TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids.

Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to resistance to CAR T-cell therapy in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. In this study, we examined the activity of B7-H3-directed CAR T cells (B7-H3.

Successful management of a multi-species outbreak of carbapenem-resistant organisms in Fiji: a prospective genomics-enhanced investigation and response.

Background: Fiji is a Pacific Island nation grappling with the increasing threat of antimicrobial resistance (AMR). While genomic technologies are increasingly utilised to understand the emergence and spread of AMR globally, its application to inform outbreak responses in low- and middle-income settings has not been reported.

Methods: Through an established capacity building program, suspected carbapenem-resistant organisms (CRO) identified at Colonial War Memorial Hospital in Fiji (Jan 2022-Oct 2023) underwent whole genome sequencing and analysis.

Wild-Type Domestication: Loss of Intrinsic Metabolic Traits Concealed by Culture in Rich Media.

Bacteria are typically isolated on rich media to maximise isolation success, removing them from their native evolutionary context. This eliminates selection pressures, enabling otherwise deleterious genomic events to accumulate. Here, we present a cautionary tale of these 'quiet mutations' which can persist unnoticed in bacterial culture lines.

Diversity, functional classification and genotyping of SHV β-lactamases in .

Interpreting the phenotypes of alleles in genomes is complex. Whilst all strains are expected to carry a chromosomal copy conferring resistance to ampicillin, they may also carry mutations in chromosomal alleles or additional plasmid-borne alleles that have extended-spectrum β-lactamase (ESBL) activity and/or β-lactamase inhibitor (BLI) resistance activity. In addition, the role of individual mutations/a changes is not completely documented or understood.

Genetic heterogeneity in the Typhi Vi capsule locus: a population genomic study from Fiji.

Typhoid fever is endemic in many parts of the world and remains a major public health concern in tropical and sub-tropical developing nations, including Fiji. To address high rates of typhoid fever, the Northern Division of Fiji implemented a mass vaccination with typhoid conjugate vaccine (Vi-polysaccharide conjugated to tetanus toxoid) as a public health control measure in 2023. In this study we define the genomic epidemiology of Typhi in the Northern Division prior to island-wide vaccination, sequencing 85% (=419) of the total cases from the Northern and Central Divisions of Fiji that occurred in the period 2017-2019.

Homophobic beliefs and attitudes among mid-adolescent boys: exploring the ideas of hybrid masculinities.

Introduction: Homophobia is well-documented as key to social regulation of masculine behavior and practices in Western settings. Yet, empirical data from a number of Western settings has shown a decline in overt homophobic attitudes in the past decade, leading some to suggest that the nature of masculinities is also changing. However, theorizing on the changing nature of masculinities among adolescents has received limited quantitative attention.

How long do nosocomial pathogens persist on inanimate surfaces? A scoping review.

Healthcare hygiene plays a crucial role in the prevention of healthcare-associated infections. Patients admitted to a room where the previous occupant had a multi-drug-resistant bacterial infection are at an increased risk of colonization and infection with the same organism. A 2006 systematic review by Kramer et al.

Genomic investigation of multispecies and multivariant outbreak reveals key role of horizontal plasmid transmission.

Objectives: New Delhi metallo-β-lactamases (NDMs) are major contributors to the spread of carbapenem resistance globally. In Australia, NDMs were previously associated with international travel, but from 2019 we noted increasing incidence of NDM-positive clinical isolates. We investigated the clinical and genomic epidemiology of NDM carriage at a tertiary-care Australian hospital from 2016 to 2021.

Development of a cross-sectoral antimicrobial resistance capability assessment framework.

Antimicrobial resistance (AMR) is an urgent and growing global health concern, and a clear understanding of existing capacities to address AMR, particularly in low-income and middle-income countries (LMICs), is needed to inform national priorities, investment targets and development activities. Across LMICs, there are limited data regarding existing mechanisms to address AMR, including national AMR policies, current infection prevention and antimicrobial prescribing practices, antimicrobial use in animals, and microbiological testing capacity for AMR. Despite the development of numerous individual tools designed to inform policy formulation and implementation or surveillance interventions to address AMR, there is an unmet need for easy-to-use instruments that together provide a detailed overview of AMR policy, practice and capacity.

Bactabolize is a tool for high-throughput generation of bacterial strain-specific metabolic models.

Metabolic capacity can vary substantially within a bacterial species, leading to ecological niche separation, as well as differences in virulence and antimicrobial susceptibility. Genome-scale metabolic models are useful tools for studying the metabolic potential of individuals, and with the rapid expansion of genomic sequencing there is a wealth of data that can be leveraged for comparative analysis. However, there exist few tools to construct strain-specific metabolic models at scale.

Genomic dissection of endemic carbapenem resistance reveals metallo-beta-lactamase dissemination through clonal, plasmid and integron transfer.

Infections caused by metallo-beta-lactamase-producing organisms (MBLs) are a global health threat. Our understanding of transmission dynamics and how MBLs establish endemicity remains limited. We analysed two decades of bla evolution in a hospital using sequence data from 270 clinical and environmental isolates (including 169 completed genomes) and identified the bla gene across 7 Gram-negative genera, 68 bacterial strains and 7 distinct plasmid types.

A Scoping Review on the Use of Experiential Learning in Professional Education on Intimate Partner Violence.

Purpose: Intimate partner violence (IPV) involves any form of emotional, physical, and sexual abuse including controlling behaviors by an intimate partner. Front line service workers such as social workers, nurses, lawyers, and physicians are often the first professionals to come into contact with individuals experiencing IPV but are often inadequately prepared to respond appropriately as IPV education is highly variable. Experiential learning (EL), also known as learning by doing, has gained much attention from educators; however, the extent and type of EL strategies used to teach IPV competencies has not yet been explored.

Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria.

Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20-40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection.

Antimicrobial susceptibility of bacterial isolates from clinical specimens in four Pacific Island countries, 2017-2021.

Background: There are limited antimicrobial resistance (AMR) surveillance data from low- and middle-income countries, especially from the Pacific Islands region. AMR surveillance data is essential to inform strategies for AMR pathogen control.

Methods: We performed a retrospective analysis of antimicrobial susceptibility results from the national microbiology laboratories of four Pacific Island countries - the Cook Islands, Kiribati, Samoa and Tonga - between 2017 and 2021.

Epidemiology and genomic analysis of Klebsiella oxytoca from a single hospital network in Australia.

Background: Infections caused by Klebsiella oxytoca are the second most common cause of Klebsiella infections in humans. Most studies have focused on K. oxytoca outbreaks and few have examined the broader clinical context of K.

ESBL plasmids in Klebsiella pneumoniae: diversity, transmission and contribution to infection burden in the hospital setting.

Background: Resistance to third-generation cephalosporins, often mediated by extended-spectrum beta-lactamases (ESBLs), is a considerable issue in hospital-associated infections as few drugs remain for treatment. ESBL genes are often located on large plasmids that transfer horizontally between strains and species of Enterobacteriaceae and frequently confer resistance to additional drug classes. Whilst plasmid transmission is recognised to occur in the hospital setting, the frequency and impact of plasmid transmission on infection burden, compared to ESBL + strain transmission, is not well understood.

LPS O Antigen Plays a Key Role in Klebsiella pneumoniae Capsule Retention.

Despite the importance of encapsulation in bacterial pathogenesis, the biochemical mechanisms and forces that underpin retention of capsule by encapsulated bacteria are poorly understood. In Gram-negative bacteria, there may be interactions between lipopolysaccharide (LPS) core and capsule polymers, between capsule polymers with retained acyl carriers and the outer membrane, and in some bacteria, between the capsule polymers and Wzi, an outer membrane protein lectin. Our transposon studies in Klebsiella pneumoniae B5055 identified additional genes that, when insertionally inactivated, resulted in reduced encapsulation.

Surveillance testing using salivary RT-PCR for SARS-CoV-2 in managed quarantine facilities in Australia: A laboratory validation and implementation study.

Background: Regular repeat surveillance testing is a strategy to identify asymptomatic individuals with SARS-CoV-2 infections in high-risk work settings to prevent onward community transmission. Saliva sampling is less invasive compared to nasal/oropharyngeal sampling, thus making it suitable for regular testing. In this multi-centre evaluation, we aimed to validate RT-PCR using salivary swab testing of SARS-CoV-2 for large-scale surveillance testing and assess implementation amongst staff working in the hotel quarantine system in Victoria, Australia.

Genomic epidemiology of Typhi in Central Division, Fiji, 2012 to 2016.

Background: Typhoid fever is endemic in some Pacific Island Countries including Fiji and Samoa yet genomic surveillance is not routine in such settings. Previous studies suggested imports of the global H58 clade of var Typhi ( Typhi) contribute to disease in these countries which, given the MDR potential of H58, does not auger well for treatment. The objective of the study was to define the genomic epidemiology of Typhi in Fiji.

Attributable mortality and excess length of stay associated with third-generation cephalosporin-resistant Enterobacterales bloodstream infections: a prospective cohort study in Suva, Fiji.

Objectives: There are scant primary clinical data on antimicrobial resistance (AMR) burden from low- and middle-income countries (LMICs). We adapted recent World Health Organization methodology to measure the effect of third-generation cephalosporin resistance (3GC-R) on mortality and excess length of hospital stay in Fiji.

Methods: We conducted a prospective cohort study of inpatients with Enterobacterales bloodstream infections (BSIs) at Colonial War Memorial Hospital, Suva.

Genomic dissection of Klebsiella pneumoniae infections in hospital patients reveals insights into an opportunistic pathogen.

Klebsiella pneumoniae is a major cause of opportunistic healthcare-associated infections, which are increasingly complicated by the presence of extended-spectrum beta-lactamases (ESBLs) and carbapenem resistance. We conducted a year-long prospective surveillance study of K. pneumoniae clinical isolates in hospital patients.

Higher childhood pneumonia admission threshold remains in Lao PDR: an observational study.

Objectives: WHO Integrated Management of Childhood Illness (IMCI) guidelines changed pneumonia hospitalisation criteria in 2014, which was implemented in Lao People's Democratic Republic (Lao PDR) in 2015. We determined adherence to: current (2014) IMCI guidelines for children presenting to hospitals with pneumonia, current outpatient management guidelines and identified hospitalisation predictors.

Design: Prospective observational study (January 2017 to December 2018).