The 2017 Vermont Opioid Prescribing Rules: Prescriber Attitudes

Introduction. In July of 2017, Vermont enacted new rules on acute opioid pre- scribing to reduce misuse, addiction, and overdose associated with prescription opioids. The new rules include requirements of non-opioid therapy use when possible, querying VPMS, patient education and informed consent, and co-prescription of naloxone. Our study objective was to gain insight into the perspectives of opioid prescribers on the new rules. Methods. The 17-item survey included closed and open-ended questions addressing prescriber perceptions about the new rules as well as demographic information about respondents. The survey was sent to Vermont-based opioid prescribers via email, to multiple healthcare organizations and professional societies, and through personal contacts. Open-ended responses were categorized using paired reviewers and group consensus, using a grounded theory approach. Results. A total of 431 responses were obtained, with MD/DOs accounting for 65%, APRNs- 14%, DDS/DMD- 7%, PAs-13%, and NDs- 1%. Of the respondents, 75% thought that more restrictive opioid prescribing rules were necessary, 74% felt the new rules would have some positive effect on the opioid crisis, but only 48% were in favor of the new rules. Barriers to implementation included co-prescribing naloxone (50% were unsuccessful), justifying exceptions to rules in medical record (46% unsuc- cessful), considering non-pharmacologic therapies (39% unsuccessful), and adhering to prescription limits (31% unsuccessful). Conclusions. Roll-out of the new rules has been criticized for implementation issues, overall reducing favorability among prescribers. Feedback obtained may be utilized by the Vermont Health Department and by other states to improve current models of opioid prescribing.https://scholarworks.uvm.edu/comphp_gallery/1264/thumbnail.jp

Antimicrobial activity of extracts from native plants of temperate Australia

Introduction: Significant effort has been invested in looking at the antimicrobial activity of plant extracts from tropical regions of Australia, with less interest in those from more temperate environments. We sought to redress this imbalance by examining antimicrobial activities of extracts from native plants of Victoria. Methods: Sixteen plant samples were obtained around the Ballarat region of Victoria. Plant material was desiccated, ground and extracted with methanol at room temperature. Methanol extracts were subsequently dissolved in water, filtered and freeze dried. Extracts were dissolved in water and their activity determined against eight bacterial species. Plant extracts that showed appreciable antibacterial activity in the initial antimicrobial screen were examined further with both their MICs and MBCs determined. Results: Ten of the sixteen plant extracts showed antimicrobial activity. Extracts of Eucalyptus, Melaleuca, Prostanthera and Westringia were particularly active with MICs as low as 0.25 mg/ml against organisms including P. aeruginosa and S. aureus. Conclusion: The current study demonstrates the antimicrobial activity of plant extracts from temperate Australia. These may serve as precursors for future chemotherapy agents

Ischemic preconditioning in the liver is independent of regulatory T cell activity

Ischemic preconditioning (IPC) protects organs from ischemia reperfusion injury (IRI) through unknown mechanisms. Effector T cell populations have been implicated in the pathogenesis of IRI, and T regulatory cells (Treg) have become a putative therapeutic target, with suggested involvement in IPC. We explored the role of Treg in hepatic IRI and IPC in detail. IPC significantly reduced injury following ischemia reperfusion insults. Treg were mobilized rapidly to the circulation and liver after IRI, but IPC did not further increase Treg numbers, nor was it associated with modulation of circulating pro-inflammatory chemokine or cytokine profiles. We used two techniques to deplete Treg from mice prior to IRI. Neither Treg depleted FoxP3.LuciDTR mice, nor wildtyoe mice depleted of Tregs with PC61, were more susceptible to IRI compared with controls. Despite successful enrichment of Treg in the liver, by adoptive transfer of both iTreg and nTreg or by in vivo expansion of Treg with IL-2/anti-IL-2 complexes, no protection against IRI was observed.We have explored the role of Treg in IRI and IPC using a variety of techniques to deplete and enrich them within both the liver and systemically. This work represents an important negative finding that Treg are not implicated in IPC and are unlikely to have translational potential in hepatic IRI

Identifying cell enriched miRNAs in kidney injury and repair

Small noncoding RNAs, miRNAs (miRNAs), are emerging as important modulators in the pathogenesis of kidney disease, with potential as biomarkers of kidney disease onset, progression, or therapeutic efficacy. Bulk tissue small RNA-sequencing (sRNA-Seq) and microarrays are widely used to identify dysregulated miRNA expression but are limited by the lack of precision regarding the cellular origin of the miRNA. In this study, we performed cell-specific sRNA-Seq on tubular cells, endothelial cells, PDGFR-β+ cells, and macrophages isolated from injured and repairing kidneys in the murine reversible unilateral ureteric obstruction model. We devised an unbiased bioinformatics pipeline to define the miRNA enrichment within these cell populations, constructing a miRNA catalog of injury and repair. Our analysis revealed that a significant proportion of cell-specific miRNAs in healthy animals were no longer specific following injury. We then applied this knowledge of the relative cell specificity of miRNAs to deconvolute bulk miRNA expression profiles in the renal cortex in murine models and human kidney disease. Finally, we used our data-driven approach to rationally select macrophage-enriched miR-16-5p and miR-18a-5p and demonstrate that they are promising urinary biomarkers of acute kidney injury in renal transplant recipients

Notch3 drives development and progression of cholangiocarcinoma

The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of the mediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent

Acute Liver Injury Is Independent of B Cells or Immunoglobulin M

Acute liver injury is a clinically important pathology and results in the release of Danger Associated Molecular Patterns, which initiate an immune response. Withdrawal of the injurious agent and curtailing any pathogenic secondary immune response may allow spontaneous resolution of injury. The role B cells and Immunoglobulin M (IgM) play in acute liver injury is largely unknown and it was proposed that B cells and/or IgM would play a significant role in its pathogenesis.Tissue from 3 models of experimental liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury) and patients transplanted following paracetamol overdose were stained for evidence of IgM deposition. Mice deficient in B cells (and IgM) were used to dissect out the role B cells and/or IgM played in the development or resolution of injury. Serum transfer into mice lacking IgM was used to establish the role IgM plays in injury.Significant deposition of IgM was seen in the explanted livers of patients transplanted following paracetamol overdose as well as in 3 experimental models of acute liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury). Serum transfer into IgM-deficient mice failed to reconstitute injury (p = 0.66), despite successful engraftment of IgM. Mice deficient in both T and B cells (RAG1-/-) mice (p<0.001), but not B cell deficient (μMT) mice (p = 0.93), were significantly protected from injury. Further interrogation with T cell deficient (CD3εKO) mice confirmed that the T cell component is a key mediator of sterile liver injury. Mice deficient in B cells and IgM mice did not have a significant delay in resolution following acute liver injury.IgM deposition appears to be common feature of both human and murine sterile liver injury. However, neither IgM nor B cells, play a significant role in the development of or resolution from acute liver injury. T cells appear to be key mediators of injury. In conclusion, the therapeutic targeting of IgM or B cells (e.g. with Rituximab) would have limited benefit in protecting patients from acute liver injury

Carriage rate and antibiotic susceptibility of coagulase-positive staphylococci isolated from healthy dogs in Victoria, Australia

Background: Studies in Australia and elsewhere have shown high levels of antibiotic resistance in coagulase-positive staphylococci in dogs visiting veterinary clinics with pyoderma and related conditions. Although important, such studies tend to overestimate the burden of resistance. The aim of the current study was to investigate the prevalence of coagulase-positive staphylococci in healthy dogs in Central Victoria to assess the level of antibiotic resistance among these isolates. Methods: We recruited 117 healthy dogs into the study. Swabs were taken at four sites (ear, mouth, nose, perineum) and staphylococcal species identified and isolated using culture and biochemical techniques. Results: Staphylococcus pseudintermedius and S. aureus were recovered from 100 and 17 dogs, respectively; 15 dogs were simultaneously co-colonised with both organisms. The mouth and perineum were the most sensitive sites for recovery of these organisms. The most commonly encountered resistances were penicillin (95.2% and 72.4% in S. aureus and S. pseudintermedius, respectively) and doxycycline/tetracycline (19.7% in S. pseudintermedius). No methicillin-resistant S. aureus were recovered, but two phenotypically methicillin-resistant S. pseudintermedius (MRSP) isolates were recovered, although only one was PCR-positive for the mecA gene. Notably the MRSP isolate was multidrug resistant, as it also exhibited resistance to mupirocin and erythromycin. Conclusion: With the exception of penicillin, doxycycline and tetracycline, the level of resistance to the antimicrobial agents tested was minimal. Prudent antibiotic use in treating companion animals with skin infections will reduce the selection of MRSP and other multidrug-resistant bacteria. © 2016 Australian Veterinary Associatio

Polymyxin resistant bacteria in Australian poultry

Resistance to last-resort antibiotics is significant public health issue. Antibiotic use in animal husbandry may be a driver of resistance that can subsequently be disseminated via the food chain. This study sought to determine the level of polymyxin resistance in Gram-negative pathogens present in Australian poultry, particularly the presence of mobilizable mechanisms of polymyxin resistance. Cloacal swabs from 213 birds were taken in a point prevalence survey from six different farms at a Victorian chicken processing facility. Colistin resistant organisms were recovered by direct plating on CHROMagar COL-APSE media. Bacterial isolates were identified and analyzed by MALDI-TOF, biochemical and genotypic assays. The 213 specimens yielded 57 (26.8%) colistin-resistant Gram-negative organisms, all of which have been previously described as exhibiting intrinsic resistance to polymyxin antibiotics. The most frequent organism was identified as Hafnia paralvei (40/57; 70%). Other colistin-resistant organisms included Aeromonas hydrophila (16%), Myroides odoratus (7%), Alcaligenes faecalis (5%), and Pseudochrobactrum spp. (2%). No mobile colistin resistance (mcr) genes were detected, although the arnA gene was identified in two A. hydrophila isolates and may mediate colistin resistance in these isolates. Intrinsic polymyxin-resistant organisms are widely distributed in the food chain, with over a quarter of the birds tested yielding a polymyxin-resistant organism. However, strains containing mcr genes remain rare in Australian poultry. © Copyright © 2020 Bean, Wigmore, Abdul Momin and Wareham