Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

Outcomes from the use of computerized neurocognitive testing in a recurrent glioblastoma clinical trial.

Assessment of neurocognitive function (NCF) is important in brain tumor clinical trials, however there are varying methodologies available. We used the Cogstate computerized NCF testing battery and the mini-mental state examination (MMSE) to prospectively assess cognition in adult patients with recurrent glioblastoma (GBM) enrolled in the CABARET randomized phase II clinical trial of bevacizumab versus bevacizumab plus carboplatin chemotherapy. We determined completion rates; compared NCF results between trial arms; and assessed baseline NCF as a predictor of survival outcome. 93 of 103 eligible patients completed baseline Cogstate NCF testing. Completion rates were between 60 and 100% across each timepoint, and 38% at disease progression. There was no evidence of difference between arms in time to deterioration in NCF using either test. Prior to disease progression, deterioration on the Cogstate tests was substantially more common (90%) than deterioration on the MMSE (37%), and decline in the Cogstate composite score within the first 8 weeks was associated with shorter overall survival. This testing methodology may be useful when determining net clinical benefit for therapies in patients with recurrent GBM.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Increases in anaphylaxis fatalities in Australia from 1997 to 2013.

BACKGROUND: Recent epidemiological studies indicate increases in Australian, UK and US hospital anaphylaxis admission rates. OBJECTIVES: The aim of this study was to determine whether Australian anaphylaxis fatalities are increasing in parallel and to examine the characteristics of fatalities recorded in the National Coronial Information System (NCIS). METHODS: Time trends in Australian anaphylaxis fatalities were examined using data derived from the Australian Bureau of Statistics (ABS) 1997-2013 and the NCIS 2000-2013, the latter providing additional information to verify cause and identify risk factors. RESULTS: The ABS recorded 324 anaphylaxis fatalities by cause: unspecified (n = 205); medication (n = 52); insect stings/tick bites (n = 41); food (n = 23); and blood products (n = 3). From 1997 to 2013, all-cause fatal anaphylaxis rates increased by 6.2%/year (95% CI: 3.8-8.6%, P < 0.0001) or from 0.054% to 0.099/10(5) population. Fatal food anaphylaxis increased by 9.7%/year (95% CI: 0.25-20%, P = 0.04) and unspecified anaphylaxis deaths by 7.8% (95% CI: 4.6-11.0, P < 0.0001). There was an insignificant change in medication-related fatalities (5.6% increase/year; 95% CI: 0.3% decrease to 11.8% increase, P = 0.06), and sting/bite fatalities remained unchanged. Hospital anaphylaxis admission rates for all-cause, food, unspecified and medication anaphylaxis increased at rates of 8%, 10%, 4.4% and 6.8%/year, respectively. A total of 147 verified NCIS deaths were examined in detail: medication- and sting/bite-related fatalities occurred predominantly in older individuals with multiple comorbidities. Upright posture after anaphylaxis was associated with risk of sudden death (all causes). Seafood (not nuts) was the most common trigger for food-related anaphylaxis deaths. CONCLUSIONS: Australian anaphylaxis fatality rates (most causes) have increased over the last 16 years, contrasting with UK- and US-based studies that describe overall lower and static overall anaphylaxis fatality rates (0.047-0.069/10(5) population).

The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.

BACKGROUND: Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain. METHODS: This meta-analysis included individual participant data from 22 trials of statin versus control (n=134,537; mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin (n=39,612; difference 0·51 mmol/L; 5·1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1·0 mmol/L LDL cholesterol reduction was estimated. FINDINGS: Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, 95% CI 0·77-0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1·0 mmol/L reduction from lowest to highest risk: 0·62 [99% CI 0·47-0·81], 0·69 [99% CI 0·60-0·79], 0·79 [99% CI 0·74-0·85], 0·81 [99% CI 0·77-0·86], and 0·79 [99% CI 0·74-0·84]; trend p=0·04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0·57, 99% CI 0·36-0·89, p=0·0012, and 0·61, 99% CI 0·50-0·74, p<0·0001) and in coronary revascularisations (RR 0·52, 99% CI 0·35-0·75, and 0·63, 99% CI 0·51-0·79; both p<0·0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1·0 mmol/L LDL cholesterol reduction 0·76, 99% CI 0·61-0·95, p=0·0012) was also similar to that seen in higher risk categories (trend p=0·3). In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1·0 mmol/L LDL cholesterol reduction 0·85, 95% CI 0·77-0·95) and all-cause mortality (RR 0·91, 95% CI 0·85-0·97), and the proportional reductions were similar by baseline risk. There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1·0 mmol/L LDL cholesterol reduction 1·00, 95% CI 0·96-1·04), cancer mortality (RR 0·99, 95% CI 0·93-1·06), or other non-vascular mortality. INTERPRETATION: In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. FUNDING: British Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.

A multi-species model to assess the effect of refugia on worm control and anthelmintic resistance in sheep grazing systems.

OBJECTIVE: Develop a computer simulation model that uses daily meteorological data and farm management practices to predict populations of Trichostrongylus colubriformis, Haemonchus contortus and Teladorsagia (Ostertagia) circumcincta and the evolution of anthelmintic resistance within a sheep flock. Use the model to explore if increased refugia, provided by leaving some adult sheep untreated, would delay development of anthelmintic resistance without compromising nematode control. PROCEDURES: Compare model predictions with field observations from a breeding flock in Armidale, NSW. Simulate the impact of leaving 1-10% of adult sheep untreated in diverse sheep-grazing systems. RESULTS: Predicted populations of Tr. colubriformis and T. circumcincta were less than those observed in the field, attributed to nutritional stress experienced by the sheep during drought and not accounted for by the model. Observed variation in faecal egg counts explained by the model (R(2) ) for these species was 40-50%. The H. contortus populations and R(2) were both low. Leaving some sheep untreated worked best in situations where animals were already grazing or were moved onto pastures with low populations of infective larvae. In those cases, anthelmintic resistance was delayed and nematode control was maintained when 1-4% of adult stock remained untreated. CONCLUSIONS: In general, the model predicted that leaving more than 4% of adults untreated did not sufficiently delay the development of anthelmintic resistance to justify the increased production risk from such a strategy. The choice of a drug rotation strategy had an equal or larger effect on nematode control, and selection for resistance, than leaving 1-10% of adults untreated.

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.

BACKGROUND: Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. METHODS: We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. FINDINGS: In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7-19; p<0·0001), in coronary revascularisation of 19% (95% CI 15-24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81-1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96-1·04; p=0·9), even at low LDL cholesterol concentrations. INTERPRETATION: Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%. FUNDING: UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

Leptin, but not adiponectin, is a predictor of recurrent cardiovascular events in men: results from the LIPID study.

OBJECTIVE: To investigate the relationships between plasma leptin and adiponectin levels and recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes. DESIGN, SUBJECTS AND MEASUREMENTS: A nested case-control study examined circulating leptin and adiponectin levels in plasma obtained 4-6 years after entry into the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial. Plasma was assayed from 184 men who suffered recurrent events within 4.4 years after blood collection and 184 matched controls who remained free of further events. The association between cardiovascular events and the explanatory variables was examined by conditional logistic regression analysis. RESULTS: Relative risk (RR) increased across increasing leptin quartiles; the highest quartile compared with the lowest quartile was related to the highest risk (P for trend=0.002); the increased risk remained after adjustment for risk factors (P=0.018) or for obesity (P=0.038), but in the final model (adjusted for randomized treatment, other drugs, LIPID risk score, age and body mass index), the risk was attenuated (RR=1.61, 95% CI: 0.72-3.57, P for trend=0.34). Adiponectin did not predict cardiovascular events. Subjects randomly allocated to pravastatin had 6% lower leptin levels (P=0.04) than those allocated to placebo. CONCLUSION: Plasma leptin was a significant and independent predictor of recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes.

Weight status and perception barriers to healthy physical activity and diet behavior.

BACKGROUND: Physical inactivity and insufficient fruit and vegetable consumption are key risk factors for obesity and noncommunicable diseases. Weight perceptions may affect physical activity and diet behaviors. We report current prevalence estimates of Australian adults meeting recommended levels of leisure-time physical activity (LTPA) (> or =150 min/week or more of at least moderate-intensity physical activity (including walking) on > or =5 days/week) and fruit (> or =2 servings/day) and vegetable (> or =5 servings/day) consumption for health benefits, by weight status and perceptions. METHODS: We conducted a cross-sectional survey analysis of data for 16 314 adults from the Australian National Health Survey 2004-2005. All variables were collected by self-report. Weighted estimates were age- and gender-specific, and data were analyzed using logistic regression with acceptable weight referent categories, adjusting for covariates. RESULTS: Among acceptable, overweight and obese adults, the prevalence of LTPA was 26.8, 26.1 and 19.3% for men, and 27.7, 23.7 and 19.7% for women, respectively. Approximately 55 and 15% of adults consumed sufficient fruit servings/day and vegetable servings/day, respectively, and less than 5% of adults met combined LTPA and diet guidelines. Overweight decreased the odds ratio for LTPA among women but not men, and obesity decreased the odds ratio for LTPA among both men and women. Overweight perception conferred odds ratios of 0.83 (95% CI 0.70-0.97, P=0.021) for overweight men, and of 0.74 (95% CI 0.62-0.88, P=0.001) and 0.69 (95% CI 0.59-0.80, P<0.001) for obese men and women, respectively; for LTPA, whereas no significant associations were found for acceptable weight perception. No consistent associations between weight status or perceptions and diet behaviors were found. CONCLUSIONS: Overweight perception may be another barrier to physical activity participation among men and women with excess body weight. Public health strategies might need to focus on overcoming weight perception as well as weight status barriers to adopting healthy physical activity behaviors.

Efficacy of exercise for treating overweight in children and adolescents: a systematic review.

BACKGROUND: Overweight prevalence among children/adolescents is increasing, while adult obesity may potentially cause a decline in life expectancy. More exercise is uniformly recommended, although treatment efficacy remains unclear. OBJECTIVE: To determine the efficacy of exercise alone for treating overweight in children/adolescents. DESIGN: A systematic review and meta-analysis of randomized trials published in English were completed following multiple database searches performed on December 10, 2004. Studies of isolated or adjunctive exercise/physical activity treatment in overweight/obese children or adolescents which reported any overweight outcome were included. Literature searches identified 645 papers which were manually searched, of which 45 were considered for inclusion, of which 13 papers which reported 14 studies were included (N=481 overweight boys and girls, aged approximately 12 years). Two reviewers independently identified relevant papers for potential inclusion and assessed methodological quality. Principal measures of effects included the mean difference (MD) (between treatment and control groups), the weighted MD (WMD), and the standardized MD (SMD). RESULTS: Few studies were of robust design. The pooled SMD was -0.4 (-0.7, -0.1, P=0.006) for percent body fat, and -0.2 (-0.6, 0.1, P=0.07) for central obesity outcomes, whereas the pooled WMD was -2.7 kg (-6.1 kg, 0.8 kg, P=0.07) for body weight, all of which favored exercise. Pooled effects on body weight were significant and larger for studies of higher doses, whereas nonsignificant and smaller effects were seen for studies of lower doses of exercise (155-180 min/weeks vs 120-150 min/weeks). CONCLUSIONS: Based on the small number of short-term randomized trials currently available, an aerobic exercise prescription of 155-180 min/weeks at moderate-to-high intensity is effective for reducing body fat in overweight children/adolescents, but effects on body weight and central obesity are inconclusive. Recommendations for future study designs are discussed.

Selection of different genotype larvae and adult worms for anthelmintic resistance by persistent and short-acting avermectin/milbemycins.

To understand the factors that influence selection for anthelmintic resistance, it is necessary to examine the impact of drug treatment, particularly persistent drugs, on all phases of the worm life cycle. The efficacy of various avermectin/milbemycin anthelmintics was determined against resident worms, incoming larvae (L3) and development of eggs in faecal culture. Homozygote-resistant and maternal and paternal F1-heterozygote genotypes of Haemonchus contortus were used to infect sheep before or after treatment with ivermectin (IVM) oral, IVM capsule, moxidectin (MOX) oral or MOX injectable. Total worm count and quantitative larval culture were used to determine efficacy against parasitic and free-living stages, respectively. Selection for resistance by IVM capsules occurred at the adult and L3 stages because of poor efficacy against these stages for all resistant genotypes. However, the selective advantage of these surviving worms was reduced due to the low development of their eggs to L3 in faecal culture. For MOX, selection for resistance predominantly occurred after treatment because of high efficacy against resident adult worms of all resistant genotypes but poor efficacy against resistant L3 ingested after drug administration. The results indicated no evidence of sex-linked inheritance for IVM resistance. Mean IVM efficacies against homozygous and heterozygous resistant adult worms were not different, and IVM capsule efficacy against incoming L3 was approximately 70% for all resistant genotypes, consistent with a dominant trait. MOX was highly effective against adults of all resistant genotypes and approximately 76% effective against incoming L3 regardless of resistance genotype, also consistent with a dominant trait. These results will enable the impact of persistent drugs on worm control and anthelmintic resistance to be estimated. The results indicate that IVM capsules should not be used in populations where avermectin/milbemycin resistance is present.

Principles for the use of macrocyclic lactones to minimise selection for resistance.

OBJECTIVE: To provide principles for the appropriate use of avermectin/milbemycin or macrocyclic lactone (ML) anthelmintics in sheep, to ensure effective worm control and to minimise selection for ML resistance. STRATEGY: The principles were based on an assessment of the information currently available. The MLs were categorised into three groups (ivermectin [IVM], abamectin [ABA] and moxidectin [MOX]) based on structural differences, persistence and efficacy against ML resistant strains. The reported order of activity or efficacy against ML resistant worm strains was IVM

Selection for anthelmintic resistance by macrocyclic lactones in Haemonchus contortus.

Two morphologically marked strains of Haemonchus contortus, CAVRS (smooth-macrocyclic lactone resistant) and McMaster (linguiform-macrocyclic lactone susceptible), were used to investigate the selection for anthelmintic resistance following exposure to ivermectin (IVM), a non-persistent anthelmintic. and a more persistent anthelmintic, oral moxidectin (MOX). Three types of selection were investigated: (1) selection of resident worms at the time of treatment (Head selection); (2) selection of incoming-larvae post-treatment (Tail selection); and (3) selection of both resident population and incoming larvae (Head + Tail selection). The experimental animals were adult sheep and lambs. In the controls where there was no anthelmintic selection, the proportion of CAVRS in the adult worm population was the same as the proportion in larvae given to both adults and lambs indicating that CAVRS and McMaster H. contortus were equally infective. There was a significant effect of anthelmintic on total worm numbers in adult sheep with MOX treated adults having less worms, but selection type was non-significant. Anthelmintic type had a significant effect on numbers of resistant worms in adult sheep with less resistant worms in the MOX treated groups, but selection type had no effect. Analysis of variance of arcsine-transformed proportions of resistant worms found that the type of anthelmintic had a highly significant effect, with MOX treated adults having a higher proportion of resistant worms, while type of selection was not significant. In the lambs, nil treated controls and IVM Head + Tail and Tail selected groups had similar geometric mean total worm burdens while Head selected had less total worms. In the MOX treated lamb groups the worm burdens were similar within selection type but less than the IVM treated groups. In the lambs, the types of selection that resulted in more resistant worms were IVM Tail, MOX Head + Tail and MOX Tail. Resistant worm numbers were similar in both adult and lamb groups with Head selection by either MOX or IVM. Moxidectin selected out higher proportions of resistant worms than did IVM in the lambs, with Tail and Head + Tail being stronger selectors than Head. Computer simulations were used to estimate the rate at which resistance developed in the field using the information generated in the present study. The anthelmintic treatments used in the simulation followed a strategic parasite control program for H. contortus in which all sheep receive three Closantel (CLS) treatments in summer. all sheep receive a broad-spectrum (BS) drench or capsule at weaning and lambs receive an additional two BS drenches insummer or no further treatment in the case of the capsule. Moxidectin, IVM-capsule and IVM were the broad spectrum anthelmintics simulated. All simulations were run four times assuming high or low efficacy against resident resistant worms and in the presence or absence of CLS resistance. The simulations indicated that the presence of CLS resistance hastened selection for macrocyclic lactone (ML) resistance. While the IVM-capsule will select most rapidly for ML resistance, IVM oral is expected to be least selective. Moxidectin treatment is intermediate, except in simulations with no CLS resistance and when MOX is assumed to be highly effective against resident ML-resistant worms, in which case MOX can be expected to select more slowly than IVM oral treatments.

A comparison of in vitro tests and a faecal egg count reduction test in detecting anthelmintic resistance in horse strongyles.

This study reports a comparison between faecal egg count reduction test (FECRT), egg hatch assay (EHA) and larval development assay (LDA) for detecting anthelmintic resistance in equine strongyles. Resistance to benzimidazoles was demonstrated in 33 of 42 (79%) farms tested by FECRT and in 32 (62%) of the 52 farms tested by EHA. As the reference strain used was not fully susceptible to benzimidazoles it was not possible to determine the level of resistance by LDA. Pyrantel resistance was indicated on three of 15 farms by faecal egg count reduction. Resistance was also indicated by LDA for one of these farms. In addition resistance was indicated by LDA on two more farms that were not tested by FECRT. Further testing is needed to confirm if these findings are truly indicative of resistance. Generally, correlations between the tests were poor and it was not possible to use the outcome of one test to predict the outcome of another.

A new technic for counting Schistosoma japonicum eggs in pig feces.

An improved laboratory method was developed for counting Schistosoma japonicum eggs in pig feces, which involves filtration, sedimentation and centrifugation, but avoids toxic chemicals. It is sensitive, allows easy differentiation from similar-sized and shaped protozoan cysts, and permits evaluation of egg viability both by direct viewing of eggs and miracidial hatching. It was found to be significantly better at recovering eggs than the modified Bell filtration technic. The sensitivity, specificity and practicality of this technic make it our method of choice for studies on porcine schistosomiasis japonica.

The potential of nematophagous fungi to control the free-living stages of nematode parasites of sheep: pasture plot study with Duddingtonia flagrans.

The potential of nematophagous fungi to control the free-living stages of nematode parasites of sheep: Pasture plot study with the fungus Duddingtonia flagrans. Vet. Parasitol. The experiment was designed to test the ability of D. flagrans to reduce infective larval populations on pasture after passage through the gastrointestinal tract of sheep. Merino sheep were given chlamydospores by intra-ruminal infusion at a rate of 5 million chlamydospores/sheep/day and faeces collected from these sheep was deposited on pasture plots. Numbers of larvae recovered from faeces and pasture were both lower on plots from sheep dosed with fungus (P < 0.001 and P < 0.01, respectively) than on plots from control sheep.

Experimental Oesophagostomum dentatum infections in the pig: worm populations at regular intervals during trickle infections with three dose levels of larvae.

A trickle infection experiment was undertaken to study in detail the population dynamics of Oesophagostomum dentatum in pigs. Three groups of 32 pigs were inoculated via the feed twice weekly with 100 (Group A), 1000 (Group B) or 10,000 (Group C) O. dentatum infective larvae (L3). Five pigs from each group were killed 2, 4, 8, 12, 16, and 20 weeks after the first inoculation (p.i.) to determine their worm burdens. Weekly faecal egg counts were determined. At slaughter, worms were counted, differentiated according to sex and developmental stage, and their length measured. Faecal egg counts ranked with dose rate until week 15, but later were more variable. The proportion of the total number of L3 administered which were recovered at slaughter inversely ranked with dose rate. In group C it decreased over time, whereas in groups A and B there was no consistent pattern. Worm fecundities (epg/female) in groups A and B were higher than in group C. The lengths of the female worms increased over time, whereas the lengths of the male worms remained approximately constant from week 8. The study suggests reduced establishment of incoming larvae and lower fecundity of the female worms at high dose levels.

The effect of concurrent or sequential Oesophagostomum dentatum and O. quadrispinulatum infections on the worm burdens of the two species in pigs.

The interaction between the 2 nodular worm species in the pig, Oesophagostomum dentatum (O.d.) and Oesophagostomum quadrispinulatum (O.q.), was studied by comparing the development and distribution of the species following single or mixed infections. The faecal egg excretion levels were assessed at regular intervals from week 3 post-inoculation, and indicated a strong negative impact of the introduction of O.q. on the continued egg excretion of O.d. All pigs were killed 9 weeks after the first inoculations to determine the composition and location of the worm burdens in the large intestine. O.q. was found more anteriorly located in the intestine than O.d., thus confirming previous descriptions. When both species were present, the distribution of O.d. was moved further posteriorly and was more spread out than in single-species infections. There appeared to be no adverse effect of O.d. on the establishment and fecundity of O.q. However, the worm recoveries corroborated the egg excretion observations, namely reduced worm burdens of O.d. if O.q. was introduced, or if O.q. was already present. It is uncertain whether this effect is caused by differences in host reaction against the two species, or whether a more specific competition occurs between the two nodular worm species in pigs.

Faecal egg count reduction percentage calculations to detect anthelmintic resistance in Oesophagostomum spp. in pigs.

The results of four alternative methods of mean faecal egg count reduction percentage (FECR%) calculations were evaluated and compared using data obtained for Oesophagostomum spp. from ten sow herds. The estimates of FECR% and 95% confidence limits obtained using the four methods were different. However, there were few discrepancies in the final decision as to whether a given herd carried drug resistant isolates or not. The methods that used geometric means were more appropriate than those that used the arithmetic mean as the measure of central tendency for eggs per gram of faeces (EPG) values. The use of geometric mean EPG values in calculations has been criticized from several viewpoints, one of which is that its use reduces the comparability of reports between laboratories. If the geometric mean is to be used as we suggest in FECR% calculations, the appropriate references, number of animals in each group, minimum and maximum EPG values and the factor added to zero EPG counts should be reported in order to improve the comparability. The difficulty in obtaining groups with similar pre-treatment EPG values in field situations suggested the inclusion of pre-treatment EPG values in the calculations as an adjustment procedure. The importance of including a non-treated control group in calculations was demonstrated during this study. Therefore, we suggest the use of geometric mean EPG values, to include pre-treatment EPG values and to include the egg counts from the control group in FECR% calculations. The interpretation of the resulting FECR estimate may be different according to the purpose for which the testing procedure is carried out, e.g. survey in detecting anthelmintic resistance, control field tests, etc.