Swine influenza A virus infection dynamics and evolution in intensive pig production systems.

Swine influenza A virus (swIAV) is one of the main viral pathogens responsible for respiratory disease in farmed pigs. While outbreaks are often epidemic in nature, increasing reports suggest that continuous, endemic infection of herds is now common. The move towards larger herd sizes and increased intensification in the commercial pig industry may promote endemic infection; however, the impact that intensification has on swIAV infection dynamics and evolution is unclear. We carried out a longitudinal surveillance study for over 18 months on two enzootically infected, intensive, indoor, and multi-site pig production flows. Frequent sampling of all production stages using individual and group sampling methods was performed, followed by virological and immunological testing and whole-genome sequencing. We identified weaned pigs between 4 and 12-weeks old as the main reservoir of swIAV in the production flows, with continuous, year-round infection. Despite the continuous nature of viral circulation, infection levels were not uniform, with increasing exposure at the herd level associated with reduced viral prevalence followed by subsequent rebound infection. A single virus subtype was maintained on each farm for the entire duration of the study. Viral evolution was characterised by long periods of stasis punctuated by periods of rapid change coinciding with increasing exposure within the herd. An accumulation of mutations in the surface glycoproteins consistent with antigenic drift was observed, in addition to amino acid substitutions in the internal gene products as well as reassortment exchange of internal gene segments from newly introduced strains. These data demonstrate that long-term, continuous infection of herds with a single subtype is possible and document the evolutionary mechanisms utilised to achieve this.

Examining the forgotten valve: outcomes of tricuspid valve surgery, a 15-year experience.

BACKGROUND: We have entered an era of renewed interest in novel approaches to surgical intervention and minimally invasive and transcatheter technique. With an aging population, isolated tricuspid valve regurgitation incidence is rising; however, referral for surgical intervention remains low. AIMS: We undertook this retrospective review to assess outcomes and challenges associated with tricuspid valve intervention. METHODS: A comprehensive retrospective review of all patients undergoing tricuspid valve intervention in our institution between 2004 and 2018 was carried out. RESULTS: A total of 259 patients who underwent a tricuspid intervention between 2004 and 2018 were identified. Of those, 229 underwent a repair and 30 underwent a replacement. Median survival for repair was 3124 days, and replacement was 2294 days. In-patient mortality was 12% for those undergoing repair and 7% for the replacement patients. Of those undergoing redo tricuspid valve intervention, eight patients (61.5%) were alive at most recent follow-up. Eight patients required intraoperative pacemakers, 2 required postoperative pacemakers. Of those who had intraoperative epicardial pacing systems placed, 5 of the 8 remained pacing dependent on most recent follow up. CONCLUSION: Beyond technical challenges, decision making regarding pacemaker requirement requires further exploration. Redo tricuspid valve surgery carries a significant mortality risk and consideration should be given to earlier intervention in this context.

c-Met inhibition in a HOXA9/Meis1 model of CN-AML.

BACKGROUND: Hematopoiesis is a paradigm for developmental processes, hierarchically organized, with stem cells at its origin. Hematopoietic stem cells (HSCs) replenish progenitor and precursor cells of multiple lineages, which normally differentiate into short-lived mature circulating cells. Hematopoiesis has provided insight into the molecular basis of tissue homeostasis and malignancy. Malignant hematopoiesis, in particular acute myeloid leukemia (AML), results from impaired development or differentiation of HSCs and progenitors. Co-overexpression of HOX and TALE genes, particularly the HOXA cluster and MEIS1, is associated with AML. Clinically relevant models of AML are required to advance drug development for an aging patient cohort. RESULTS: Molecular analysis identified altered gene, microRNA, and protein expression in HOXA9/Meis1 leukemic bone marrow compared to normal controls. A candidate drug screen identified the c-Met inhibitor SU11274 for further analysis. Altered cell cycle status, apoptosis, differentiation, and impaired colony formation were shown for SU11274 in AML cell lines and primary leukemic bone marrow. CONCLUSIONS: The clonal HOXA9/Meis1 AML model is amenable to drug screening analysis. The data presented indicate that human AML cells respond in a similar manner to the HOXA9/Meis1 cells, indicating pre-clinical relevance of the mouse model.