Personalized Antihypertensive Treatment Optimization With Smartphone-Enabled Remote Precision Dosing of Amlodipine During the COVID-19 Pandemic (PERSONAL-CovidBP Trial).

BACKGROUND: The objective of the PERSONAL-CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID-19 Pandemic) trial was to assess the efficacy and safety of smartphone-enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID-19 pandemic. METHODS AND RESULTS: This was an open-label, remote, dose titration trial using daily home self-monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5-7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10-12)/7 (95% CI, 6-7) mm Hg, P<0.001). The majority of participants achieved BP control on novel doses (84%); of those participants, 35% were controlled by 1 mg daily. The majority (88%) controlled on novel doses had no peripheral edema. Adherence to BP recording and reported adherence to medication was 84% and 94%, respectively. Patient retention was 96% (196/205). Treatment was well tolerated with no withdrawals from adverse events. CONCLUSIONS: Personalized dose titration with amlodipine was safe, well tolerated, and efficacious in treating primary hypertension. The majority of participants achieved BP control on novel doses, and with personalization of dose there were no trial discontinuations due to drug intolerance. App-assisted remote clinician dose titration may better balance BP control and adverse effects and help optimize long-term care. REGISTRATION: URL: clinicaltrials.gov. Identifier: NCT04559074.

Gut microbiota predicts body fat change following a low-energy diet: a PREVIEW intervention study.

BACKGROUND: Low-energy diets (LEDs) comprise commercially formulated food products that provide between 800 and 1200 kcal/day (3.3-5 MJ/day) to aid body weight loss. Recent small-scale studies suggest that LEDs are associated with marked changes in the gut microbiota that may modify the effect of the LED on host metabolism and weight loss. We investigated how the gut microbiota changed during 8 weeks of total meal replacement LED and determined their associations with host response in a sub-analysis of 211 overweight adults with pre-diabetes participating in the large multicentre PREVIEW (PREVention of diabetes through lifestyle intervention and population studies In Europe and around the World) clinical trial. METHODS: Microbial community composition was analysed by Illumina sequencing of the hypervariable V3-V4 regions of the 16S ribosomal RNA (rRNA) gene. Butyrate production capacity was estimated by qPCR targeting the butyryl-CoA:acetate CoA-transferase gene. Bioinformatics and statistical analyses, such as comparison of alpha and beta diversity measures, correlative and differential abundances analysis, were undertaken on the 16S rRNA gene sequences of 211 paired (pre- and post-LED) samples as well as their integration with the clinical, biomedical and dietary datasets for predictive modelling. RESULTS: The overall composition of the gut microbiota changed markedly and consistently from pre- to post-LED (P = 0.001), along with increased richness and diversity (both P < 0.001). Following the intervention, the relative abundance of several genera previously associated with metabolic improvements (e.g., Akkermansia and Christensenellaceae R-7 group) was significantly increased (P < 0.001), while flagellated Pseudobutyrivibrio, acetogenic Blautia and Bifidobacterium spp. were decreased (all P < 0.001). Butyrate production capacity was reduced (P < 0.001). The changes in microbiota composition and predicted functions were significantly associated with body weight loss (P < 0.05). Baseline gut microbiota features were able to explain ~25% of variation in total body fat change (post-pre-LED). CONCLUSIONS: The gut microbiota and individual taxa were significantly influenced by the LED intervention and correlated with changes in total body fat and body weight in individuals with overweight and pre-diabetes. Despite inter-individual variation, the baseline gut microbiota was a strong predictor of total body fat change during the energy restriction period. TRIAL REGISTRATION: The PREVIEW trial was prospectively registered at ClinicalTrials.gov ( NCT01777893 ) on January 29, 2013.

Stability of Listeria monocytogenes in non-fat dry milk powder during isothermal treatment and storage.

Dry dairy powder is a commonly used ingredient for ready-to-eat foods. It has been implicated in multiple foodborne outbreaks. Listeria monocytogenes can survive in low-moisture conditions for a long duration. However, there is no information on Listeria survival in dry milk powder during storage and thermal treatments. The objectives of this study were to examine the stability of L. monocytogenes in non-fat dry milk (NFDM) during extended storage and further analyze thermal resistance of L. monocytogenes in NFDM under different water activities (aw) and its thermal stability after 1-year storage. We observed approximately 1.75 and 2.93 log CFU/g reduction of L. monocytogenes in aw 0.25 NFDM over 1-year storage at 4 and 22 °C, respectively. Thermal resistance of L. monocytogenes was inversely related to aw, and the inactivation kinetic curves of L. monocytogenes in NFDM at target aw showed a log-linear trend under all tested conditions. For aw 0.25, 0.30, and 0.45 NFDM, the ranges of D-values, were 66.2-21.3, 33.5-9.4, and 14.6-4.3 min at 70, 75 and 80 °C, respectively. The z-values for L. monocytogenes in NFDM at aw 0.25-0.45 were 14.6-16.0 C°. Furthermore, the thermal stability of L. monocytogenes in aw 0.25 NFDM post 6-month or 12-month storage under refrigerated or ambient temperature did not deviate much from that in NFDM prior to the storage. Data indicated that a 60-min heat treatment at 80 °C resulted in ~ 5-log reduction of L. monocytogenes in NFDM of aw 0.30. This provides a promising intervention strategy to enhance bactericidal efficacy of thermal treatment while maintaining the quality of milk powder.

Molecular tracking of multiple disease resistance in a winter wheat diversity panel.

KEY MESSAGE: About 10% of cultivars possessed superior resistance to four fungal diseases and association mapping for multiple disease resistance identified loci which are not detected by analyzing individual disease resistances. Multiple disease resistance (MDR) aims for cultivars that are resistant to more than one disease which is an important prerequisite for the registration of commercial cultivars. We analyzed a European winter wheat diversity panel of 158 old and new cultivars for four diseases by natural (powdery mildew) and artificial inoculation (yellow rust, stem rust, Fusarium head blight) observed on the same plot in a multilocation trial. Genotypic analyses were based on 21,543 genotype-by-sequencing markers. By association mapping, eight to 18 quantitative-trait loci (QTL) were detected for individual disease resistances, explaining in total 67-90% of the total genotypic variation. For MDR, nine QTL could be found explaining 62% of the total genotypic variation. Only three of them were also found as QTL for a single disease resistance illustrating that mapping of MDR-associated QTL can be regarded as a complementary approach. The high prediction ability obtained for MDR (> 0.9) implies that genomic prediction could be used in future, thereby eliminating the necessity to separately screen large numbers of lines in breeding programs for several diseases.

A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease.

PURPOSE: To evaluate the safety and efficacy of topical TOP1630, a novel nonsystemic kinase inhibitor, in dry eye disease (DED). PATIENTS AND METHODS: A randomized, double-masked, parallel-group trial of 0.1% TOP1630 ophthalmic solution TID or placebo (vehicle without active drug) was conducted in DED subjects (n=61). Key eligibility criteria consistent with enrolling a moderate to severe DED population included >6 months DED history; OSDI© score ≥18; Schirmer's test score ≤10 and ≥1 mm/5 minutes; tear film break-up time >1 and <7 seconds; and dry eye exacerbation in corneal staining and ocular discomfort in a Controlled Adverse Environment (CAE®). After a 7-day run-in period with placebo TID, eligible subjects were randomized to TOP1630 or placebo for 28 days. No supplemental artificial tears or rescue medication were allowed. RESULTS: TOP1630 was safe, well-tolerated, and efficacious in treating DED symptoms and signs. No serious adverse events (AEs) or withdrawals due to treatment emergent AEs occurred. Drop comfort scores showed TOP1630 to be comfortable and comparable with placebo. Significant symptom improvements were seen for TOP1630 vs placebo for ocular discomfort (P=0.02 post-CAE), grittiness/foreign body sensation (on four independent assessment scales, each P<0.05), worst DED symptom (diary, P=0.06), and ocular pain (VAS, P=0.03). Sign improvements were seen for total ocular surface (all regions), corneal sum, and conjunctival sum staining with TOP1630 compared with placebo (each P<0.05). CONCLUSION: TOP1630 had placebo-like tolerability and produced improvements in multiple symptom and sign endpoints in both environmental and challenge settings. The emergent TOP1630 benefit-risk profile for DED treatment is highly favorable and supports further development.

An observational study of ewe treatments at lambing on early infection in lambs on UK sheep farms.

Anthelmintic treatments to ewes around lambing time, often with long acting products, have become common practice on UK sheep farms, but these treatments have also been shown to be highly selective for anthelmintic resistance in New Zealand and Australia, with field data supported by modelling results. The purpose of this study was to determine (1) the effect of treating or withholding anthelmintic treatments and (2) the effect of treatment of ewes with a persistent or non-persistent anthelmintic, on early infection in lambs in the UK. Faecal egg count data for 10-16 weeks old lambs collected over a three year period (2012-2014) was analysed. Samples were grouped according to whether the ewes on the farm had or had not been treated with an anthelmintic at lambing. For both analyses, data for early infection were analysed by generalised linear mixed model. There was no effect of withholding or treating ewes on subsequent early infection in lambs. In addition, there was no effect of region, farm type or management type on the faecal egg counts. There was, however an effect of year, with lambs having lower counts in 2014 than in 2012 and an interaction between year and ewe treatment, with data suggesting lower infection levels over time for those farms withholding anthelmintic treatments altogether. There was no effect of drug type on early infection in lambs nor region, farm type or treatment on the lamb faecal egg counts. However, there was an effect of year and an interaction between year and drug type with lower egg count over time with the short acting drugs. Our study supports data generated by other researchers suggesting that the practice of treating ewes at lambing to reduce contamination on pasture and minimise subsequent disease may not in fact always result in lower levels of infection in lambs. The study also demonstrated no significant benefit in early infection in lambs when ewes were treated with long acting compared to short acting anthelmintics. This provides further evidence to support the potential benefits of a more targeted approach to anthelmintic treatment on sheep farms.

Resistance delaying strategies on UK sheep farms: A cost benefit analysis.

UK guidelines for the sustainable control of parasites in sheep (SCOPS) were formulated with the primary aim of delaying development of anthelmintic resistance (AR) on UK sheep farms. Promoting their use requires the engagement and commitment of stakeholders. An important driver for behavioural change in sheep farmers is evidence of economic benefits. A recent evaluation of SCOPS guidance in practice demonstrated a significant reduction in anthelmintic use, suggesting economic benefits through a direct reduction in product and labour costs. However, in order to maintain production, a range of alternative control strategies are advised, resulting in additional costs to farmers and so a full cost benefit analysis of best practice management was undertaken. We allocated financial values to the management recommendations described in the SCOPS technical manual. Benefits were calculated using data for production variables and anthelmintic use measured during studies to evaluate the effect of SCOPS recommendations on 16 UK sheep farms and from other published work. As SCOPS control is not prescriptive and a range of different diagnostics are available, best and worst case scenarios were presented, comparing the cheapest methods (e.g. egg counts without larval culture) and management situations (e.g closed flocks not requiring quarantine treatments) with the most laborious and expensive. Simulations were run for farms with a small, medium or large flock (300; 1000; 1900 ewes) as well as comparing scenarios with and without potential production benefits from using effective wormers. Analysis demonstrated a moderate cost for all farms under both scenarios when production benefits were not included. A cost benefit was demonstrated for medium and large farms when production benefits were included and the benefit could be perceived as significant in the case of the large farms for the best case scenario (>£5000 per annum). Despite a significant potential reduction in anthelmintic use by farmers employing SCOPS guidance, the very low price of the older anthelmintic classes meant that the benefit did not always outweigh the additional management/diagnostic costs unless an increase in production was also achieved. This is an important finding. Focussing research on key innovations that will improve the cost effectiveness of diagnostic assays in a diagnostic driven control strategy, as well as designing treatment options that can improve production outcomes, and presenting them in a clear and transparent way, must be high priority goals. Coupling targeted research with improvements in the delivery of messages to the end user is important in the light of increasing global concerns over drug resistance.

Narrow Spectrum Kinase Inhibitors Demonstrate Promise for the Treatment of Dry Eye Disease and Other Ocular Inflammatory Disorders.

Purpose: The purpose of this study is to determine the potential of narrow spectrum kinase inhibitors (NSKIs) to treat inflammatory eye disorders. Methods: Human conjunctival epithelial (HCE) cells were retrieved from subjects via impression cytology. Real-time quantitative PCR (qPCR) was performed on HCE cells to determine gene expression of NSKI kinase targets and proinflammatory cytokines in dry eye disease (DED) patients versus healthy controls. qPCR also assessed p38α expression in hyperosmolar-treated Chang conjunctival epithelial cells. Interaction of NSKI TOP1362 with the kinases was evaluated in ATP-dependent Z-LYTE and competition binding assays. Anti-inflammatory activity was assessed in human peripheral blood mononuclear cells and primary macrophages. In an endotoxin-induced uveitis (EIU) study, lipopolysaccharide (LPS) was administered intravitreally to Lewis rats. TOP1362, dexamethasone, or vehicle was administered topically, and inflammatory cytokine levels were measured 6 hours after LPS injection. Results: HCE cells from DED patients showed significantly increased expression of p38α, spleen tyrosine kinase (Syk), Src, lymphocyte-specific protein tyrosine kinase (Lck), interleukin one beta (IL-1ß), interleukin eight (IL-8), monocyte chemotactic protein-1 (MCP-1), and matrix metalloproteinase-9 (MMP-9). TOP1362 strongly inhibited the kinase targets p38α, Syk, Src, and Lck, blocked the rise in p38α expression in hyperosmolar Chang cells, and potently reduced inflammatory cytokine release in cellular models of innate and adaptive immunities. In the EIU model, TOP1362 dose-dependently attenuated the LPS-induced rise in inflammatory cell infiltration and ocular cytokine levels with efficacy comparable to that of dexamethasone. Conclusions: TOP1362 is a potent inhibitor of kinases upregulated in DED and markedly attenuates proinflammatory cytokine release in vitro and in vivo, highlighting the therapeutic potential of NSKIs for treating ocular inflammation, such as that observed in DED.

Three-year evaluation of best practice guidelines for nematode control on commercial sheep farms in the UK.

Anthelmintics are commonly used on the majority of UK commercial sheep farms to reduce major economic losses associated with parasitic diseases. With increasing anthelmintic resistance worldwide, several countries have produced evidence-based, best practice guidelines with an example being the UK's Sustainable Control of Parasites in Sheep (SCOPS) initiative. In 2012, a pilot study demonstrated that SCOPS-managed farms used fewer anthelmintic treatments than traditionally managed farms, with no impact on lamb productivity and worm burden. Building on these results, we collected data for three consecutive years (2012-2014) with the following aims: (1) To compare the effects of traditional and SCOPS-based parasite management on lamb productivity and worm burden; (2) To evaluate the effect of region and farm type on lamb productivity and worm burden; (3) To compare the frequency and patterns of use of anthelmintic treatment on traditional and SCOPS-managed farms. The study was carried out on 16 farms located in the North east and the South west of England and Wales. Lamb productivity was assessed by quantifying birth, mid-season and finish weights and calculating daily live-weight gains and time to finish in a cohort of 40-50 lambs on each farm. Five annual faecal egg counts were carried out on each farm to assess worm burden. No differences in lamb productivity and worm burdens were found between farms that adopted SCOPS guidelines and traditional farms across the three years. However, mean infection levels increased for both the SCOPS and the traditional groups. Lamb production was not significantly different for farm type and region but the effect of region on infection was significant. For both ewes and lambs, SCOPS farms carried out significantly fewer anthelmintic treatments per year, and used fewer anthelmintic doses/animal than traditional farms. The data suggest a trend to increasing use of anthelmintics in ewes on traditional but not on the SCOPS farms and a decreasing use of anthelmintics in lambs on both SCOPS and traditional farms. Across time, an increasing number of SCOPS farmers left their ewes and lambs untreated and the reverse was true for traditional farmers. Overall, farms implementing SCOPS guidelines used less anthelmintic treatments and less frequently than traditionally managed farms, without loss of animal performance or increased worm burden. Implementing SCOPS guidelines might have economic benefits for farmers, help reduce development of anthelmintic resistance on farms and decrease any environmental impact of anthelmintics. Furthermore, these data suggest some important epidemiological trends that should be investigated in long-term studies.

Building the infrastructure to make science metrics more scientific.

Research leaders, policy makers and science strategists need evidence to support decision-making around research funding investment, policy and strategy.  In recent years there has been a rapid expansion in the data sources available that shed light onto aspects of research quality, excellence, use, re-use and attention, and engagement. This is at a time when the modes and routes to share and communicate research findings and data are also changing.  In this opinion piece, we outline a series of considerations and interventions that are needed to ensure that research metric development is accompanied by appropriate scrutiny and governance, to properly support the needs of research assessors and decision-makers, while securing the confidence of the research community. Key among these are: agreed 'gold standards' around datasets and methodologies; full transparency around the calculation and derivation of research-related indicators; and a strategy and roadmap to take the discipline of scientific indicators and research assessment to a more robust and sustainable place.

Revision of the species of the Merodon nanus group (Diptera: Syrphidae) including three new species.

The nanus group of the genus Merodon Meigen (Diptera, Syrphidae) is revised, yielding an illustrated key, a discussion of taxonomic characters and morphological diagnosis for the five species of this group. Three new cryptic species are described, Merodon kopensis Vujic et Hayat sp. n., M. neonanus Vujic et Taylor sp. n. and M. rasicus Vujic et Radenkovic sp. n. New diagnostic characters are given for M. nanus Sack and M. telmateia Hurkmans. In addition, environmental profiles for each investigated species have been defined and compared, and maps of distribution and richness created. Niche dissimilarity was found for each species. Eastern Anatolia and the southern Aegean region of Turkey are reported as the most species rich regions for the nanus group.

Achieving human and machine accessibility of cited data in scholarly publications.

Reproducibility and reusability of research results is an important concern in scientific communication and science policy. A foundational element of reproducibility and reusability is the open and persistently available presentation of research data. However, many common approaches for primary data publication in use today do not achieve sufficient long-term robustness, openness, accessibility or uniformity. Nor do they permit comprehensive exploitation by modern Web technologies. This has led to several authoritative studies recommending uniform direct citation of data archived in persistent repositories. Data are to be considered as first-class scholarly objects, and treated similarly in many ways to cited and archived scientific and scholarly literature. Here we briefly review the most current and widely agreed set of principle-based recommendations for scholarly data citation, the Joint Declaration of Data Citation Principles (JDDCP). We then present a framework for operationalizing the JDDCP; and a set of initial recommendations on identifier schemes, identifier resolution behavior, required metadata elements, and best practices for realizing programmatic machine actionability of cited data. The main target audience for the common implementation guidelines in this article consists of publishers, scholarly organizations, and persistent data repositories, including technical staff members in these organizations. But ordinary researchers can also benefit from these recommendations. The guidance provided here is intended to help achieve widespread, uniform human and machine accessibility of deposited data, in support of significantly improved verification, validation, reproducibility and re-use of scholarly/scientific data.

Evaluation of 'best practice' (SCOPS) guidelines for nematode control on commercial sheep farms in England and Wales.

Parasitic diseases are a major constraint to optimum livestock production and are the major cause of economic loss in UK sheep flocks, with farmers remaining dependant on anthelmintics for control. In the UK, research and evidence based, "best practice" guidelines for sustainable control of parasites in sheep (SCOPS) were first produced in 2004 and have been regularly updated since. This study was designed to evaluate the effect of these best practice guidelines for worm control on lamb production and infection levels, compared with more traditional management. Sixteen farms were selected based on a 2 cube factorial design with 3 factors known to affect worm epidemiology: control regimen; farm type; and climatic region. A formalised plan for worm control using 7 potential resistance-delaying practices was prepared for each of the 8 best practice (SCOPS) farms, in conjunction with the farms veterinarians. The 8 farms in the traditional management group (CONTROL farms) were selected based on ongoing evidence of them using worm control strategies deemed to be "higher-risk". A cohort of 40-50 study lambs at each farm was monitored from birth to finishing, allowing evaluation of lamb productivity, worm infection levels and for comparison of numbers of anthelmintic treatments. Birth and mid-season weights were used to calculate daily live-weight gain. Birth and finish dates were used to calculate time to finish and finish weights were also compared. Faecal egg counts, larval culture and species differentiation were undertaken throughout the year to assess the impact of the control strategies on worm burdens. There was no significant difference in results for any of the 3 production responses when comparing predicted means accounting for the differences in birth weight. In fact SCOPS farms had, on average, a higher daily weight gain and finish weight than CONTROL farms when comparing observed means. Statistical analysis of infection levels clearly showed no significant effect according to farm type (p=0.71) or treatment (p=0.81). In contrast the effect of region (p=0.08), although not significant, had a much larger effect size (standardised mean difference) with lower parasite burdens based on faecal egg counts on Northern farms compared to Southern farms. For both ewes and lambs, significantly fewer treatments were carried out on the SCOPS farms. The data collected from this study suggests that farms implementing SCOPS principles use less anthelmintic than other farms, without loss of animal performance or increased worm burden.

The efficacy of a combined oral formulation of derquantel-abamectin against anthelmintic resistant gastro-intestinal nematodes of sheep in the UK.

The objective of the present studies was to evaluate the efficacy of a combined formulation (Startect(®) Dual Active Oral Solution for Sheep, Pfizer Animal Health) of derquantel (DQL) and abamectin (ABA) for the treatment of: (1) sheep experimentally infected with a moxidectin (MOX)-resistant isolate of Teladorsagia circumcincta, and (2) multi-drug resistant gastrointestinal nematode parasites under UK field conditions. In the first study, a total of 40 animals were allocated into 4 treatment groups, and were either left untreated or treated with DQL+ABA, MOX or ABA. Faecal samples were collected on days 1-5 and on day 7 after treatment to examine the reduction in faecal egg excretion and to evaluate the egg viability. On day 14 post treatment all animals were euthanised for abomasal worm counts. There was a 100% reduction in geometric mean worm counts for the DQL+ABA treated animals compared to the untreated control animals (P<0.0001), whereas the percentage reduction in worm counts for the MOX- (P>0.05) and ABA-treated (P=0.0004) animals was 12.4% and 71.8%, respectively. The data from the egg hatch assay (EHA) indicated that in the MOX-treated and the ABA-treated animals, the majority of the eggs hatched after treatment. In the field study, performed on four farms, animals were allocated into 6 groups of 11-15 animals each in order to conduct a faecal egg count reduction test (FECRT), based on arithmetic mean egg counts. One group of animals remained untreated, whereas the other animals were treated with DQL+ABA, MOX, fenbendazole (FBZ), levamisole (LV) or ivermectin (IVM). On each of the farms the reduction in egg excretion after treatment with FBZ, LV or IVM was below 95.0%, indicating anthelmintic resistance. The efficacy of DQL+ABA ranged from 99.1 to 100%, yielding significantly lower egg counts compared to the untreated control group (P ≤ 0.003). For MOX the egg counts were significantly (P ≤ 0.003) lower compared to the untreated group at each farm, with reductions varying from 98.2 to 100%. The post-treatment copro-cultures for larva identification indicated that T. circumcincta was the most abundant worm species after treatment (52-99% of the larvae). The results of these studies confirm the high efficacy of the DQL+ABA combination formulation against anthelmintic resistant nematodes in the UK.

The role of combination anthelmintic formulations in the sustainable control of sheep nematodes.

Combinations of anthelmintics with a similar spectrum of activity and different mechanisms of action and resistance are widely available in several regions of the world for the control of sheep nematodes. There are two main justifications for the use of such combinations: (1) to enable the effective control of nematodes in the presence of single or multiple drug resistance, and (2) to slow the development of resistance to the component anthelmintic classes. Computer model simulations of sheep nematode populations indicate that the ability of combinations to slow the development of resistance is maximised if certain prerequisite criteria are met, the most important of which appear to concern the opportunity for survival of susceptible nematodes in refugia and the pre-existing levels of resistance to each of the anthelmintics in the combination. Combinations slow the development of a resistant parasite population by reducing the number of resistant genotypes which survive treatment, because multiple alleles conferring resistance to all the component anthelmintic classes must be present in the same parasite for survival. Individuals carrying multiple resistance alleles are rarer than those carrying single resistance alleles. This enhanced efficacy leads to greater dilution of resistant genotypes by the unselected parasites in refugia, thus reducing the proportion of resistant parasites available to reproduce with other resistant adults that have survived treatment. Concerns over the use of anthelmintic combinations include the potential to select for resistance to multiple anthelmintic classes concurrently if there are insufficient parasites in refugia; the potential for shared mechanisms of resistance between chemical classes; and the pre-existing frequency of resistance alleles may be too high on some farms to warrant the introduction of certain combinations. In conclusion, anthelmintic combinations can play an important role in resistance management. However, they are not a panacea and should always be used in accordance with contemporary principles for sustainable anthelmintic use.