The epidemiology of enterococci in a tertiary hospital and primary healthcare facilities in Fiji (2019-2022).

OBJECTIVES: We analysed 4 y of laboratory data to characterise the species and determine the antimicrobial susceptibility profiles of enterococci as human pathogens in Fiji. The study also investigated the molecular epidemiology amongst the subset of vancomycin-resistant enterococci (VRE). METHODS: This retrospective study reviewed bacteriological data from Colonial War Memorial Hospital (CWMH) and other healthcare facilities in the Central and Eastern divisions of Fiji. Phenotypic, antimicrobial susceptibility and vanA and vanB PCR testing were performed using locally approved protocols. The first clinical isolates per patient with antimicrobial susceptibility testing results in a single year were included in the analysis. Data was analysed using WHONET software and Microsoft Excel. RESULTS: A total of 1817 enterococcal isolates were reported, 1415 from CWMH and 402 from other healthcare facilities. The majority of isolates, 75% (n = 1362) were reported as undifferentiated Enterococcus spp., 17.8% (n = 324) were specifically identified as Enterococcus faecalis and 6.7% (n = 122) as E. faecium. Overall, 10% of the enterococci isolates were from blood cultures. Among isolates from CWMH, <15% of E. faecium were susceptible to ampicillin, and 17.2% were vancomycin resistant. Overall, 874 enterococcal isolates (including the undifferentiated species) were tested against vancomycin, of which 4.8% (n = 42) were resistance. All of the VRE isolates tested (n = 15) expressed vanA genes. CONCLUSIONS: This study demonstrates the clinical importance of VRE, particularly van A E. faecium in the national referral hospital in Fiji. Enhanced phenotypic and molecular surveillance data are needed to better understand enterococci epidemiology and help guide specific infection prevention and control measures and antibiotic prescribing guidelines.

The changing epidemiology of antimicrobial resistance in Fiji: a descriptive analysis of antimicrobial susceptibility and trends of endemic and emerging pathogens, 2019-2022.

Background: There is a paucity of data on antimicrobial resistance in Fiji. The aim of this study was to determine the antimicrobial susceptibility profile of bacterial isolates from clinical samples at Colonial War Memorial Hospital in Fiji. Methods: This retrospective study reviewed four-year of data from January 1, 2019, through December 31, 2022. Laboratory testing was carried out using locally approved protocols. Selective antimicrobial susceptibility testing was performed whereby only isolates resistant to first line antimicrobials were tested against second line antimicrobials. Only the first isolate of a given species per patient in a single year were included in the analysis. WHONET software and Microsoft Excel were used for analysis. Findings: A total of 29,222 bacterial isolates were included, 62% (n = 18,084) were Gram-negative bacteria. K. pneumoniae was the most common (n = 5363), followed by E. coli (n = 4321). Extended spectrum beta lactamase (ESBL) production increased from 30% in 2019 to 43% in 2022 amongst K. pneumoniae, and 10%-23% in E coli. There were 733 carbapenem-resistant isolates identified from clinical samples, 61% (n = 445) were A. baumannii, 15% (n = 110) E. coli and 14% (n = 101) P. aeruginosa. Amongst the E. coli isolates tested, susceptibility to meropenem declined from 99% (272/274) in 2019 to 79% (255/325) in 2022. The rate of methicillin resistance amongst Staphylococcus aureus was steady, remaining between 11% and 13%. Interpretation: This study demonstrated a high rate of MDR amongst Gram-negative bacteria, especially ESBL producing K. pneumoniae and E. coli and carbapenem-resistant A. baumannii. The emergence and rapid spread of carbapenemase producing E. coli in Fiji's largest hospital is of particular concern. There is an urgent need to allocate resources to improve existing capacity and to develop effective multimodal strategies to detect, manage and control the spread of MDR organisms. Funding: This study was supported by the Medical Research Future Fund through the Australian government (grant number APP 1200970).

Correction: Reproducible big data science: A case study in continuous FAIRness.

[This corrects the article DOI: 10.1371/journal.pone.0213013.].

Patterns of emergency department presentations for a youth mental health cohort: data-linkage cohort study.

BACKGROUND: Primary youth mental health services in Australia have increased access to care for young people, yet the longer-term outcomes and utilisation of other health services among these populations is unclear. AIMS: To describe the emergency department presentation patterns of a help-seeking youth mental health cohort. METHOD: Data linkage was performed to extract Emergency Department Data Collection registry data (i.e. emergency department presentations, pattern of re-presentations) for a transdiagnostic cohort of 7024 youths (aged 12-30 years) who presented to mental health services. Outcome measures were pattern of presentations and reason for presentations (i.e. mental illness; suicidal behaviours and self-harm; alcohol and substance use; accident and injury; physical illness; and other). RESULTS: During the follow-up period, 5372 (76.5%) had at least one emergency department presentation. The presentation rate was lower for males (IRR = 0.87, 95% CI 0.86-0.89) and highest among those aged 18 to 24 (IRR = 1.117, 95% CI 1.086-1.148). Almost one-third (31.12%) had an emergency department presentation that was directly associated with mental illness or substance use, and the most common reasons for presentation were for physical illness and accident or injury. Index visits for mental illness or substance use were associated with a higher rate of re-presentation. CONCLUSIONS: Most young people presenting to primary mental health services also utilised emergency services. The preventable and repeated nature of many presentations suggests that reducing the ongoing secondary risks of mental disorders (i.e. substance misuse, suicidality, physical illness) could substantially improve the mental and physical health outcomes of young people.

Characterising variability in youth mental health service populations: A detailed and scalable approach using digital technology.

OBJECTIVE: This study utilised digital technology to assess the clinical needs of young people presenting for care at headspace centres across Australia. METHOD: 1490 young people (12-25 years) who presented to one of 11 headspace services from four geographical locations (urban New South Wales, urban South Australia, regional New South Wales, and regional Queensland) completed a digital multidimensional assessment at initial presentation. Characteristics were compared between services and geographical locations. RESULTS: We identified major variation in the demographics, and the type and severity of needs across different services. Individuals from regional services were more likely to be younger, of Aboriginal and Torres Strait Islander origin, and present with psychotic-like symptoms and suicidality, while those in urban areas were more likely to have previously sought help and have problematic alcohol use. Further differences in age, distress, depressive symptoms, psychotic-like experiences, trauma, family history, alcohol use, education/employment engagement, and days out of role were identified between different urban sites. CONCLUSIONS: The variability between services provides insight into the heterogeneity of youth mental health populations which has implications for appropriate early intervention and prevention service provisions. We propose that integrating digital technologies has the potential to provide insights for smarter service planning and evaluation.

SAR towards indoline and 3-azaindoline classes of IDO1 inhibitors.

A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.

Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.

Atlas of Transcription Factor Binding Sites from ENCODE DNase Hypersensitivity Data across 27 Tissue Types.

Characterizing the tissue-specific binding sites of transcription factors (TFs) is essential to reconstruct gene regulatory networks and predict functions for non-coding genetic variation. DNase-seq footprinting enables the prediction of genome-wide binding sites for hundreds of TFs simultaneously. Despite the public availability of high-quality DNase-seq data from hundreds of samples, a comprehensive, up-to-date resource for the locations of genomic footprints is lacking. Here, we develop a scalable footprinting workflow using two state-of-the-art algorithms: Wellington and HINT. We apply our workflow to detect footprints in 192 ENCODE DNase-seq experiments and predict the genomic occupancy of 1,515 human TFs in 27 human tissues. We validate that these footprints overlap true-positive TF binding sites from ChIP-seq. We demonstrate that the locations, depth, and tissue specificity of footprints predict effects of genetic variants on gene expression and capture a substantial proportion of genetic risk for complex traits.

A synthesis of bacterial and archaeal phenotypic trait data.

A synthesis of phenotypic and quantitative genomic traits is provided for bacteria and archaea, in the form of a scripted, reproducible workflow that standardizes and merges 26 sources. The resulting unified dataset covers 14 phenotypic traits, 5 quantitative genomic traits, and 4 environmental characteristics for approximately 170,000 strain-level and 15,000 species-aggregated records. It spans all habitats including soils, marine and fresh waters and sediments, host-associated and thermal. Trait data can find use in clarifying major dimensions of ecological strategy variation across species. They can also be used in conjunction with species and abundance sampling to characterize trait mixtures in communities and responses of traits along environmental gradients.

A multivariate prognostic model for pain and activity limitation in people undergoing lumbar discectomy.

Purpose: The purpose of this study was to identify a multivariate predictive model for 6-month outcomes on overall pain, leg pain and activity limitation in patients undergoing lumbar discectomy. Identification of predictors of outcome for lumbar discectomy has the potential to assist identifying treatment targets, clinical decision making and disease understanding.Materials and methods: Prospective cohort design. Ninety-seven patients deemed by study surgeons to be suitable for lumbar discectomy completed a comprehensive clinical and radiological baseline assessment. At 6-months post surgery outcome measures of overall and leg pain (visual analogue scale) as well as activity limitation (Oswestry Disability Index) were completed. Univariate and multivariate analyses were conducted to determine the best multivariate predictive model of outcome.Results: In the multivariate model, presence of a compensation claim, longer duration of injury and presence of below knee pain and/or parasthesia were negative prognostic indicators for at least two of the outcomes. Peripheralization in response to mechanical loading strategies was a positive prognostic indicator for overall pain and leg pain. A range of other prognostic indicators for one outcome were also identified. The prognostic model explained up to 32% of the variance in outcome.Conclusions: An 11-factor prognostic model was identified from a range of clinically and radiologically assessed variables in accordance with a biopsychosocial model. The multivariate model has potential implications for researchers and practitioners in the field. Further high quality research is required to externally validate the prognostic model, evaluate effect of the identified prognostic factors on treatment effectiveness and explore potential mechanisms of effect.

Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like Chemical Space.

Although the potential value of RNA as a target for new small molecule therapeutics is becoming increasingly credible, the physicochemical properties required for small molecules to selectively bind to RNA remain relatively unexplored. To investigate the druggability of RNAs with small molecules, we have employed affinity mass spectrometry, using the Automated Ligand Identification System (ALIS), to screen 42 RNAs from a variety of RNA classes, each against an array of chemically diverse drug-like small molecules (~50,000 compounds) and functionally annotated tool compounds (~5100 compounds). The set of RNA-small molecule interactions that was generated was compared with that for protein-small molecule interactions, and naïve Bayesian models were constructed to determine the types of specific chemical properties that bias small molecules toward binding to RNA. This set of RNA-selective chemical features was then used to build an RNA-focused set of ~3800 small molecules that demonstrated increased propensity toward binding the RNA target set. In addition, the data provide an overview of the specific physicochemical properties that help to enable binding to potential RNA targets. This work has increased the understanding of the chemical properties that are involved in small molecule binding to RNA, and the methodology used here is generally applicable to RNA-focused drug discovery efforts.

The Evolving Case Supporting Individualised Physiotherapy for Low Back Pain.

Low-back pain (LBP) is one of the most burdensome health problems in the world. Guidelines recommend simple treatments such as advice that may result in suboptimal outcomes, particularly when applied to people with complex biopsychosocial barriers to recovery. Individualised physiotherapy has the potential of being more effective for people with LBP; however, there is limited evidence supporting this approach. A series of studies supporting the mechanisms underpinning and effectiveness of the Specific Treatment of Problems of the Spine (STOPS) approach to individualised physiotherapy have been published. The clinical and research implications of these findings are presented and discussed. Treatment based on the STOPS approach should also be considered as an approach to individualised physiotherapy in people with LBP.

Reproducible big data science: A case study in continuous FAIRness.

Big biomedical data create exciting opportunities for discovery, but make it difficult to capture analyses and outputs in forms that are findable, accessible, interoperable, and reusable (FAIR). In response, we describe tools that make it easy to capture, and assign identifiers to, data and code throughout the data lifecycle. We illustrate the use of these tools via a case study involving a multi-step analysis that creates an atlas of putative transcription factor binding sites from terabytes of ENCODE DNase I hypersensitive sites sequencing data. We show how the tools automate routine but complex tasks, capture analysis algorithms in understandable and reusable forms, and harness fast networks and powerful cloud computers to process data rapidly, all without sacrificing usability or reproducibility-thus ensuring that big data are not hard-to-(re)use data. We evaluate our approach via a user study, and show that 91% of participants were able to replicate a complex analysis involving considerable data volumes.

Individualised manual therapy plus guideline-based advice vs advice alone for people with clinical features of lumbar zygapophyseal joint pain: a randomised controlled trial.

OBJECTIVES: To determine whether individualised manual therapy plus guideline-based advice results in superior outcomes to advice alone in participants with clinical features potentially indicative of lumbar zygapophyseal joint pain. DESIGN: Multi centre parallel group randomised controlled trial. SETTING: 14 physiotherapy clinics in Melbourne, Australia. PARTICIPANTS: Sixty-four participants with clinical features potentially indicative of lumbar zygapophyseal joint pain. INTERVENTIONS: 10-weeks of physiotherapy comprising individualised manual therapy based on pathoanatomical, psychosocial and neurophysiological barriers to recovery plus guideline-based advice (10 sessions) or advice alone (two sessions). MAIN OUTCOME MEASURES: Primary outcomes were activity limitation (Oswestry Disability Index), and separate 0 to 10 numerical rating scales for leg pain and back pain. Measures were taken at baseline and 5, 10, 26 and 52-week. RESULTS: Between-group differences for back pain favoured individualised manual therapy over advice for back pain at 5 (1.0; 95% CI 0.6 to 2.0), 10 (1.5; 95% CI 0.5 to 2.4) and 26-weeks (1.4; 95% CI 0.4 to 2.3) as well as for activity limitation at 26 (8.3; 95% CI 2.6 to 14.2) and 52-weeks (8.2; 95% CI 2.3 to 14.2). There were no significant between-group differences for leg pain. Secondary outcomes and responder analyses also favoured individualised manual therapy at almost all time-points. CONCLUSIONS: In participants with clinical features potentially indicative of lumbar zygapophyseal joint pain, individualised manual therapy led to greater reduction in back pain at 5, 10 and 26-week follow-up as well as activity limitation at 26 and 52-weeks. Between-group differences were likely to be clinically important. TRIAL REGISTRATION: ACTRN12609000334202.

A 5-day intensive curriculum for interns utilizing simulation and active-learning techniques: addressing domains important across internal medicine practice.

OBJECTIVE: Simulation-based learning strategies have demonstrated improved procedural competency, teamwork skills, and acute patient management skills in learners. "Boot camp" curricula have shown immediate and delayed performance in surgical and medical residents. We created a 5-day intensive, simulation and active learning-based curriculum for internal medicine interns to address perceived gaps in cognitive, affective and psychomotor domains. Intern confidence and self-perceived competence was assessed via survey before and after the curriculum, along with qualitative data. RESULTS: A total of 33 interns completed the curriculum in 2014, 32 in 2015. Interns had a significant increase in confidence and self-perceived competence in procedural, cognitive and affective domains (all p values < .05).

Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus.

Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer's disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD.

Nanoscale synthesis and affinity ranking.

Most drugs are developed through iterative rounds of chemical synthesis and biochemical testing to optimize the affinity of a particular compound for a protein target of therapeutic interest. This process is challenging because candidate molecules must be selected from a chemical space of more than 1060 drug-like possibilities 1 , and a single reaction used to synthesize each molecule has more than 107 plausible permutations of catalysts, ligands, additives and other parameters 2 . The merger of a method for high-throughput chemical synthesis with a biochemical assay would facilitate the exploration of this enormous search space and streamline the hunt for new drugs and chemical probes. Miniaturized high-throughput chemical synthesis3-7 has enabled rapid evaluation of reaction space, but so far the merger of such syntheses with bioassays has been achieved with only low-density reaction arrays, which analyse only a handful of analogues prepared under a single reaction condition8-13. High-density chemical synthesis approaches that have been coupled to bioassays, including on-bead 14 , on-surface 15 , on-DNA 16 and mass-encoding technologies 17 , greatly reduce material requirements, but they require the covalent linkage of substrates to a potentially reactive support, must be performed under high dilution and must operate in a mixture format. These reaction attributes limit the application of transition-metal catalysts, which are easily poisoned by the many functional groups present in a complex mixture, and of transformations for which the kinetics require a high concentration of reactant. Here we couple high-throughput nanomole-scale synthesis with a label-free affinity-selection mass spectrometry bioassay. Each reaction is performed at a 0.1-molar concentration in a discrete well to enable transition-metal catalysis while consuming less than 0.05 milligrams of substrate per reaction. The affinity-selection mass spectrometry bioassay is then used to rank the affinity of the reaction products to target proteins, removing the need for time-intensive reaction purification. This method enables the primary synthesis and testing steps that are critical to the invention of protein inhibitors to be performed rapidly and with minimal consumption of starting materials.

Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry.

Recent advances in understanding the relevance of noncoding RNA (ncRNA) to disease have increased interest in drugging ncRNA with small molecules. The recent discovery of ribocil, a structurally distinct synthetic mimic of the natural ligand of the flavin mononucleotide (FMN) riboswitch, has revealed the potential chemical diversity of small molecules that target ncRNA. Affinity-selection mass spectrometry (AS-MS) is theoretically applicable to high-throughput screening (HTS) of small molecules binding to ncRNA. Here, we report the first application of the Automated Ligand Detection System (ALIS), an indirect AS-MS technique, for the selective detection of small molecule-ncRNA interactions, high-throughput screening against large unbiased small-molecule libraries, and identification and characterization of novel compounds (structurally distinct from both FMN and ribocil) that target the FMN riboswitch. Crystal structures reveal that different compounds induce various conformations of the FMN riboswitch, leading to different activity profiles. Our findings validate the ALIS platform for HTS screening for RNA-binding small molecules and further demonstrate that ncRNA can be broadly targeted by chemically diverse yet selective small molecules as therapeutics.