The interaction between Fasciola hepatica and other pathogens naturally co-infecting dairy and beef cattle in the UK

Liver flukes are helminth parasites of ruminants which cause economic losses and adverse effects on animal welfare. The common liver fluke Fasciola hepatica is prevalent in temperate regions, including the UK where up to 80% of dairy herds are exposed to the parasite, whilst the tropical liver fluke, F. gigantica, is found in tropical climates. Both flukes require an intermediate snail host to complete their life cycle, and this determines where infection occurs. Liver fluke is challenging to control, especially in dairy cattle. Chronic liver fluke infection moderates the host immune system towards a non- protective T helper cell type 2 (Th2) / regulatory T cell (Treg) response, characterised by IgG, IL4 and IL10, which suppress T helper cell type 1 (Th1) cytokines such as interferon (IFNγ). Previous studies have shown that this may affect the pathogenesis and diagnosis of other diseases, particularly bovine tuberculosis (bTB). However, most studies have been performed in experimentally infected animals under laboratory conditions, and the importance of the findings have not been verified in naturally infected cattle. The aims of this thesis were to investigate the effects of fluke infection on two mycobacterial diseases, bTB and Johne’s disease, and on the food poisoning bacterium Eschericia coli O157. Chapter 2 describes the dynamics of F. hepatica exposure in UK herds as measured by antibody detection ELISA. Individual results from 5937 cattle from 30 herds and 24 bulk milk tank results are used. The distributions of the antibody percent positivity (PP) values were right-skewed for all herds. The bulk milk result correlated with individual results. A significant effect of season was seen, but age was not significantly associated with antibody levels, both of which are in agreement with other recent studies. Chapter 3 contains the results of cross sectional and case-control studies looking at the association between liver fluke exposure with the bTB skin test. A comparison of IgG isotype ratios between fluke positive cattle testing positive and negative for bTB is also included. No significant effect was seen, but these studies were underpowered due to difficulties in obtaining samples. Overall there was a trend that fluke antibodies were associated with a decrease in the odds ratio (OR) of a positive bTB skin test. Chapter 4 is a systematic review of the literature on co-infection with liver fluke and tuberculosis. We extracted data on the association between fluke infection and the bTB skin test, interferon gamma test, lesion detection and culture/bacterial recovery. Evidence from nine studies included in the review points to liver fluke infection having the effect of decreasing all of the four measures of bTB diagnosis, but most studies showed a small and/or non-significant effect, and there was a high risk of bias across all studies. In Chapter 5, the hypothesis that there is an association between F. hepatica and Mycobacterium paratuberculosis subsp. avium (MAP, which causes Johne’s disease) was tested. The spatial distribution of MAP was examined using MAP antibody results from 885606 cows from 1245 herds, but no spatial pattern was seen. 3766 samples from 17 herds were tested for MAP antibody and F. hepatica antibody. Subsequently six farms were followed longitudinally for 1 year and up to four samples for each animal were obtained. No association between the two pathogens was found using any of these approaches. Chapter 6 describes a study on co-infection between fluke and E. coli O157 in finishing cattle. A significant association between the log PP of the F. hepatica copro-antigen ELISA and E. coli O157 shedding was found when the fixed effects of day of sampling and the age of the youngest animal in the group, and the random effect of farm were adjusted for, although the result should be interpreted cautiously due to the many study limitations, particularly a very low level of fluke infection. The effect of this association was that a change from the 25th quartile of F. hepatica PP to the 75th quartile corresponded with a 6.7% increased OR of E. coli O157 shedding (p = 0.01). Overall, these findings suggest that fluke infection may have an effect on bTB and E. coli O157 in naturally exposed animals, although conclusive evidence was lacking. Subtle effects may be obscured in field studies due to the large amount of natural variation between animals, and many unknown factors may introduce bias. Concentrating research on particular subgroups of animals that may be disproportionately at risk of adverse effects of co-infection, and evaluating immune profiles alongside diagnostic measures, may help to provide more certain evidence

Co-infection with <i>Fasciola hepatica</i> may increase the risk of <i>Escherichia coli</i> O157 shedding in British cattle destined for the food chain

© 2017 The Authors Escherichia coli O157 is a zoonotic bacterium that can cause haemorrhagic diarrhoea in humans and is of worldwide public health concern. Cattle are considered to be the main reservoir for human infection. Fasciola hepatica is a globally important parasite of ruminant livestock that is known to modulate its host's immune response and affect susceptibility to bacterial pathogens such as Salmonella Dublin. Shedding of E. coli O157 is triggered by unknown events, but the immune system is thought to play a part. We investigated the hypothesis that shedding of E. coli O157 is associated with F. hepatica infection in cattle. Three hundred and thirty four cattle destined for the food chain, from 14 British farms, were tested between January and October 2015. E. coli O157 was detected by immunomagnetic separation and bacterial load enumerated. F. hepatica infection status was assessed by copro-antigen ELISA. A significant association (p = 0.01) was found between the log percent positivity (PP) of the F. hepatica copro-antigen ELISA and E. coli O157 shedding when the fixed effects of day of sampling and the age of the youngest animal in the group, plus the random effect of farm were adjusted for. The results should be interpreted cautiously due to the lower than predicted level of fluke infection in the animals sampled. Nevertheless these results indicate that control of F. hepatica infection may have an impact on the shedding of E. coli O157 in cattle destined for the human food chain

Identifying critically important vascular access outcomes for trials in haemodialysis : an international survey with patients, caregivers and health professionals

BACKGROUND: Vascular access outcomes reported across haemodialysis (HD) trials are numerous, heterogeneous and not always relevant to patients and clinicians. This study aimed to identify critically important vascular access outcomes. METHOD: Outcomes derived from a systematic review, multi-disciplinary expert panel and patient input were included in a multilanguage online survey. Participants rated the absolute importance of outcomes using a 9-point Likert scale (7-9 being critically important). The relative importance was determined by a best-worst scale using multinomial logistic regression. Open text responses were analysed thematically. RESULTS: The survey was completed by 873 participants [224 (26%) patients/caregivers and 649 (74%) health professionals] from 58 countries. Vascular access function was considered the most important outcome (mean score 7.8 for patients and caregivers/8.5 for health professionals, with 85%/95% rating it critically important, and top ranked on best-worst scale), followed by infection (mean 7.4/8.2, 79%/92% rating it critically important, second rank on best-worst scale). Health professionals rated all outcomes of equal or higher importance than patients/caregivers, except for aneurysms. We identified six themes: necessity for HD, applicability across vascular access types, frequency and severity of debilitation, minimizing the risk of hospitalization and death, optimizing technical competence and adherence to best practice and direct impact on appearance and lifestyle. CONCLUSIONS: Vascular access function was the most critically important outcome among patients/caregivers and health professionals. Consistent reporting of this outcome across trials in HD will strengthen their value in supporting vascular access practice and shared decision making in patients requiring HD

Serendipitous Kepler observations of a background dwarf nova of SU UMa type

We have discovered a dwarf nova (DN) of type SU UMa in Kepler data which is 7.0 arcsec from the G-type exoplanet survey target KIC 4378554. The DN appears as a background source in the pixel aperture of the foreground G star. We extracted only the pixels where the DN is present and observed the source to undergo five outbursts -- one a superoutburst -- over a timespan of 22 months. The superoutburst was triggered by a normal outburst, a feature that has been seen in all DNe superoutburst observed by Kepler. Superhumps during the super outburst had a period of 1.842+/-0.004 h and we see a transition from disc-dominated superhump signal to a mix of disc and accretion stream impact. Predictions of the number of DNe present in Kepler data based on previously published space densities vary from 0.3 to 258. An investigation of the background pixels targets would lead to firmer constraints on the space density of DN.Comment: Accepted for publication in MNRA

In-the-Gap SU UMa-Type Dwarf Nova, Var73 Dra with a Supercycle of about 60 Days

An intensive photometric-observation campaign of the recently discovered SU UMa-type dwarf nova, Var73 Dra was conducted from 2002 August to 2003 February. We caught three superoutbursts in 2002 October, December and 2003 February. The recurrence cycle of the superoutburst (supercycle) is indicated to be $\sim$60 d, the shortest among the values known so far in SU UMa stars and close to those of ER UMa stars. The superhump periods measured during the first two superoutbursts were 0.104885(93) d, and 0.10623(16) d, respectively. A 0.10424(3)-d periodicity was detected in quiescence. The change rate of the superhump period during the second superoutburst was $1.7\times10^{-3}$, which is an order of magnitude larger than the largest value ever known. Outburst activity has changed from a phase of frequent normal outbursts and infrequent superoutbursts in 2001 to a phase of infrequent normal outbursts and frequent superoutbursts in 2002. Our observations are negative to an idea that this star is an related object to ER UMa stars in terms of the duty cycle of the superoutburst and the recurrence cycle of the normal outburst. However, to trace the superhump evolution throughout a superoutburst, and from quiescence more effectively, may give a fruitful result on this matter.Comment: 9 pages, 8 figures, submitted to A&

Memory properties and charge effect study in Si nanocrystals by scanning capacitance microscopy and spectroscopy

In this letter, isolated Si nanocrystal has been formed by dewetting process with a thin silicon dioxide layer on top. Scanning capacitance microscopy and spectroscopy were used to study the memory properties and charge effect in the Si nanocrystal in ambient temperature. The retention time of trapped charges injected by different direct current (DC) bias were evaluated and compared. By ramp process, strong hysteresis window was observed. The DC spectra curve shift direction and distance was observed differently for quantitative measurements. Holes or electrons can be separately injected into these Si-ncs and the capacitance changes caused by these trapped charges can be easily detected by scanning capacitance microscopy/spectroscopy at the nanometer scale. This study is very useful for nanocrystal charge trap memory application

Gonadal function in male patients after treatment for malignant lymphomas, with emphasis on chemotherapy

Gonadal function was assessed in male lymphoma survivors based on serum hormone levels (LH, FSH, testosterone, SHBG), and was related to treatment, age and observation time. Male patients ⩽50 years at diagnosis treated for Hodgkin's (HL) and/or non-Hodgkin's lymphoma (NHL) at the Norwegian Radium Hospital from 1 January 1980 to 31 December 2002 were included. Five treatment groups were defined: 1: radiotherapy only and/or low gonadotoxic chemotherapy (both HL and NHL)(‘No/low'), 2: medium gonadotoxicity chemotherapy for NHL (‘med-NHL'), 3: medium gonadotoxicity chemotherapy for HL (‘med-HL'), 4: highly gonadotoxic chemotherapy for NHL (‘high-NHL'), 5: highly gonadotoxic chemotherapy for HL (‘high-HL'). Gonadal hormone levels were categorised into three groups: 1: All gonadal hormones within normal range (normal), 2: Isolated elevated FSH, with LH, SHBG and testosterone within normal range (exocrine hypogonadism), 3: Testosterone below and/or LH above normal range (endocrine hypogonadism). One hundred and forty-four (49%) of the patients had normal gonadal hormones, 60 (20%) displayed exocrine hypogonadism and almost one-third (n=90, 30%) had endocrine hypogonadism. Compared to those treated with no/low gonadotoxic chemotherapy patients from all other treatment groups had significantly elevated risk for exocrine hypogonadism. Patients from the other treatment groups, except those in the med-NHL group, also had significantly elevated risk for endocrine hypogonadism compared with the group treated with no/low gonadotoxic chemotherapy. Men aged above 50 years at survey were about five times more likely to have endocrine hypogonadism compared with those less than 40 years. Because of the adverse health effects following long-lasting endocrine hypogonadism, gonadal hormones should be assessed regularly in male lymphoma survivors, especially after treatment with alkylating agents and high-dose chemotherapy with autologous stem cell support and in male patients who are 50 years and older

Identifying critically important cardiovascular outcomes for trials in hemodialysis: an international survey with patients, caregivers and health professionals

BACKGROUND: Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in people on hemodialysis (HD). Cardiovascular outcomes are reported infrequently and inconsistently across trials in HD. This study aimed to identify the priorities of patients/caregivers and health professionals (HPs) for CVD outcomes to be incorporated into a core outcome set reported in all HD trials. METHODS: In an international online survey, participants rated the absolute importance of 10 cardiovascular outcomes (derived from a systematic review) on a 9-point Likert scale, with 7-9 being critically important. The relative importance was determined using a best-worst scale. Likert means, medians and proportions and best-worst preference scores were calculated for each outcome. Comments were thematically analyzed. RESULTS: Participants included 127 (19%) patients/caregivers and 549 (81%) HPs from 53 countries, of whom 530 (78%) completed the survey in English and 146 (22%) in Chinese. All but one cardiovascular outcome ('valve replacement') was rated as critically important (Likert 7-9) by all participants; 'sudden cardiac death', 'heart attack', 'stroke' and 'heart failure' were all rated at the top by patients/caregivers (median Likert score 9). Patients/caregivers ranked the same four outcomes as the most important outcomes with mean preference scores of 6.2 (95% confidence interval 4.8-7.5), 5.9 (4.6-7.2), 5.3 (4.0-6.6) and 4.9 (3.6-6.3), respectively. The same four outcomes were ranked most highly by HPs. We identified five themes underpinning the prioritization of outcomes: 'clinical equipoise and potential for intervention', 'specific or attributable to HD', 'severity or impact on the quality of life', 'strengthen knowledge and education', and 'inextricably linked burden and risk'. CONCLUSIONS: Patients and HPs believe that all cardiovascular outcomes are of critical importance but consistently identify sudden cardiac death, myocardial infarction, stroke and heart failure as the most important outcomes to be measured in all HD trials

Predicted risks of radiogenic cardiac toxicity in two pediatric patients undergoing photon or proton radiotherapy

BACKGROUND: Hodgkin disease (HD) and medulloblastoma (MB) are common malignancies found in children and young adults, and radiotherapy is part of the standard treatment. It was reported that these patients who received radiation therapy have an increased risk of cardiovascular late effects. We compared the predicted risk of developing radiogenic cardiac toxicity after photon versus proton radiotherapies for a pediatric patient with HD and a pediatric patient with MB. METHODS: In the treatment plans, each patient’s heart was contoured in fine detail, including substructures of the pericardium and myocardium. Risk calculations took into account both therapeutic and stray radiation doses. We calculated the relative risk (RR) of cardiac toxicity using a linear risk model and the normal tissue complication probability (NTCP) values using relative seriality and Lyman models. Uncertainty analyses were also performed. RESULTS: The RR values of cardiac toxicity for the HD patient were 7.27 (proton) and 8.37 (photon), respectively; the RR values for the MB patient were 1.28 (proton) and 8.39 (photon), respectively. The predicted NTCP values for the HD patient were 2.17% (proton) and 2.67% (photon) for the myocardium, and were 2.11% (proton) and 1.92% (photon) for the whole heart. The predicted ratios of NTCP values (proton/photon) for the MB patient were much less than unity. Uncertainty analyses revealed that the predicted ratio of risk between proton and photon therapies was sensitive to uncertainties in the NTCP model parameters and the mean radiation weighting factor for neutrons, but was not sensitive to heart structure contours. The qualitative findings of the study were not sensitive to uncertainties in these factors. CONCLUSIONS: We conclude that proton and photon radiotherapies confer similar predicted risks of cardiac toxicity for the HD patient in this study, and that proton therapy reduced the predicted risk for the MB patient in this study