Veterinary Parasitology 216 (2016) 72–83

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Veterinary Parasitology
journal homepage: www.elsevier.com/locate/vetpar

Research paper

Liver fluke control on sheep farms in Northern Ireland: A survey of

changing management practices in relation to disease prevalence and
perceived triclabendazole resistance
C. McMahon a , H.W.J. Edgar b , R.E.B. Hanna b , S.E. Ellison a , A.M. Flanagan a , M. McCoy c ,
P.-E. Kajugu b , A.W. Gordon d , D. Irwin e , J.E. Barley b , F.E. Malone b , G.P. Brennan a ,
I. Fairweather a,∗
a
Parasite Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen’s University of Belfast, 97 Lisburn Road, Belfast BT9
7BL, United Kingdom
b
Veterinary Sciences Division, Agri-Food and Biosciences Institute (AFBI) Stormont, Belfast BT4 3SD, United Kingdom
c
Department of Agriculture and Rural Development, Dundonald House, Upper Newtownards Road, Belfast BT4 3SB, United Kingdom
d
Biometrics Division, Agri-Food and Biosciences Institute (AFBI), Newforge Lane, Belfast BT9 5PX, United Kingdom
e
Agriculture Branch, Agri-Food and Environmental Science Division, Agri-Food and Biosciences Institute (AFBI), Hillsborough BT26 6DR, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Reports of resistance to triclabendazole (TCBZ) among fluke populations have increased in recent years.
Received 19 October 2015 Allied to this, there has been a rise in the prevalence of the disease, which has been linked to climate
Received in revised form change. Results from questionnaire surveys conducted in Northern Ireland (NI) in 2005 (covering the
25 November 2015
years 1999–2004) and 2011 (covering the years 2008–2011) have provided an opportunity to examine
Accepted 30 November 2015
the extent to which fluke control practices have changed over a prolonged time-frame, in light of these
changes.
Keywords:
A number of differences were highlighted. There was a significant shift away from the use of TCBZ over
Fasciola hepatica
Liver fluke
time, with it being replaced largely by closantel. The timing of treatments had moved earlier in the year,
Northern Ireland perhaps in response to climate change (and an altered pattern of disease). In relation to the frequency of
Questionnaire drug treatments, there were no major changes in the overall pattern of drug treatments between the two
Survey survey points, although on both occasions approximately one-third of flock owners gave more than 3
Faecal egg count reduction test treatments per year to ewes. In lowland areas in 2011, flock owners were rotating drug classes more often
Coproantigen ELISA reduction test (each year and at each treatment) than in 2005, whereas in upland areas, flock owners were rotating less
often and more were not rotating at all. Between 2005 and 2011, the percentage of flock owners giving
quarantine treatments to bought-in stock had halved, to a very low level (approximately 10%).
Using data from a complementary TCBZ resistance survey (Hanna et al., 2015), it has been shown that
the way in which data are selected and which efficacy formula is applied can influence the calculation of
drug efficiency and impact on diagnosis of resistance.
© 2015 Elsevier B.V. All rights reserved.

1. Introduction
Successful control of fasciolosis is confronted by two major chal-
lenges: an increased incidence of the disease and the spread of
resistance to triclabendazole (TCBZ), the drug most active against
acute and chronic fluke infections. The upsurge in incidence has
been attributed to the effect of climate change, which has favoured
the snail intermediate host, and long-range forecasts have sug-
∗ Corresponding author. Fax: +44 28 90975877.
E-mail address: i.fairweather@qub.ac.uk (I. Fairweather).
gested that this trend will become more pronounced (Fox et al.,
2011). TCBZ resistance has emerged in several areas of the World
and, again, the situation is likely to become more serious in the
future. Allied to this is the problem of accurate diagnosis of resis-
tance, so that genuine cases can be separated from reports that
are simply cases of “treatment failure”, for whatever reason. For a
more detailed discussion of these topics, the reader is referred to
the reviews by Fairweather (2011a,b).
Of crucial significance to fluke control are the management
strategies put in place by farmers; also, how well the farmers per-
ceive the issues described above and how they are responding to
them. Farmers are able to source and obtain advice from veter-

http://dx.doi.org/10.1016/j.vetpar.2015.11.018
0304-4017/© 2015 Elsevier B.V. All rights reserved.
 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83
inarians, the agricultural press, farm advisors, suitably qualified
personnel (SQP), other farmers, government agencies and drug
company representatives, for example. However, few large-scale
surveys have been carried out to determine farmers’ attitudes and
control practices. Of those that have, more surveys have been con-
cerned with dairy cattle (eg Mezo et al., 2008; Bloemhoff et al.,
2014; Selemetas et al., 2015) than sheep (e.g. Morgan et al., 2012;
Rojo-Vazquez and Hosking, 2013) and not all were restricted to
fluke. This communication presents information derived from two
Questionnaire surveys in Northern Ireland (NI), conducted in 2005
and 2011. They were designed to gather data on control and sheep
management practices in relation to fasciolosis and how the latter
may have contributed to the levels of resistance described in a sep-
arate study (Hanna et al., 2015). Particular attention was given to
the pattern of anthelmintic use, the timing and frequency of treat-
ments, drug rotation and quarantine strategy. The Questionnaires
covered a time-span of more than a decade and so provide a good
view of changing practices over a relatively prolonged period of
time.
This paper also extends the analysis of data stemming from a
field survey of TCBZ resistance in NI carried out in 2011 and pub-
lished by Hanna et al. (2015). Data taken from that survey has been
used to test how the calculation of reductions in faecal egg count
(FEC) and coproantigen levels can be affected by the selection of
data and efficacy formulae applied. The results of the 2011 survey
will be compared with those of a similar field survey carried out in
2008. The combined field efficacy and Questionnaire data should
give a good overall view of fluke control in the Province. The data
on fluke will complement that of nematode control in NI published
previously (McMahon et al., 2013a,b,c).
2. Materials and methods
2.1. TCBZ field resistance surveys
2.1.1. Field survey
The survey was carried out on 13 sheep farms, designated A–M.
For details of experimental design and FEC and coproantigen ELISA
methodology, see Hanna et al. (2015).
2.1.2. Field survey
The protocol as described for sampling in 2011 was based on a
similar survey conducted in 2008 on 12 of the aforementioned hold-
ings (Flanagan, 2010; Chapter 5). Raw data were obtained from the
author and analysed using the approach described in the next sec-
tion (Section 2.2). The inclusion of these data is intended to provide
a comparison of efficacy results between different time points.
2.2. Statistical analysis of field survey data
Initial analysis of the FEC and coproantigen ELISA data was car-
ried out as described by Hanna et al. (2015).
A second analysis was performed to examine the effect of dif-
ferent formulae on calculating treatment efficacy and anthelmintic
resistance. As per WAAVP guidelines (although developed for gas-
trointestinal nematodes and not fluke specifically), anthelmintic
resistance was declared when the calculated treatment efficacy
was <90% (Coles et al., 2006). Reductions in FECs and coproantigen
levels were calculated using Microsoft Excel. Percentage reduc-
tion was based either: on the formula of Kohapakdee et al.
(1995), where percentage reduction = [(T1 − T2)/T1] × 100, where
T1 is the arithmetic mean FEC pre-treatment and T2 is the
arithmetic mean FEC post-treatment (pt) for a group of treated
animals (referred to subsequently as FECRT1); or on the iFE-
CRT3 formula of Cabaret and Berrag (2004), where percentage
reduction = (1/n)(100 × (1 − [Ti2/Ti1])), where Ti2 is pt and Ti1 is
73
pre-treatment eggs per gram (epg) of faeces in host I from a total of n
hosts. Each host serves as its own control. Referred to subsequently
as FECRT2, it is the individual animal counterpart of FECRT1.
Using the available data, 3 datasets were constructed. They rep-
resented different combinations of FEC and coproantigen ELISA
data and were used to assess their bearing on the calculation of
drug efficacy. The datasets were:
Dataset 1. Pre- and post-treatment epg averages, calculated
using all 20 (or total number of collected) faeces samples;
Dataset 2. The pre-treatment epg average, calculated using only
the values generated from sheep with a current infection (i.e. pos-
itive by coproantigen ELISA). The pt average was calculated using
all 20 (or total number of collected) faeces samples; and
Dataset 3. Pre- and post-treatment epg averages, calculated
using only the values generated from sheep with a current infection.
2.3. Questionnaire surveys
2.3.1. Questionnaire
The questionnaire contained 42 questions, which covered con-
trol of gastrointestinal nematodes, liver fluke and ectoparasites.
The analysis of the nematode control data has been published by
McMahon et al. (2013a,b).
In relation to fluke, questions referred to product use over a
5-year period (2000–2004), the timing and frequency of treat-
ment, product rotation, quarantine treatments and perception of
the prevalence of resistance. The survey was conducted by personal
interview, with 81 farmers.
For further details of the survey, see McMahon et al. (2013a,b).
2.3.2. Questionnaire
The questionnaire comprised 51 questions, organised into
three main sections, namely, parasite control practices (Section
1, McMahon et al., 2013a), farm management (sheep) (Section 2,
McMahon et al., 2013a,b) and farm management (cattle) (Section 3,
nematode control, McMahon, 2015 Thesis). Questions included the
same topics as listed for the 2005 edition, but covering the period
2008–2011.
Between May and September, 2011, the questionnaire was sent
to 1,000 farmers, amongst whom were sheep-only farmers, cattle-
only farmers and mixed sheep and cattle farmers. There were 305
returns, of which 252 were relevant to sheep.
For further details of the survey, see McMahon et al. (2013a,b).
2.4. Recorded cases of acute fluke
2.4.1. Diagnoses of acute fasciolosis, post-mortem findings (Great
Britain)
Since 1975, the Veterinary Investigation Diagnosis Analysis
Database (VIDA) has documented the findings from every sub-
mission made to regional laboratories of the Animal Health and
Veterinary Laboratories Agency and Scottish Agricultural College
Disease Surveillance Centre (www.gov.uk/government/statistics/
veterinary-investigation-diagnostic-analysis-vida-reports). The
aggregate data of these 23 centres provide a useful indication of
the level of disease reported across England, Scotland and Wales.
2.4.2. Diagnoses of acute fasciolosis, post-mortem findings
(Northern Ireland)
Similar data are recorded for NI in the 2 diagnostic centres:
AFBI Omagh (west of the Province) and AFBI Stormont (east of
the Province). Information was retrieved from the AFBI Pathology
Database and was limited to diagnoses of acute fluke between 2000
and 2014. The limitation to acute fluke enabled direct comparison
of recorded cases in NI and GB. The data were filtered to remove
carcasses or viscera received from independent researchers, other
74 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83

research institutes, pharmaceutical companies and “in-house” ani- Table 1

Faecal egg count reduction test (FECRT) values of TCBZ treatment on Farms A–E using
mals on VSD premises. Results were limited to flocks held in NI.
the constructed datasets and described formulae (2011 field resistance survey data).
The recorded numbers of cases per year in the VIDA database
were compared graphically with the recorded numbers of cases Farm A Farm B Farm C Farm D Farm E
per year in the AFBI Laboratory Information Management System 2011 survey
(LIMS) database n-Pre 19 20 20 20 20
n-Post 18 18 16 13 18
Dataset 1 FECRT1 76.3 0.0 8.6 0.0 37.7
2.5. Literature search for reports of “triclabendazole resistance” FECRT2 0.0 4.1 0.0 0.0 33.7
Dataset 2 FECRT1 80.9 0.0 0.0 0.0 37.7
Using “triclabendazole resistance” as the initial search term, FECRT2 8.8 0.0 0.0 0.0 33.7
Dataset 3 FECRT1 80.3 0.0 0.0 0.0 31.9
the ISI Web of Science database was searched: the database
FECRT2 14.4 0.0 0.0 0.0 43.4
returned publications detailing studies in ruminants (sheep and
cattle) and in humans. Publications were selected that dealt with 2008 survey
n-Pre 15 15 – 12 –
both experimental infections and/or natural infection. One hun-
n-Post 14 12 – 9 –
dred and sixty-two papers were identified; removing publications Dataset 1 FECRT1 84.2 100 – 34.4 –
which related to human fasciolosis (6 papers), or other verte- FECRT2 80.5 100 – 20.5 –
brate infection with different trematode species [Fasciola gigantica Dataset 2 FECRT1 82.4 100 – 34.4 –
FECRT2 86.2 100 – 20.5 –
(10), Schistosoma mansoni (2), Clonorchis sinensis (1) and Parago-
Dataset 3 FECRT1 94.1 100 – 37.2 –
nimus westermani (4)] left 138 database entries. These remaining FECRT2 86.2 100 – 53.4 –
entries were classified as belonging to one of the following cate-
Note: FECRT1 = method as described by Kohapakdee et al. (1995); FECRT2 = method
gories: diagnosis of infection (3), review article (27), histological
as described by Cabaret and Berrag (2004); n-Pre = number of animals included
or morphological investigation (85) or diagnosis of resistance (23). in pre-treatment mean calculations; n-Post = number of animals included in post-
Considering only the diagnosis of resistance publications, abstracts treatment mean calculations.
were mined for experimental methodology behind the diagnosis of
resistance and the number of holdings investigated. The results of
On 3 of the 12 farms visited in 2008, all of which were in low-
this search are discussed in Section 4.3.
land areas, there was sufficient evidence of liver fluke infection
(eggs in faeces) in pre-treatment samples to warrant the collec-
3. Results tion of pt samples. In the remaining 9 flocks, no further analyses
were conducted. Coproantigen ELISA testing was conducted on the
3.1. General 3 holdings where fluke infection was evident, but no optical density
(OD) data remain available, and the status of infection was recorded
Results are presented in 4 Sections: the TCBZ field resistance as either positive or negative.
surveys; the impact of calculation formula on drug efficacy eval- As (mostly) the same holdings were visited in both surveys, the
uation; analysis of the questionnaire surveys; and a comparison designation of each holding is conserved, i.e. farm A from 2008 is
between the number of cases of fasciolosis recorded in NI and the the same premises as farm A from 2011.
rest of the UK.
3.2.3.1. Faecal egg count reduction testing (FECRT). Considerable
3.2. TCBZ field resistance surveys variation was observed between holdings and between animals
on each holding, which reflects the over-dispersed nature of nat-
3.2.1. Field survey ural fluke infections. TCBZ resistance, or TCBZ treatment failure,
The results of the survey have been published elsewhere (Hanna is defined as less than a 90% reduction in FEC (Brockwell et al.,
et al., 2015). Briefly, the FECRT data revealed evidence for substan- 2014). Substantial levels of resistance were found in 4/5 (farms B–E)
tial TCBZ resistance on 5 of the 13 farms studied (farms A–E). Each properties in 2011 (Table 1), an increase over the (1/3, Farm D) lev-
of these 5 farms had a high level of fluke infection (determined els seen in 2008, with another (farm A) holding falling below the
by pre-treatment FECs) in comparison to the remaining 8 farms. 90% threshold in 2011 (Table 1). Both efficacy calculation meth-
This result was supported by those of the coproantigen reduction ods detected resistance using the group data, but the percentage
test (CRT) and fluke histology. Nitroxynil (NIT) and closantel (CLOS) reductions varied: FECRT2 generally indicated higher levels of TCBZ
were fully effective against the fluke populations in these flocks resistance than FECRT1.
(Hanna et al., 2015). Calculation of treatment efficacy in the individual animal
(Table 2), rather than the efficacy per group of animals, revealed
3.2.2. Field survey considerable variation. Typically, when an efficacy of 100% was
TCBZ resistance was diagnosed by both FECRT and CRT on farm observed, pre-treatment FEC values were low and, in many
D only, amongst the 12 farms studied (Flanagan, 2010). instances, egg counts rose between sample points, resulting in
“negative” efficacy values (recorded as 0.0 in Table 2). The fact that
3.2.3. Analysis of the effect of calculation formula on the level of a greater number of animals could be included in the latter (2011)
resistance declared survey than the initial (2008) survey (Table 3) may be indicative
On 5 of the 13 farms studied in 2011 (farms A–E), all of which of a greater incidence of fluke at pasture, although that cannot be
managed animals in lowland areas, the pre-dose F. hepatica FEC explicitly determined from the available data. Where calculated,
values indicated that a significant level of chronic fluke infection treatment efficacy in the individual animal was higher in 2008
was present in the flocks. On the remaining farms in the study, (Table 3) than in 2011 (Table 2).
the pre-dose F. hepatica FECs were too low to allow meaningful
comparison of pre-treatment and pt faeces samples and, in these 3.2.3.2. Coproantigen reduction testing. As stated previously, OD
cases, post-dose coproantigen ELISA testing was not carried out. values were not available for the survey data of 2008 and so the
The remaining results in this section will be limited to flocks A–E following is limited to the 2011 data. TCBZ resistance, or TCBZ
for the 2011 data. treatment failure, is defined as less than a 90% reduction in CRT
 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83 75

Table 2 3.3.1.1. Survey. Over the period 1999–2004, TCBZ was consistently
Efficacy of TCBZ treatment in the individual sheep calculated using the formula of
the most frequently selected anthelmintic (>60%) (Fig. 1A). The
Kohapakdee et al. (1995). Values were calculated for each animal sampled on both
day 0 and day 21 for field resistance survey data in 2011. relative contribution of CLOS to treat fasciolosis, both as a sin-
gle active and in combination, increased over the 5-year period.
Animal Farm A Farm B Farm C Farm D Farm E
This was balanced by a decreased contribution of NIT, which fell
1 25.0 P 38.9 P 0.0 0.0 P 18.1 P from approximately 15% to 8% over the course of the survey. Oxy-
2 0.0 P 0 0.0 P 0.0 57.3 P clozanide (OXY) and albendazole (ALB) comprised less than 5% of
3 0.0 P 88.9 57.9 P 0.0 P 28.8 P
all treatments given.
4 45.5 P 0P 100 72.9 P 0.0 P
5 0.0 P 0 54.1 P 19.6 P 39.7 P
6 0.0 P 100.0 0.0 P 0.0 P 0.0 3.3.1.2. Survey. In contrast to the initial survey period, CLOS was
7 0.0 P 50 0.0 P 0.0 P 19.0 the dominant anthelmintic used in the control of fluke during
8 1.2 P 0 3.1 P 0.0 P 61.8 P
2008–2011 (Fig. 1B). Approximately 50% of all treatments given
9 0.0 P 100.0 0.0 P 0.0 P 0.0
10 0.0 P 0 66.7 P 0.0 P 24.4 P comprised CLOS, with a more pronounced contribution of combi-
11 29.7 P 0 100 0.0 P 61.3 P nation products to this total (12.2–19.0%) than in the 1999–2004
12 52.8 P 0.0 P 0.0 P 67.0 P survey. Use of TCBZ decreased each successive year through
13 38.8 P 0.0 P 0.0 P 44.9 P 2008–2011. As before, products containing NIT were the third most
14 0.0 P 17.5 P 51.0 P
commonly identified anthelmintic used. ALB made a greater con-
15 62.5 P 20.0 P 74.7 P
16 100.0 45.4 P tribution to total anthelmintic use in this period, but remained
17 100.0 57.2 P below 5% of all treatments given. The increased use of OXY between
18 0.0 2010 and 2011 may reflect an increased awareness of rumen fluke,
Note: P = positive by coproantigen ELISA on day 21 post-treatment. although that cannot be explicitly determined from the available
data.
Table 3
Efficacy of TCBZ treatment in the individual sheep calculated using the formula of 3.3.2. Timing of treatment
Kohapakdee et al. (1995). Values were calculated for each animal sampled on both There exists a generally recognised seasonal pattern of liver
day 0 and day 21 for field resistance survey data in 2008. fluke infection (Fig. 2A) over the grazing season (Abbott et al.,
Animal Farm A Farm B Farm C Farm D Farm E 2012; AFBI, 2012). Similarly, the recognised months of highest
risk for liver fluke infection are January, February, September and
1 100 100 – 11.6 P –
2 92.9 P 100 – 58.1 P – October; the medium risk months are March, April, November
3 0 100 – 83.4 P – and December; and the months of lowest risk of fasciolosis are
4 0 100 – 0 – May–August.
5 100 – 64.7 P – Generally speaking, treatments appeared to be given largely to
6 – 100 –
7 – 0P –
combat acute and sub-acute phases of infection, with less empha-
8 – 100 – sis placed on chronic infections (Fig. 2B–E). When the patterns are
9 – 0P – examined, treatment timing generally appeared to be moving ear-
10 – 0 – lier in the year and the marked decrease in December treatments
Note: P = positive by coproantigen ELISA on day 21 post-treatment. has split the “treatment window” of August to February seen in
2005 (Fig. 2B and D) into two smaller windows of July to November
Table 4
and January to February, as seen in 2011 (Fig. 2C and E).
Coproantigen reduction test (CRT) values of TCBZ treatment on Farms A–E using the
constructed datasets and described formulae (2011 field resistance survey data). 3.3.3. Treatment frequency
Farm A Farm B Farm C Farm D Farm E
3.3.3.1. Ewes. The percentage of flock owners giving no treatments
for fluke infections in ewes grazing exclusively lowland areas
n-Pre 18 20 14 14 15
remained roughly constant between survey points (<17.0%, Fig. 3A).
n-Post 17 15 14 12 12
Dataset 1 CRT1 0.0 58.2 41.1 0.0 27.1 The percentages of flock owners giving 1 or 3 treatments per year
CRT2 0.0 0.0 35.9 8.1 40.5 increased (by 7.9% and 1.8%, respectively), while the percentages of
Dataset 2 CRT1 0.0 89.8 44.9 0.0 27.1 flock owners treating 2 or 4 times per year fell between 2005 and
CRT2 0.0 18.9 16.1 0.0 40.5 2011 (by 7.9% and 2.1%, respectively).
Dataset 3 CRT1 0.0 67.2 31.3 0.0 14.1
CRT2 0.0 3.8 5.5 0.0 18.6
The percentage of flock owners giving no treatments for fluke
infections in ewes grazing exclusively upland areas increased by
Note: CRT1 = method as described by Kohapakdee et al. (1995); CRT2 = method as
18.7% (from 0%) between 2005 and 2011 (Fig. 3B). Small increases
described by Cabaret and Berrag (2004); n-Pre = number of animals included in
pre-treatment mean calculations; n-Post = number of animals included in post- in frequency were also observed for 1 treatment and 4 treatments
treatment mean calculations. per year (of 2.5% and 1.2%, respectively), while treating 2 or 3 times
per year was seen less commonly in the results of the second ques-
tionnaire (7.9% and 14.5% less, respectively).
(Brockwell et al., 2014). There was good agreement between FECRT
In flocks grazed on both lowland and upland pastures, there was
(Table 1) and CRT data (Table 4), in that resistance was found across
a small increase (of 4.3%) in the percentage of flock owners who
all 5 holdings. In general, FECRT2 again indicated a greater level of
gave no treatments per year (Fig. 3C). Small increases in frequency
resistance in the holdings than FECRT1.
were also seen for 2, 3 and 4 treatments per year (of 2.8%, 4.3%
and 8.7%, respectively), while a lower percentage (20.1% less) of
3.3. Analysis of the questionnaire survey results flock owners treated their ewes once per year between the two
time-points.
The analysis is based on 252 returns from the 2011 survey and The data can be viewed in a different way, by considering the
81 returns from the 2005 survey. “intensity” of treatment. This parameter was calculated by multi-
plying the percentage by the number of treatments: for example,
3.3.1. Anthelmintic use by active ingredient 41.7% × 2 = 83.4 for treatment of ewes in lowland flocks in 2005.
76 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83

Fig. 1. Anthelmintic use, by active ingredient, over the periods 1999–2004 (A) and 2008–2011 (B).
Alb = albendazole, TCBZ = triclabendazole, TCBZ* = triclabendazole plus broad spectrum anthelmintic, CLOS = closantel, CLOS* = closantel plus broad spectrum anthelmintic,
NIT = nitroxynil, OXY* = oxyclozanide plus levamisole.

Adding the values together showed that the intensity of treatment
did not change much between 2005 and 2011 for ewes in low-
land flocks (183.4 and 172.5, respectively), although there was a
decrease for ewes in upland flocks (from 248.1 to 196.1). For flocks
grazed on both lowland and upland areas, there was an increase
from 164.0 to 197.2 between 2005 and 2011.
3.3.3.2. Lambs. Generally speaking, lambs grazed exclusively in
lowland areas (Fig. 4A), exclusively in upland areas (Fig. 4B), or in
both lowland and upland pastures (Fig. 4C) were treated for fluke
infection less routinely than their adult counterparts.
In lowland areas, there was a lower percentage (6.0% less) of
flock owners who gave no treatments per year between survey
points (Fig. 4B). Increased percentages of flock owners said that
either 1, 3 or 4 treatments were given to lambs per year (15.6%,
1.5% and 1.5%, respectively), while decreased numbers of owners
gave 2 treatments per year (12.7% less).
In upland areas, the percentage of flock owners that gave no
treatments per year was similar at the two survey points (Fig. 4C).
A (12.0%) greater percentage of flock owners treated lambs once per
year in 2011 than in 2005, while the percentage of owners treating
2, 3 or 4 times per year fell by 3.2%, 2.7% and 4.0%, respectively.
For animals that were grazed on both lowland and upland areas,
there was an increase (of 5.1%) in the percentage of flock owners
who gave no treatments per year. There were smaller increases in
those giving 3 or 4 treatments per year (1.4% and 1.6%, respectively).
A decrease was seen in the percentage of flock owners giving 1 or
2 treatments per year (5.5% and 2.6%, respectively) (Fig. 4C).
For lambs, the intensity of treatment was essentially unchanged
between 2005 and 2011 for lowland flocks (66.7 and 67.4) and both
lowland and upland flocks (78.0 and 77.9), but there was a decrease
for lambs in upland flocks (from 121.4 to 102.9).
3.3.4. Product rotation
3.3.4.1. Survey. Flock owners were asked to state the frequency
with which products were rotated (considering active ingredients,
as distinct from product name). Responses to the 2005 question-
naire suggested that no rotation between anthelmintic groups was
practised by 54.3%, 7.1% and 11.2% of lowland, upland and both
lowland and upland flock owners, respectively; that the same active
ingredient would be given for a period of greater than one calen-
dar year by 37.1%, 17.9% and 22.2% of lowland, upland and both
lowland and upland flock owners, respectively; that only 4.3% of
lowland flock owners would rotate anthelmintic class every year;
and, lastly, that changing the anthelmintic used with each succes-
sive treatment was practised by 4.3%, 75.0% and 66.7%, of lowland,
upland and both lowland and upland flock owners, respectively.
 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83 77

Fig. 2. Timing of anthelmintic treatments for fasciolosis by calendar year. Data is shown as the percentages (%) of owners who indicate that they treat their animals in
each month. (A) Seasonality of liver fluke; (B) treatment of ewes 1999–2004; (C) treatment of ewes 2008–2011; (D) Treatment of lambs 1999–2004; (E) treatment of lambs
2008–2011.
78 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83

Fig. 3. Frequency of treatments given to ewes for F. hepatica infection. A = Lowland; B = Upland; C = Both.

Fig. 4. Frequency of treatments given to lambs for F. hepatica infection. A = Lowland; B = Upland; C = Both

3.3.4.2. Survey. Analysis of the responses to the 2011 question-
naire indicated alterations in the product rotation practices of flock
owners, namely, that no rotation between anthelmintic groups
was practised by 42.1%, 32.1% and 44.9% of lowland, upland and
both lowland and upland flock owners, respectively; that the same
active ingredient would be given for a period of greater than one
calendar year by 6.8%, 3.8% and 2.0% by lowland, upland and
both lowland and upland flock owners, respectively; that rota-
tion between anthelmintic groups each calendar year was now a
practice employed by 29.5%, 28.3% and 34.7%, of lowland, upland
and both lowland and upland flock owners respectively; and, lastly,
that changing the anthelmintic used with each successive treat-
ment was practised by 20.5%, 35.8% and 18.4%, of lowland, upland
and both lowland and upland flock owners, respectively.
The data can be evaluated in a different way, by considering
the farmers’ “interest in drug rotation”. This parameter was calcu-
lated by multiplying the percentage for using the same product for
more than 1 year by 1, for rotating each year by 2 and for rotating
with each successive treatment by 3. For example, 4.3% × 2 = 8.6 for
rotating drugs each year by lowland flock owners in 2005. These
values for rotation intensity were then combined to give an esti-
mate of the overall interest in rotating drugs. On this basis, there
was an increase in interest by lowland flock owners (from 58.6
to 127.3) between 2005 and 2011 and there was more intense
rotation on these farms; in contrast, there was a decrease in the
percentage for no rotation (from 54.3% to 42.1%). For upland flock
owners, the percentage for no rotation increased from 7.1% to 32.1%
between 2005 and 2011, but there was a decrease in interest in
rotation (from 242.9 to 167.8). For owners of both lowland and
upland flocks, the percentage for no rotation rose from 11.2% to
44.9% between 2005 and 2011 and there was a decline in interest
for rotation (from 222.3 to 126.6).
A summary of the changes in rotation practices between the 2
surveys is presented in Table 5.
3.3.5. Quarantine
In the 2005 survey, quarantine treatments (that is, treatment of
newly or re-introduced animals) for liver fluke infection were prac-
tised by 31.0%, 25.9% and 6.9% of lowland, upland and both lowland
and upland flock owners, respectively. By 2011, the percentages
had dropped to 15.2% and 13.9% for lowland and upland flock
owners, respectively, while the percentage remained the same for
both lowland and upland flock owners.
3.3.6. Dosing regime
3.3.6.1. Survey. When flock owners were asked which products (in
their opinion) no longer worked as well as they once did, respon-
dents in the 2005 survey indicated that TCBZ (3 lowland, 6 upland),
TCBZ plus levamisole (LV) (1 lowland), CLOS (1 lowland, 1 upland),
mebendazole (MEB) plus CLOS (1 lowland), NIT (1 lowland) and LV
 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83
Table 5
General changes in the product rotation strategies of flock owners between survey
time-points.
Product rotation
Lowland Upland Both
No rotation
Longer than one year
Annual
Successive treatments
plus OXY (1 lowland) were less effective than they had been pre-
viously. It should be emphasised that this opinion represents the
farmers’ perception, which may not have been supported by any
testing having been carried out. Two respondents who held both
upland and lowland flocks indicated that certain products were no
longer as effective as they were, but failed to indicate which.
Also in this survey, flock owners indicated 8 instances of
laboratory-confirmed flukicide resistance, but the identity of the
diagnostic laboratory and the method of diagnosis were not queried
in the questionnaire, so cannot be corroborated. Such ‘diagnoses’
of flukicide-resistant populations were more common in upland
flocks [TCBZ (4), CLOS (1), OXY plus LV (1)], than lowland flocks
[TCBZ (1), MEB plus CLOS (1)].
3.3.6.2. Survey. In the 2011 survey, 19 instances of laboratory-
confirmed flukicide resistance were noted but, as before, the
method and identity of the laboratory were not asked in the ques-
tionnaire. In all cases, TCBZ was identified as the active ingredient
against which fluke resistance was suspected.
Modification to the (then) current parasite control strategies
were identified in the 2011 survey and deemed to be necessary
by 58%, 40% and 52% of lowland, upland and both lowland and
upland flock owners, respectively.
3.4. Comparison between the number of cases of acute fluke
recorded across the VIDA diagnostic network (mainland UK) and
those recorded at the VSD stormont and Omagh centres (NI)
By direct comparison of the total number of cases per annum of
acute fluke (as revealed by post-mortem examination of carcases)
in the AFBI and VIDA databases, it can be noted that during the
very high risk years (2002 and 2012), the two centres in NI (AFBI
Stormont and AFBI Omagh) together diagnosed a comparable total
number of cases to the combined total number of cases diagnosed
by the 23 centres across mainland UK (Fig. 5). This may be indica-
tive of a greater prevalence of F. hepatica infections in sheep flocks
across NI than in their GB counterparts.
4. Discussion
4.1. General discussion
The results of the 2011 TCBZ resistance survey have been dis-
cussed in depth by Hanna et al. (2015), so will not be repeated
here. Briefly, resistance was identified on 5 farms, all located in
79
lowland areas; this conclusion was based on the application of
3 diagnostic techniques (FECRT, CRT and fluke histology). When
the results were compared with those of the 2008 survey, it was
revealed that the level of resistance had increased considerably
in the 3-year period between surveys. The following discussion
will focus on: the relative merits of different tests for the diag-
nosis of TCBZ resistance; the possible impact of different formulae
on the calculation of reductions in FECs and coproantigen levels;
a comparison between reports of TCBZ resistance in NI and else-
where in the world (specifically the methods used in the testing
for resistance); and a discussion of control and management prac-
tices carried out by farmers in the Province and how they changed
between the Questionnaire surveys conducted in 2005 and 2011.
4.2. FEC/FECRT and coproantigen ELISA/CRT as diagnostic tools
For the detection of infections of F. hepatica, FEC by sedimen-
tation is known to have a sensitivity of 30-60% and a specificity
of 100% (Daniel et al., 2012). A number of biological drawbacks to
this technique are well known: they include no eggs shed for up to
12 weeks post initial infection, followed by intermittent shedding
thereafter; difficulty in detecting eggs in dilute faecal samples; and
over-dispersion of infection within the flock/herd. Another compli-
cation is the periodic release of eggs stored in the gall bladder, even
in the absence of an active infection (Flanagan et al., 2011a,b).
A disadvantage in the FECRT methodology itself for the diag-
nosis of drug resistance in fluke infections is the requirement of
a 21-day window between sample points, which presents a long
interval to leave non-thriving animals untreated. Similarly, on the
receipt of samples, specialist skills (including microscopy and egg
identification) are necessary. Lastly, in analysing results, differ-
ent methods of calculating FECR (based on different formulae and
inclusion/exclusion of certain data points) may lead to a different
classification of a farm’s resistance status. By way of example, Farm
A in 2011 (Table 1) would no longer be likely to see therapeutic ben-
efit of treatment according to the results of FECRT2, although the
farmer may still see clinical improvement if the level of resistance
was as recorded for FECRT1.
Consequently, in the absence of formalised guidelines, the
FECRT alone is not suitable for the determination of resistance.
The ELISA platform is ubiquitous in diagnostic laboratories and,
as an alternative diagnostic test, the CRT offers a number of advan-
tages. The advantages are: a good association with parasite burden
(Mezo et al., 2004; Brockwell et al., 2013); a reduction in the time
interval between sample collection dates, as coproantigen levels
reach an optical density of zero within 14 days following success-
ful treatment (Brockwell et al., 2014); the stability of coproantigens
on freezing, which allows samples to be batched, delivering a more
cost-effective analysis (Flanagan et al., 2011a,b); and high speci-
ficity (Gordon et al., 2012a,b; Kajugu et al., 2012).
Nested PCR has been shown to be more sensitive than both
FECRT and CRT in terms of the early detection of fluke infection
(Robles-Pérez et al., 2013). However, the necessity for further eval-
uation of the PCR techniques has been advised (Brockwell et al.,
2014). Until such time as that has been achieved, coproantigen
ELISA remains the simplest quantitative technique in the routine
diagnosis of fasciolosis in livestock and it provides a robust and
accessible test to use in conjunction with the FECRT.
4.3. Reports of resistance from around the world
By way of comparison, the methods used to declare the pres-
ence of anthelmintic resistance in F. hepatica populations in the last
9 years are presented in Table 6. Most commonly (11/15), reports
focussed on a single flock or two flocks, and so widespread preva-
lence studies are not the norm. In reports where multiple flocks
80 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83

Fig. 5. The annual prevalence of acute fasciolosis as diagnosed at post-mortem in AFBI and VIDA diagnostic networks.

Table 6
The methods used to diagnose the presence of anthelmintic resistance in Fasciola hepatica populations in sheep-producing areas around the world.

Country Farms F CRT CET FH GGT/GOT Reference

Argentina 1 X Olaechea et al. (2011)

– X X Sanabria et al. (2013)
Peru 1 X X X Ortiz et al. (2013)
1 X Gomez-Puerta et al. (2012)
Australia 15 X X Elliott et al. (2015)
7 X X Brockwell et al. (2014)
18 X Stevenson et al. (2002)
Netherlands 1 X X Borgsteede et al. (2008)
Spain 1 X Alvarez-Sanchez et al. (2006)
1 X Martínez-Valladares et al. (2010)
1 X Martinez-Valladares et al. (2014)
Sweden 1 X Novobilsky et al. (2012)
England/Wales 25 X Daniel et al. (2012)
Scotland 2 X X Gordon et al. (2012a)
2 X Gordon et al. (2012b)
N. Ireland 13 X X X Hanna et al. (2015)
12 X X Flanagan et al. (2011a,b)
Ireland 1 X Mooney et al. (2009)

Note: F = faecal egg count reduction test; CRT = coproantigen reduction test; CET = controlled efficacy test; FH = fluke histology; GGT/GOT = gamma-glutamyl transpeptidase
(GGT) and glutamic-oxaloacetic transaminase (GOT); – = research flock.

were examined, multiple methods for resistance determination
were not always used: therefore, the reports for NI represent one
of the most in-depth analyses of the prevalence of flukicide resis-
tance thus far conducted. The FECRT was a linchpin of diagnosis
in all but one report, although the analytical methods used varied
by country (presence/absence of control groups, group size, sta-
tistical calculations), complicating any possibility of international
comparisons.
4.4. Fluke control practices and sheep management strategies
4.4.1. Product selection
Over the period 1999–2004, TCBZ accounted for over 65% of
all products used (Fig. 1A), but in 2011 it accounted for only 25%
(Fig. 1B), with the value falling steadily in the intervening years. In
the absence of widespread confirmed anthelmintic resistance and
industry publications recommending the shift away from TCBZ, this
change seems likely to be a response to anecdotal accounts of treat-
ment failure amongst the flock owners of NI. This represents the
first empirical evidence of a shift away from TCBZ use by the farm-
ing community in the absence of widespread resistance testing and
confirmed diagnosis.
In 1999, CLOS use accounted for 12% of all treatments given to
control fasciolosis (4% as single active and 8% in combination with
broad spectrum wormer). In 2011, this percentage had increased to
52.5% (35.5% as single active and 19% in combination, respectively).
Approximately 12% of all treatments given were NIT-based in the
surveyed periods, suggesting that oral drench formulations were
preferable to the majority of flock owners over injectable formula-
tions. This is similar to previous findings for nematode control in
NI (McMahon et al., 2013a,b). NIT is known to be difficult to inject
and causes tissue staining. The use of OXY rose sharply between
2010 and 2011, which may be a reflection of increased awareness
of rumen fluke infection in the farming community. In the survey
carried out by Morgan et al. (2012), which covered Great Britain and
Ireland, NIT was the drug most commonly used, followed by TCBZ
(mainly in combination with levamisole), CLOS, ALB and OXY. Six
per cent of farmers reported the use of inappropriate drugs (mainly
macrocyclic lactones); similar low levels of unsuitable drug use
have been described in other surveys (3%, Bloemhoff et al., 2014;
2%, Selemetas et al., 2015).
Overall, then, the decrease in TCBZ use in NI has been matched
largely by the increase in use of CLOS.
4.4.2. Treatment timing
As stated previously, May-August represents the lowest period
of risk of fasciolosis in sheep flocks in temperate regions;
periods of medium risk are considered to be March–April
and November–December; and the months of highest risk are
January–February and September–October. Between the question-
 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83
naire surveys of 2005 and 2011, the proportion of flock owners
treating at low risk time approximately doubled (9% in 2005 and
19% in 2011, for ewes; 13% in 2005 and 32% in 2011, for lambs).
There was a corresponding decrease in those treating at times of
medium risk (41% in 2005 and 29% in 2011, for ewes; 40% in 2005
and 27% in 2011, for lambs), while those treating at high risk times
remained roughly constant (50% in 2005 and 52% in 2011, for ewes;
47% in 2005 and 41% in 2011, for lambs).
Sargison (2011) has described the changes in severity, season-
ality and local prevalence of fasciolosis in the UK over the last
decade (i.e. 2000–2010). These changes have been linked to chang-
ing climate, localised flooding and increased rainfall, ultimately
compromising effective management of the disease and leading
to production losses. These changes have been forecast to continue
well into the future (Fairweather, 2011a,b; Fox et al., 2011). While
the effects of climate change on fluke prevalence were beyond
the scope of this investigation, their consequences may be behind
the observed shift in treating earlier in the year. Alternatively, the
change in treatment timing may be linked to the shift in product
selection towards CLOS, with the emphasis being placed on adult
fluke control earlier in the season, in order to prevent pasture con-
tamination, that is, a change in emphasis of control strategy to
pasture protection.
4.4.3. Treatment frequency
No real changes were seen, the basic pattern of treatment fre-
quency remaining the same over time. Two treatments per year
for ewes was the most practised option (by ∼1/3 of flock owners).
Approximately 30% of flock owners gave 3 or more treatments,
while the proportion giving no treatments was small, but rose
between 2005 and 2011, particularly in upland areas.
For lambs, the basic pattern also remained much the same, the
only change involving the use of 1 or 2 treatments. There was a
decrease in the number of 2 treatments, particularly in lowland
areas, counterbalanced by an increase in the use of a single treat-
ment, in both lowland and upland areas. In 2011, ∼ a quarter of
flock owners gave one treatment. More than half of flock owners
gave no treatments at all and the number of 3 or more treatments
was low (<10%).
Looking at the intensity of treatment between 2005 and 2011
in different areas for ewes, there was little change in the propor-
tion of lowland flock owners treating as opposed to not treating
and no real change in the intensity of treatment. On upland farms,
there was an increase in the percentage of farmers not treating
and a decrease in treatment intensity. On both lowland and upland
farms, there was a slight increase in the percentage of flock owners
not treating, but this was balanced by a slight increase in intensity
of treatment. Decisions to treat ewes and how often may depend
on the cost benefits of doing so, bearing in mind the price of sheep
meat. Other factors include the farmer’s perception of the fluke bur-
den and of the level of TCBZ resistance—in the latter case, whether
it is worth treating at all.
For lambs, there was a slight reduction in the percentage of low-
land farmers not treating between the two time-points, but the
intensity of treatment was the same. In upland areas, there was
a very slight decline in the proportion of flock owners not treat-
ing, although there was a distinct drop in treatment intensity. On
both lowland and upland farms, the percentage of flock owners
not treating showed a slight increase, although the intensity of
treatment remained the same. Overall, there was not much change
in treatment frequency, with approximately half of flock owners
not treating lambs at all. More treatments were given to lambs in
upland areas, presumably because of the longer fattening period,
but this would be offset by lower fluke burdens in these areas. Treat-
ment of lambs also has to take into account the withdrawal period
for drugs (e.g. 56 days for TCBZ).
81
Treatment frequency showed significant regional variation in
the survey conducted by Morgan et al. (2012), with lambs in NI
receiving more treatments (>6) than the general annual average of
3.6. Overall, approximately two-thirds of farmers treated sheep 3
or 4 times per year 43% and 22%, respectively, with 17% treating two
times per year and 18% once (Morgan et al., 2012). Such high figures
were not encountered in the present NI survey. The frequency and
timing of treatment is important for maintaining effective parasite
control. In Ireland, for example, dairy cattle are typically treated
just once per year and this is not an optimal strategy (Bloemhoff
et al., 2014; Selemetas et al., 2015).
4.4.4. Product rotation
In lowland areas, flock owners rotated more in 2011 than 2005
and the intensity of rotation was greater, which represents a sub-
stantial increase in interest in rotation in this group of farmers.
Probably, this is because they have a more severe fluke problem in
their flocks (and potentially more of a drug resistance problem as
well), so they are more aware of the need to rotate drug classes.
Faced with the decision to rotate or not, they are more likely to
choose to do so. In contrast, in upland areas and both lowland and
upland areas, fewer farmers practised drug rotation in 2011 than
2005 and there was a significant decrease in the interest to rotate.
Fasciolosis is less of a problem in these areas (as, in all likelihood, is
resistance) and there is probably lower drug use overall. Therefore,
the farmers are not so appreciative of the need to rotate.
A lack of rotation was highlighted in the survey conducted by
Rojo-Vazquez and Hosking (2013), with 42% of farmers not carry-
ing this out, although it was not clear whether this figure applied
specifically to fluke or to helminths generally. Even amongst those
farmers that rotated annually (36%), 25% of the group used the same
drug class (the benzimidazoles), simply switching to a different
product.
4.4.5. Quarantine treatment
Overall, only ∼ one-fifth of flock owners gave quarantine treat-
ments in 2005 and this proportion had dropped by approximately
half in 2011. The decreases were seen in lowland and upland areas;
in flocks grazed on both lowland and upland areas, the percentage
remained unchanged.
The fact that the overwhelming majority of farmers in NI do
not carry out routine quarantine treatments of new stock is a con-
cern, as it may lead to the introduction of fluke (and possibly
drug-resistant parasites) into the flock. The lack of an adequate
quarantine strategy has been highlighted in other fluke surveys
(Mezo et al., 2008; Morgan et al., 2012; Rojo-Vazquez and Hosking,
2013).
5. Conclusion
Farmers appear to be responding to the potential impact of cli-
mate change on the seasonality/epidemiology of fluke in that the
timing of treatment moved earlier in the year. In other respects,
a number of shortcomings were identified in fluke control pro-
grammes employed by NI flock owners, namely:
A significant proportion of flock owners giving a high number
of treatments (three or more) per calendar year (Figs. 3 and 4);
reduced use of effective juvenile fluke control (by TCBZ) in the
absence of empirical evidence of TCBZ resistance (Fig. 2); and
reduced levels of quarantine treatment and quarantine separation
between 2005 and 2011, increasing the possibility of importing
drug-resistant parasites. These shortcomings have highlighted the
need for more robust advice to be given to farmers so that they
can implement more effective fluke control programmes. The infor-
mation in this paper may help to better inform veterinarians and
other advisors on what farmers are actually doing and areas where
82 C. McMahon et al. / Veterinary Parasitology 216 (2016) 72–83
improvements are needed, in order for them to (be able to) give
appropriate advice on the design, development and implementa-
tion of management control programmes.
The use of faecal egg counts (pre-treatment) in local diagnos-
tic laboratories provides a simple means of determining parasite
burden, and whether there is a need to treat at all. For exam-
ple, in the survey conducted by Morgan et al. (2012), two-thirds
of farmers said they treated for fluke, even though only one-fifth
had previous problems with the parasite. Moreover, in the sur-
vey carried out in Spain, farmers reported that, when cattle were
treated, all animals in the herd were treated, without any prior
diagnosis (Mezo et al., 2008). So, accurate diagnosis of infection
may obviate a number of treatments in the calendar year. Like-
wise, use of faecal egg counts following TCBZ treatment may restore
confidence in this anthelmintic in the absence of formal resis-
tance testing and diagnosis. Few farmers test for anthelmintic
efficacy and so do not know the resistance status of the farm
(Morgan et al., 2012; Rojo-Vazquez and Hosking, 2013). These
practices, as well as increased awareness of the importance of quar-
antine, present an obvious first step in encouraging effective fluke
control.
5.1. Added note
The results of a recent survey have highlighted the lack of knowl-
edge among sheep farmers about liver fluke, the stage (in the
life cycle) targeted by different drugs and the right timings for
their use (Anon, 2015). The responses also indicated the need for
vets and suitably qualified persons (SQPs) to be familiar with cur-
rent testing options and advice on control, so that they can pass
on this information to farmers in clear, practical messages at the
appropriate time of year. An example of a potential management
strategy for disease control has been put forward by Hanna et al.
(2015). It is perhaps appropriate here to re-iterate the recommen-
dation made: “With the present circumstances of high penetration
of TCBZ resistance throughout flocks in NI, provision of advice
regarding chemotherapeutically based management of fasciolosis
is difficult. In the current absence of any other licensed prod-
uct effective against acute fasciolosis, it is considered advisable to
continue to use TCBZ in the autumn, in the hope that at least a
proportion of the fluke population remains susceptible, and that
the burden can be sufficiently reduced to save some animals in an
acute outbreak. Concurrent use of a flukicide active against late
immature and adult fluke can ensure removal of infection acquired
earlier in the season, and so reduce the overall fluke burden. How-
ever, the emphasis in control schemes should be shifted to use
of an adulticide such as closantel or nitroxynil in the winter and
spring months, to reduce potential pasture contamination for the
next season” (Hanna et al., 2015). The necessity for correct diag-
nosis is a point that has been raised previously by Fairweather
(2011a,b).
Acknowledgements
We wish to thank John Kenny, Sean Ellison and Velma Beattie
(AFBI), who helped to compile the Questionnaire in 2005. We also
wish to thank Sophie Tynan, Maria Guelbenzu, Robert Walker and
David McCoubrey (AFBI), together with Don Morrow and Steven
Johnston (CAFRE) and William Sherrard (Pfizer), who helped to
disseminate the Questionnaire in 2011.
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