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.

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.

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.

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.

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.

Population dynamics of the parasitic stages of Oesophagostomum dentatum in pigs in single and trickle infections.

A mathematical model was developed to describe the dynamics of the parasitic stages of Oesophagostomum dentatum in pigs. An immigration-death model with constant establishment, development and death rates was fitted to L3, L4 and adult worm burdens observed in a single-infection experiment. Female worm length was modelled by a function of worm age and total worm burden, while worm egg production (eggs per gram faeces per female worm) was modelled by a function of worm age and worm length. The model was then used to predict worm burdens observed in a trickle-infection experiment. The predicted worm burdens were much higher than those observed, suggesting that worm death rates were higher during the trickle infection. After increasing worm death rates to fit the observed worm burdens, female worm lengths and egg production in the trickle infection were predicted. At the medium- and high-dose rates, predicted worm lengths and, thus, egg production were lower than observed, while at the low-dose rate predicted egg production was too high. It appeared that in the trickle infections, total worm burden had less influence on observed female worm length and egg production than in the single infections. The results suggest that the demography of O. dentatum in pigs differs between single and trickle infections.

Population dynamics of Trichostrongylus colubriformis in sheep: mathematical model of worm fecundity.

A mathematical model was constructed to predict the egg production of Trichostrongylus colubriformis worms as a function of worm age and host experience of infection. The model set egg production at zero until the worm was 14 days old, when a linear increase to maximum egg production levels occurred over 7 days. It was assumed that egg production remained at maximum levels until a threshold total worm burden was exceeded, when an exponential decline in egg production occurred. The rate of decline was assumed independent of worm age or worm burden. The estimated parameters (maximum egg production, threshold, lag and rate of decline) were optimized by fitting values predicted from the model to faecal egg counts observed in continuously infected sheep, giving R2 = 0.80. The model was validated against faecal egg counts obtained in two other continuous infection experiments, one performed at the same laboratory and the other in Britain.

Population dynamics of Trichostrongylus colubriformis in sheep: computer model to simulate grazing systems and the evolution of anthelmintic resistance.

A computer model was developed to simulate Trichostrongylus colubriformis populations, their level of resistance to the common anthelmintics, host mortalities and acquired immunity. Predictions were based on sheep management practices such as lambing, weaning, sheep/paddock rotation, anthelmintic treatment, the use of controlled release devices (capsules) for anthelmintic delivery and daily meteorological records to determine the development and survival of infective larvae (L3) on pasture. Evolution of drug resistance was determined by a simple genetic system which allowed for up to three genes, each with two alleles, to give a maximum of 27 genotypes associated with one drug or three genotypes for each of three drugs. The model was validated against egg counts, L3 counts on pasture and host mortalities observed in a grazing trial, however, aspects of the model such as the development of drug resistance and use of the model in a variety of climatic zones have yet to be tested against field observations. The model was used to examine the impact of grazing management and capsule use on anthelmintic resistance and sheep production over 20 years using historical weather data. Predictions indicated that grazing management can play a dominant role in parasite control and that capsule use will reduce sheep mortalities and production losses, and in some circumstances will not cause a substantial increase in anthelmintic resistance for up to 5 years.

Interaction between Ostertagia circumcincta and Haemonchus contortus infection in young lambs.

Twenty-one-week-old, worm-free, pen-reared lambs were infected with either 6000 O. circumcincta L3 per week, or 3000 H. contortus L3 per week, or both (9000 L3 per week). Egg counts were monitored throughout the experiment, and worm burdens and larval establishment rates of both worm species were estimated after 4, 7, 10 and 13 weeks of infection. After 10-13 weeks of infection with H. contortus only, establishment of O. circumcincta was lower than in previously uninfected controls, demonstrating that a high level of immunity to H. contortus affords some cross-protection against O. circumcincta. Total H. contortus worm burdens and egg counts (about 2000 worms and 3000 e.p.g., respectively) in sheep infected with both worm species were less than half those observed in sheep infected with H. contortus alone (about 5000 worms and 10,000 e.p.g., respectively). Cross-protection between the two species was observed, but was probably less important than the reduction in H. contortus establishment that was caused by O. circumcincta disrupting abomasal physiology.

Persistence of acquired immunity to Trichostrongylus colubriformis in sheep after termination of infection.

Lambs were infected with 6000 Trichostrongylus colubriformis L3 per week for 18, 12 or 6 weeks, beginning at ages 14, 20 and 26 weeks, respectively. At the end of the primary infection subgroups had geometric mean adult worm burdens of 5000, 15,000 and 18,000, respectively. In the remaining sheep the worm population was removed with anthelmintic, and sheep had no further larval intake until challenged with T. colubriformis 1, 6, 12, 18 or 24 weeks later. In the groups given 18 or 12 weeks primary infection, establishment of challenge doses was low (less than 25% of establishment in helminth naive controls) in most animals at all challenge times. However, for the groups given 6 weeks primary infection, establishment was low only at the first two challenge times. Thereafter it had similar mean to control groups, but much greater variance. Other subgroups were challenged with T. colubriformis, Ostertagia circumcincta and Haemonchus contortus 1 week after worm removal. In these animals T. colubriformis establishment was not different to animals challenged at the same time with T. colubriformis alone, however immunity to T. colubriformis afforded little protection against the other species. The results of this experiment were incorporated into a simulation model of the population dynamics of T. colubriformis.

Population dynamics of Trichostrongylus colubriformis and Ostertagia circumcincta in single and concurrent infections.

Twenty-one-week-old worm-free pen-reared lambs were infected weekly with either 10,000 T. colubriformis larvae, 5000 O. circumcincta larvae, or with both species (15,000 larvae per week). Larval establishment and total worm burdens were estimated after 4, 7, 10 and 13 weeks of infection. Faecal egg counts and lamb bodyweights were measured weekly, and numbers of eosinophils in blood were estimated before infection and at weeks 5, 8 and 14. For both species of worms, the dynamics of infection (establishment, worm burdens, egg counts) were not affected by concurrent or pre-existing infection with the other species. Infection with T. colubriformis alone did not protect against O. circumcincta, but infection with O. circumcincta alone provided slight protection against the T. colubriformis larvae. Blood eosinophils increased between 5 and 8 weeks of infection and were similar for the three infections. This corresponded to the reduction in establishment for both species.

Population dynamics of Trichostrongylus colubriformis in sheep: model to predict the worm population over time as a function of infection rate and host age.

The developing immunity of sheep to Trichostrongylus colubriformis infections was described by a mathematical function. The rate of adult establishment was assumed to be a measure of the host's acquired immunity to this parasite. Prediction of establishment from infection rate and host age was used to estimate worm burden, worm rejection and arrested development.

The survival of Ostertagia circumcincta and Trichostrongylus colubriformis in faecal culture as a source of bias in apportioning egg counts to worm species.

When cultured alone or concurrently with Trichostrongylus colubriformis in sheep faeces, Ostertagia circumcincta produced fewer infective larvae per 100 eggs than did T. colubriformis. Averaged over five trials 60% of T. colubriformis eggs were recovered as infective larvae while for O. circumcincta the figure was only 39%. This result was observed for two strains of O. circumcincta and was independent of when larvae were harvested from culture (days 6-10 at 25 degrees C). The mortalities of both species occurred at the first and second larval stages. These observations are of concern when using larval differentiation from faecal culture to make quantitative estimates of worm egg numbers for each species present. Species such as T. colubriformis which have a low mortality during culture are likely to have their egg numbers overestimated when cultured with a species, like O. circumcincta, that suffers high mortality in culture.

Experimental Oesophagostomum dentatum infections in the pig: worm populations resulting from trickle infections with three dose levels of larvae.

This paper describes the worm populations in pigs experimentally infected by trickle infections with different dose levels of the nodular worm, Oesophagostomum dentatum. Four groups each of 20 helminth naïve pigs, 10-12 weeks old, were inoculated with 0 (group 1), 100 (group 2), 1000 (group 3), or 10,000 (group 4) infective larvae twice weekly, and the pigs were killed after 10-13 weeks. No overt clinical signs were observed, and only group 4 had slightly lower food conversion rate (P < 0.05) than the controls. Faecal egg counts revealed that the nodular worms in pigs of groups 2 and 3 had a short prepatent period (3-4 1/2 weeks) and a fairly stable egg output, while the worms in the pigs of group 4 had prepatent periods of 3-10 weeks and low, unstable egg excretion. The mean worm burdens increased with the dose rate (group 2: 929 worms; group 3: 7467 worms; group 4: 19,847 worms), but detailed analyses of the worm populations from 10 pigs from each of the infected groups revealed a clear dose-dependency in worm recovery, percentage adult worms, worm lengths and female fecundity, as all these measures declined significantly with increasing dose level. The adult worms seemed to be shorter and less fertile when they were located posteriorly to their predilection site, and especially in group 4 many stunted infertile adults measuring only 2-5 mm were found in the posterior half of the colon, but there were no indications of worm expulsion. Superimposed on the main experiment was a cohort study in which 4 pigs of group 3 were given a single dose of 1000 pyrantel resistant larvae at day 56 (all other larvae were pyrantel sensitive), treated with 28 mg pyrantel per kg body weight at day 85 and killed at day 90. Appropriate control groups were included. The mean establishment of the cohort was similar to previously uninfected controls, but between-animal variation was much higher in the trickle infected group.

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.

Experimental Oesophagostomum dentatum infection in the pig: worm populations resulting from single infections with three doses of larvae.

This report describes the effect of different dose levels of infection upon worm burdens and development and fecundity of the parasites. Three groups each of 40, 9-week-old, helminth naive pigs were inoculated once with either 2000 (group A), 20,000 (group B), or 200,000 (group C) infective third stage larvae of Oesophagostomum dentatum. Subgroups of 5 pigs from each major group were killed 3, 6, 11, 14, 18, 25, 34 and 47 days post inoculation (p.i.) and the large intestinal worm burdens were determined. Faecal egg counts were determined at frequent intervals after day 13 p.i. There were no overt clinical signs of gastrointestinal helminthosis during the experiment. Faecal egg counts became positive in groups A and B at around day 19 p.i., whereas most pigs in the high dose group C did not have positive egg counts until day 27-33 p.i. and some pigs remained with zero egg counts until the end of the study. Throughout the experiment the worm populations in group C consisted mainly of immature larval stages, while those in groups A and B were predominantly adult stages after days 14-18. Adult worms from the low dose group A were significantly longer than those from group C. At high population densities, stunted development of worms and reduced fecundity among female worms were found. Furthermore, there was a tendency for the distribution of the worms within the intestine to be altered with increasing population size.

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.