In a world in which sheep producers are facing increasing problems due to the rapid spread of anthelmintic resistance, the battle against gastrointestinal parasitic nematodes is a difficult one. One of the potential new tools for integrated control strategies is biological control by means of the nematode-destroying microfungus Duddingtonia flagrans. This fungus forms sticky traps that catch developing larval stages of parasitic nematodes in the fecal environment. When resting spores (chlamydospores) of this fungus are fed daily to grazing animals for a period of time, the pasture infectivity and thus, the worm burden of grazing animals are lowered, especially in young lambs. Research has been conducted throughout the world covering many different climates and management systems. An Australian parasite model showed that if the fungus performs efficiently (> or =90% reduction in worm burden) for 2 or 3 mo, it should contribute significantly to a reduction in the number of dead lambs otherwise occurring when managed only by anthelmintic treatment and grazing management. Feeding or field trials have clearly demonstrated that dosing with a few hundred thousand spores per kilogram of live BW not only reduced the number of infective larvae but also increased the BW of the lambs compared with controls not given fungus. Initial Australian work with feeding spores by means of a block formulation or a slow-release device has shown some promise, but further work is needed to fully develop these delivery systems. In tropical Malaysia, small paddock trials and field studies resulted in significant improvements, in terms of lower worm burdens and increased live BW, when feeding half a million spores daily to grazing lambs. Additional benefits have been observed when the fungus is employed in combination with a fast rotational grazing system. Research has also demonstrated that spores can be delivered in slightly moist feed block material, but only if such blocks are consumed rapidly, because of their very short shelf life. In the northern, temperate Danish climate it has been demonstrated that daily feeding of half a million spores per kilogram of live BW can lead to significant production benefits, with increased live BW gain in fungus-exposed animals. Biological control of parasitic nematodes in sheep seems to hold promise for the future, but to be able to assist producers, the optimal delivery system needs to be refined and further developed. In addition, more work will be needed to define the best use of this technology in different geographic regions.
Long-term field studies were conducted on two government managed small ruminant research farms, located in different geo-climatic regions and approximately 300 km separate from each other, on Peninsula Malaysia. The Infoternak trial (48 weeks) and the Chalok trial (43 weeks) each compared nematode parasite control in separately managed groups of young sheep, either short-term rotationally grazed around a suite of 10 paddocks in addition to receiving a daily supplement of Duddingtonia flagrans spores (Fungus Group); or similar groups of sheep being rotationally grazed alone (Control Group). The prevailing weather conditions at Infoternak farm were of below average rainfall conditions for the most of the trial. As a consequence, only very low worm infections (almost exclusively Haemonchus contortus) were acquired by the 17 sets of tracer lambs that grazed sequentially with the experimental lambs. However on all except 2 occasions in the early part of the trial, the mean tracer worm burdens were significantly lower (P < 0.05) and the experimental lambs grew significantly better (P = 0.054) in the Fungus Group. Rainfall at Chalok farm during the course of the trial was also below average. As a consequence infectivity of pastures was assumed to be relatively low based on faecal egg counts (epg) of the experimental sheep, which following an anthelmintic treatment prior to allocation, remained very low in both treatment groups. Faecal egg counts of undosed replacement lambs in the latter half of the Chalok study, showed a progressive increase in the Control Group to levels exceeding 3000 epg, whereas the Fungus Group remained static at approximately 500 epg. These results show that the deployment of the nematophagous fungus, D. flagrans, can improve the level of parasite control of sheep in the tropics above that which can be achieved by the short-term rotational grazing strategy alone.
Control of nematode parasites of small ruminants in a wet, tropical environment using the nematophagous fungus, Duddingtonia flagrans, was assessed in this study. Two methods of fungal delivery were tested, namely as a daily feed supplement, or incorporated into feed blocks. Initially, pen trials were conducted with individually penned groups of sheep and goats at dose rates of 125,000 spores and 250,000 spores/kg live weight per day. At the lower dose rate this reduction was between 80 and 90% compared with the pre-treatment levels. At the higher dose rate, there was virtually complete suppression (>99% reduction) of larval recovery. Trials using the fungal feed blocks, showed that when animals were individually penned, they consumed only small amounts of the block (particularly goats), hence little effect on larval recovery in faecal cultures was observed. Grouping animals according to species and dose rate induced satisfactory block consumption and subsequent high levels of larval reduction in faecal cultures. These larval reductions were mirrored by the presence of fungus in faecal cultures. This work was followed by a small paddock trial, whereby three groups of sheep were fed either a feed supplement without fungal spores, supplement with spores, or offered fungal blocks. The dose rate of spores in the latter two groups was 500,000 spores/kg live weight per day. Egg counts were significantly reduced in the two fungal groups, compared with the control group and the latter required two salvage anthelmintic treatments to prevent mortality due to haemonchosis. Pasture larval numbers on the two fungal group plots were also much lower than on the control plot.
Approximately 2,800 fresh dung samples from animals, mainly ruminant livestock, were screened for the presence of nematophagous fungi in Malaysia. Arthrobotrys spp. was noted on numerous occasions, but only one isolate of Duddingtonia flagrans was made. For the purposes of producing sufficient quantities of this fungus for feeding trials in sheep, various, commonly available, cheap plant materials were tested as possible growth substrates. This showed that cereal grains (wheat, millet and rice) were the best media for fungal growth. Pen feeding trials were carried out using sheep, both naturally and experimentally infected with nematode parasites (predominantely Haemonchus contortus), to test the efficiency of D. flagrans when administered either in a grain supplement, or incorporated into a feed block. These showed that the fungus survived gut passage in sheep and that dose rates of approximately 1 x 10(6) D. flagrans spores / animal / day, reduced the percentage of infective larvae developing in faecal cultures by more than 90%. These results indicate that using D. flagrans as a biological control agent of nematode parasites, is a promising alternative to nematode parasite control of small ruminants in Malaysia, where anthelmintic resistance is now a major problem.
The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.