Policy, practice, and prediction: model-based approaches to evaluating N. gonorrhoeae antibiotic susceptibility test uptake in Australia.

BACKGROUND: Antimicrobial resistance (AMR) represents a significant threat to global health with Neisseria gonorrhoea emerging as a key pathogen of concern. In Australia, the Australian Gonococcal Surveillance Program (AGSP) plays a critical role in monitoring resistance patterns. However, antibiotic susceptibility test (AST) uptake - a crucial component for effective resistance surveillance - remains to be a limiting factor. The study aims to model the processes involved in generating AST tests for N. gonorrhoea isolates within the Australian healthcare system and assess the potential impact of systematic and policy-level changes. METHODS: Two models were developed. The first model was a mathematical stochastic health systems model (SHSM) and a Bayesian Belief Network (BBN) to simulate the clinician-patient dynamics influencing AST initiation. Key variables were identified through systematic literature review to inform the construction of both models. Scenario analyses were conducted with the modification of model parameters. RESULTS: The SHSM and BBN highlighted clinician education and the use of clinical support tools as effective strategies to improve AST. Scenario analysis further identified adherence to guidelines and changes in patient-level factors, such as persistence of symptoms and high-risk behaviours, as significant determinants. Both models supported the notion of mandated testing to achieve higher AST initiation rates but with considerations necessary regarding practicality, laboratory constraints, and culture failure rate. CONCLUSION: The study fundamentally demonstrates a novel approach to conceptualising the patient-clinician dynamic within AMR testing utilising a model-based approach. It suggests targeted interventions to educational, support tools, and legislative framework as feasible strategies to improve AST initiation rates. However, the research fundamentally highlights substantial research gaps in the underlying understanding of AMR.

Strengthening antimicrobial resistance surveillance systems: a scoping review.

BACKGROUND: Antimicrobial resistance (AMR) is an emerging global public health crisis. Surveillance is a fundamental component in the monitoring and evaluation of AMR mitigation endeavours. The primary aim of the scoping review is to identify successes, barriers, and gaps in implementing AMR surveillance systems and utilising data from them. METHODS: PubMed, Web of Science, SCOPUS, and EMBASE databases were searched systematically to identify literature pertaining to implementation, monitoring, and evaluation of AMR surveillance systems. A thematic analysis was conducted where themes within the literature were inductively grouped based on the described content. RESULTS: The systematic search yielded 639 journal articles for screening. Following deduplication and screening, 46 articles were determined to be appropriate for inclusion. Generally, most studies focused on human AMR surveillance (n = 38, 82.6%). Regionally, there was equal focus on low- and middle-income countries (n = 7, 15.2%) and trans-national contexts (n = 7, 14.5%). All included articles (n = 46, 100.0%) discussed barriers to either implementing or utilising AMR surveillance systems. From the scoping review, 6 themes emerged: capacity for surveillance, data infrastructure, policy, representativeness, stakeholder engagement, and sustainability. Data infrastructure was most frequently discussed as problematic in evaluation of surveillance systems (n = 36, 75.0%). The most frequent success to surveillance system implementation was stakeholder engagement (n = 30, 65.2%). CONCLUSIONS: Experiences of AMR surveillance systems are diverse across contexts. There is a distinct separation of experiences between systems with emerging surveillance systems and those with established systems. Surveillance systems require extensive refinement to become representative and meet surveillance objectives.

Enhancing Insights into Australia's Gonococcal Surveillance Programme through Stochastic Modelling.

Continued surveillance of antimicrobial resistance is critical as a feedback mechanism for the generation of concerted public health action. A characteristic of importance in evaluating disease surveillance systems is representativeness. Scenario tree modelling offers an approach to quantify system representativeness. This paper utilises the modelling approach to assess the Australian Gonococcal Surveillance Programme's representativeness as a case study. The model was built by identifying the sequence of events necessary for surveillance output generation through expert consultation and literature review. A scenario tree model was developed encompassing 16 dichotomous branches representing individual system sub-components. Key classifications included biological sex, clinical symptom status, and location of healthcare service access. The expected sensitivities for gonococcal detection and antibiotic status ascertainment were 0.624 (95% CI; 0.524, 0.736) and 0.144 (95% CI; 0.106, 0.189), respectively. Detection capacity of the system was observed to be high overall. The stochastic modelling approach has highlighted the need to consider differential risk factors such as sex, health-seeking behaviours, and clinical behaviour in sample generation. Actionable points generated by this study include modification of clinician behaviour and supplementary systems to achieve a greater contextual understanding of the surveillance data generation process.

2-Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon-like peptide 1 receptor.

We report the discovery of two new 2-aminothiophene based small molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes. One of the chemotypes, (S-1), has a molecular weight of 239 g/mol, the smallest molecule among all reported GLP-1R PAMs. When combined with GLP-1 peptide, S-1 increased the GLP-1R activity in a dose-dependent manner in a cell-based assay. When combined with the peptide agonist of vasoactive intestinal polypeptide receptor 1 (VIPR1), S-1 showed no specific activity on VIPR1, another class B GPCR present in the same HEK293-CREB cell line. Insulin secretion studies found S-1 combined with GLP-1 increased insulin secretion by 1.5-fold at 5 µM. In a mechanistic study, evidence is provided that the synergistic effect of S-1 with GLP-1 may be partly due to the enhanced impact on CREB based phosphorylation. Given the favorable profile of these chemotypes, the work reported herein suggests that 2-aminothiophene derivatives are a new and promising class of GLP-1R PAMs.

The hydroperoxyl radical scavenging activity of sulfuretin: insights from theory.

Sulfuretin (SFR), which is isolated from Rhus verniciflua, Toxicodendron vernicifluum, Dahlia, Bidens tripartite and Dipterx lacunifera, is one of the most important natural flavonoids. This compound is known to have numerous biological activities; among these, the antioxidant activity has not been thoroughly studied yet. In this study, the hydroperoxyl scavenging activity of SFR was examined by using density functional theory calculations. SFR is predicted to be an excellent HOO• scavenger in water at pH = 7.40 with k overall = 4.75 × 107 M-1 s-1, principally due to an increase in the activity of the anionic form following the single-electron transfer mechanism. Consistently, the activity of the neutral form is more prominent in the non-polar environment with k overall = 1.79 × 104 M-1 s-1 following the formal hydrogen transfer mechanism. Thus, it is predicted that SFR exhibits better HOO• antiradical activity than typical antioxidants such as resveratrol, ascorbic acid or Trolox in the lipid medium. The hydroperoxyl radical scavenging of SFR in the aqueous solution is approximately 530 times faster than that of Trolox and similar to ascorbic acid or resveratrol. This suggests that SFR is a promising radical scavenger in physiological environments.