Field evaluation of tolerance to Tobacco streak virus in sunflower germplasm, and observations of seasonal disease spread

Strong statistical evidence was found for differences in tolerance to natural infections of Tobacco streak virus (TSV) in sunflower hybrids. Data from 470 plots involving 23 different sunflower hybrids tested in multiple trials over 5 years in Australia were analysed. Using a Bayesian Hierarchical Logistic Regression model for analysis provided: (i) a rigorous method for investigating the relative effects of hybrid, seasonal rainfall and proximity to inoculum source on the incidence of severe TSV disease; (ii) a natural method for estimating the probability distributions of disease incidence in different hybrids under historical rainfall conditions; and (iii) a method for undertaking all pairwise comparisons of disease incidence between hybrids whilst controlling the familywise error rate without any drastic reduction in statistical power. The tolerance identified in field trials was effective against the main TSV strain associated with disease outbreaks, TSV-parthenium. Glasshouse tests indicate this tolerance to also be effective against the other TSV strain found in central Queensland, TSV-crownbeard. The use of tolerant germplasm is critical to minimise the risk of TSV epidemics in sunflower in this region. We found strong statistical evidence that rainfall during the early growing months of March and April had a negative effect on the incidence of severe infection with greatly reduced disease incidence in years that had high rainfall during this period

Effect of NGM282, a FGF19 analogue, in Primary Sclerosing Cholangitis: a Multicentre, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial

BACKGROUND AND AIMS: Primary Sclerosing Cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. METHODS: In this double-blind, placebo-controlled phase 2 trial, patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5xULN were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. RESULTS: 62 patients were randomized to receive NGM282 1 mg (n=21), NGM282 3 mg (n=21) or placebo (n=20). At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences −6.2 ng/mL [95% CI −10.7 to −1.7; P=0.008] and −9.4 ng/mL [−14.0 to −4.9; P<0.001] in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. CONCLUSIONS: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. LAY SUMMARY: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with PSC. By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC

Socio-economic factors associated with loss to follow-up among individuals with HCV:A Dutch nationwide cross-sectional study

Background and Aims: The path to hepatitis C virus (HCV) elimination is complicated by individuals who become lost to follow-up (LTFU) during care, particularly before receiving effective HCV treatment. We aimed to determine factors contributing to LTFU and whether LTFU is associated with mortality. Methods: In this secondary analysis, we constructed a database including individuals with HCV who were either LTFU (data from the nationwide HCV retrieval project, CELINE) or treated with directly acting antivirals (DAA) (data from Statistics Netherlands) between 2012 and 2019. This database was linked to mortality data from Statistics Netherlands. Determinants associated with being LTFU versus DAA-treated were assessed using logistic regression, and mortality rates were compared between groups using exponential survival models. These analyses were additionally stratified on calendar periods: 2012–2014, 2015–2017 and 2018–2019. Results: About 254 individuals, LTFU and 5547 DAA-treated were included. Being institutionalized (OR = 5.02, 95% confidence interval (CI) = 3.29–7.65), household income below the social minimum (OR = 1.96, 95% CI = 1.25–3.06), receiving benefits (OR = 1.74, 95% CI = 1.20–2.52) and psychiatric comorbidity (OR = 1.51, 95% CI = 1.09–2.10) were associated with LTFU. Mortality rates were significantly higher in individuals LTFU compared to those DAA-treated (2.99 vs. 1.15/100 person-years (PY), p &lt;.0001), while in those DAA-treated, mortality rates slowly increased between 2012–2014 (.22/100PY) and 2018–2019 (2.25/100PY). Conclusion: In the Netherlands, individuals who are incarcerated/institutionalized, with low household income, or with psychiatric comorbidities are prone to being LTFU, which is associated with higher mortality. HCV care needs to be adapted for these vulnerable individuals.</p

Current status of Phytophthora in Australia

Among the most economically relevant and environmentally devastating diseases globally are those caused by Phytophthora species. In Australia, production losses in agriculture and forestry results from several well-known cosmopolitan Phytophthora species and infestation of natural ecosystems by Phytophthora cinnamomi have caused irretrievable loss to biodiversity, especially in proteaceous dominated heathlands. For this review, all available records of Phytophthora in Australia were collated and curated, resulting in a database of 7 869 records, of which 2 957 have associated molecular data. Australian databases hold records for 99 species, of which 20 are undescribed. Eight species have no records linked to molecular data, and their presence in Australia is considered doubtful. The 99 species reside in 10 of the 12 clades recognised within the complete phylogeny of Phytophthora. The review includes discussion on each of these species’ status and additional information provided for another 29 species of concern. The first species reported in Australia in 1900 was Phytophthora infestans. By 2000, 27 species were known, predominantly from agriculture. The significant increase in species reported in the subsequent 20 years has coincided with extensive surveys in natural ecosystems coupled with molecular taxonomy and the recognition of numerous new phylogenetically distinct but morphologically similar species. Routine and targeted surveys within Australian natural ecosystems have resulted in the description of 27 species since 2009. Due to the new species descriptions over the last 20 years, many older records have been reclassified based on molecular identification. The distribution of records is skewed toward regions with considerable activity in high productivity agriculture, horticulture and forestry, and native vegetation at risk from P. cinnamomi. Native and exotic hosts of different Phytophthora species are found throughout the phylogeny; however, species from clades 1, 7 and 8 are more likely to be associated with exotic hosts. One of the most difficult challenges to overcome when establishing a pest status is a lack of reliable data on the current state of a species in any given country or location. The database compiled here for Australia and the information provided for each species overcomes this challenge. This review will aid federal and state governments in risk assessments and trade negotiations by providing a comprehensive resource on the current status of Phytophthora species in Australia