International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

New and Revised ICH Guidelines: Insight and Challenges

It is a forum article, abstract is not require

Hepatic Gene Expression of Angiogenic and Regeneration Markers in Cats with Congenital Portosystemic Shunts (CPSS)

Congenital portosystemic shunts (CPSS) are vascular anomalies resulting in liver hypoplasia and hepatic insufficiency. Cats with CPSS typically show signs of hepatic encephalopathy associated with increased ammonia, inflammatory cytokines, and oxidative stress. Surgical attenuation of the CPSS results in improved liver function, resolution of clinical signs, and increased portal blood flow. Hepatic gene expression has not previously been investigated in cats with CPSS. Here, we compared the hepatic expression of genes involved in the urea cycle (CPS1, NAGS), angiogenesis (VEGFR2, NPPA, NPR1, NPPC, NPR2, HIF1a), liver regeneration (SERPINB1, HGF, TGFβ), and metabolism (FGF21) from a small series of cats (n = 18) with CPSS to that of control cats (n = 10). The expression of TGFβ, VEGFR2, HGF, FGF21, and CPS1 was significantly elevated in liver biopsies from cats with CPSS. Cats that could only tolerate partial closure of their CPSS had increased hepatic expression of SERPINB1, HIF1a, and NPR2 compared with those that could tolerate complete ligation. Furthermore, there were no significant correlations between gene expression and pre-operative plasma ammonia concentrations in cats with CPSS. The changes in hepatic gene expression in cats with CPSS are in direct contrast to those seen in dogs with CPSS, suggesting alternative mechanisms may be involved in mediating hepatic changes in cats with CPSS

Hepatic Gene Expression of Angiogenic and Regeneration Markers in Cats with Congenital Portosystemic Shunts (CPSS).

Peer reviewed: TrueAcknowledgements: The authors would like to thank Séverine Tasker and colleagues at the Feline Centre and Veterinary Pathology Unit, Langford Vets, University of Bristol, who have assisted in obtaining control samples at post-mortem examination for the Bristol Vet School biobank.Publication status: PublishedCongenital portosystemic shunts (CPSS) are vascular anomalies resulting in liver hypoplasia and hepatic insufficiency. Cats with CPSS typically show signs of hepatic encephalopathy associated with increased ammonia, inflammatory cytokines, and oxidative stress. Surgical attenuation of the CPSS results in improved liver function, resolution of clinical signs, and increased portal blood flow. Hepatic gene expression has not previously been investigated in cats with CPSS. Here, we compared the hepatic expression of genes involved in the urea cycle (CPS1, NAGS), angiogenesis (VEGFR2, NPPA, NPR1, NPPC, NPR2, HIF1a), liver regeneration (SERPINB1, HGF, TGFβ), and metabolism (FGF21) from a small series of cats (n = 18) with CPSS to that of control cats (n = 10). The expression of TGFβ, VEGFR2, HGF, FGF21, and CPS1 was significantly elevated in liver biopsies from cats with CPSS. Cats that could only tolerate partial closure of their CPSS had increased hepatic expression of SERPINB1, HIF1a, and NPR2 compared with those that could tolerate complete ligation. Furthermore, there were no significant correlations between gene expression and pre-operative plasma ammonia concentrations in cats with CPSS. The changes in hepatic gene expression in cats with CPSS are in direct contrast to those seen in dogs with CPSS, suggesting alternative mechanisms may be involved in mediating hepatic changes in cats with CPSS

‘All Aboriginal and Torres Strait Islander children should have access to the ASQ‐TRAK ’ : shared vision of an implementation support model for the ASQ‐TRAK developmental screener

Issue Addressed The ASQ-TRAK, a strengths-based approach to developmental screening, has high acceptability and utility across varied Aboriginal and Torres Strait Islander contexts. While substantive knowledge translation has seen many services utilise ASQ-TRAK, we now need to move beyond distribution and support evidence-based scale-up to ensure access. Through a co-design approach, we aimed to (1) understand community partners' perspectives of barriers and enablers to ASQ-TRAK implementation and (2) develop an ASQ-TRAK implementation support model to inform scale-up. Methods The co-design process had four phases: (i) partnership development with five community partners (two Aboriginal Community Controlled Organisations); (ii) workshop planning and recruitment; (iii) co-design workshops; and (iv) analysis, draft model and feedback workshops. Results Seven co-design meetings and two feedback workshops with 41 stakeholders (17 were Aboriginal and Torres Strait Islander), identified seven key barriers and enablers, and a shared vision – all Aboriginal and Torres Strait Islander children and their families have access to the ASQ-TRAK. Implementation support model components agreed on were: (i) ASQ-TRAK training, (ii) ASQ-TRAK support, (iii) local implementation support, (iv) engagement and communications, (v) continuous quality improvement and (vi) coordination and partnerships. Conclusions This implementation support model can inform ongoing processes necessary for sustainable ASQ-TRAK implementation nationally. This will transform the way services provide developmental care to Aboriginal and Torres Strait Islander children, ensuring access to high quality, culturally safe developmental care