blood samples were collected following the 3-hour challenge period. RESULTS: LPS-treated pigs exposed to 18 C had a period of hypothermia whereas RT for LPS-treated pigs at 34 C did not differ from control pigs. The LPS-treated pigs maintained at 18 C lost the most body weight during the 3-hour period and also had the greatest increase in serum cortisol concentration. Serum prolactin (PRL) concentration was decreased in pigs at 18 C, compared with pigs at 34 C. Challenge with LPS resulted in an increase in serum PRL concentration at 18 C but had no effect on serum PRL at 34 C. Challenge with LPS resulted in an increase in expression of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 receptor mRNA in the hypothalamus. CONCLUSIONS AND CLINICAL RELEVANCE: Exposure to a cold ET can inhibit the ability of neonatal pigs to cope with an exogenous endotoxin challenge. When combined, cold stress and exposure to exogenous endotoxin induces a rapid and potentially dangerous loss of body temperature in neonatal pigs.