The increasing healthcare burden of enteric fever in a low-incidence setting.

OBJECTIVES: Enteric fever carries appreciable morbidity in non-endemic settings, particularly in returned travelers. This study aimed to characterize the healthcare burden of enteric fever in a low-incidence setting and to identify risk factors and opportunities for preventative interventions. METHODS: Analysis of a retrospective case series from a tertiary pediatric center (2015-2019), augmented by public health notification and microbiological laboratory data (2018-2019), from Western Sydney, Australia, a region with frequent travel links to South Asia. RESULTS: Eighty-nine (89) patients were diagnosed with enteric fever, including 43 children with complete demographic and travel data. Enteric fever cases increased over time (by 4.9 % per year) and incidence was three times higher in the pediatric population (<15 years old) compared to adults. Travel to India and visiting friends and relatives (VFR) travel were risk factors. Few children received enteric fever vaccination prior to travel, as pre-travel advice most commonly was not sought. CONCLUSIONS: Children visiting relatives in high-incidence countries are increasingly at risk for enteric fever, particularly when travelling to South Asia. Targeted health advice to travelers visiting friends and relatives is warranted to mitigate the healthcare burden of enteric fever in low-incidence settings.

Assessment of Inter-Laboratory Differences in SARS-CoV-2 Consensus Genome Assemblies between Public Health Laboratories in Australia.

Whole-genome sequencing of viral isolates is critical for informing transmission patterns and for the ongoing evolution of pathogens, especially during a pandemic. However, when genomes have low variability in the early stages of a pandemic, the impact of technical and/or sequencing errors increases. We quantitatively assessed inter-laboratory differences in consensus genome assemblies of 72 matched SARS-CoV-2-positive specimens sequenced at different laboratories in Sydney, Australia. Raw sequence data were assembled using two different bioinformatics pipelines in parallel, and resulting consensus genomes were compared to detect laboratory-specific differences. Matched genome sequences were predominantly concordant, with a median pairwise identity of 99.997%. Identified differences were predominantly driven by ambiguous site content. Ignoring these produced differences in only 2.3% (5/216) of pairwise comparisons, each differing by a single nucleotide. Matched samples were assigned the same Pango lineage in 98.2% (212/216) of pairwise comparisons, and were mostly assigned to the same phylogenetic clade. However, epidemiological inference based only on single nucleotide variant distances may lead to significant differences in the number of defined clusters if variant allele frequency thresholds for consensus genome generation differ between laboratories. These results underscore the need for a unified, best-practices approach to bioinformatics between laboratories working on a common outbreak problem.

Global disparities in SARS-CoV-2 genomic surveillance.

Genomic sequencing provides critical information to track the evolution and spread of SARS-CoV-2, optimize molecular tests, treatments and vaccines, and guide public health responses. To investigate the spatiotemporal heterogeneity in the global SARS-CoV-2 genomic surveillance, we estimated the impact of sequencing intensity and turnaround times (TAT) on variant detection in 167 countries. Most countries submit genomes >21 days after sample collection, and 77% of low and middle income countries sequenced <0.5% of their cases. We found that sequencing at least 0.5% of the cases, with a TAT <21 days, could be a benchmark for SARS-CoV-2 genomic surveillance efforts. Socioeconomic inequalities substantially impact our ability to quickly detect SARS-CoV-2 variants, and undermine the global pandemic preparedness.

Cost of whole genome sequencing for non-typhoidal Salmonella enterica.

BACKGROUND: While whole genome sequencing (WGS) may be more expensive than traditional testing and polymerase chain reaction (PCR), simple cost comparisons ignore the potential for WGS to reduce the societal costs of non-typhoidal Salmonella enterica through public health action to prevent illness. METHODS: We determined how many cases the use of WGS data would need to prevent to be cost-equal to serotyping and MLVA, or culture independent testing based on PCR in Australia. We then examined the costs and cost-savings of current typing methods compared with WGS in outbreak scenarios. RESULTS: A median of 275 (90% CrI -55-775) or 1.9% (90% CrI -0.4%-5.4%) of notified serotyped Salmonella cases would need to be prevented for WGS to be cost-equal to current typing methods and 1,550 (90% CrI 820-2,725) or 9.6% of all notified Salmonella cases would need to be prevented to be cost-equal to PCR. WGS is likely to result in cost savings in prolonged outbreaks, where data can support earlier public health action. CONCLUSIONS: Despite currently having a higher cost per isolate, routine WGS of Salmonella was no more expensive than existing typing methods or PCR where >2% of illness was averted.

Genomic Surveillance Enables Suitability Assessment of Salmonella Gene Targets Used for Culture-Independent Diagnostic Testing.

Salmonella is a highly diverse genus consisting of over 2,600 serovars responsible for high-burden food- and waterborne gastroenteritis worldwide. Sensitivity and specificity of PCR-based culture-independent diagnostic testing (CIDT) systems for Salmonella, which depend on a highly conserved gene target, can be affected by single nucleotide polymorphisms (SNPs), indels, and genomic rearrangements within primer and probe sequences. This report demonstrates the value of prospectively collected genomic data for verifying CIDT targets. We utilized the genomes of 3,165 Salmonella isolates prospectively collected and sequenced in Australia. The sequences of Salmonella CIDT PCR gene targets (ttrA, spaO, and invA) were systematically interrogated to measure nucleotide dissimilarity. Analysis of 52 different serovars and 79 multilocus sequencing types (MLST) demonstrated dissimilarity within and between PCR gene targets ranging between 0 and 81.3 SNP/kbp (0 and 141 SNPs). The lowest average dissimilarity was observed in the ttrA target gene used by the Roche LightMix at 2.0 SNP/kbp (range, 0 to 46.7); however, entropy across the gene demonstrates that it may not be the most stable CIDT target. While debate continues over the benefits and pitfalls of replacing bacterial culture with molecular assays, the growing volumes of genomic surveillance data enable periodic regional reassessment and validation of CIDT targets against both prevalent and emerging serovars. If PCR systems are to become the primary screening and diagnostic tool for laboratory diagnosis of salmonellosis, ongoing monitoring of the genomic diversity in PCR target regions is warranted, as is the potential inclusion of two Salmonella PCR targets in frontline diagnostic systems.

Antibiotic Use Associated with Confirmed Influenza, Pertussis, and Nontyphoidal Salmonella Infections.

Purpose: Antibiotics are not the recommended treatment for uncomplicated influenza or nontyphoidal salmonella infections, whereas they are for current pertussis infection. We investigated adherence to these recommendations in a population of older community-dwelling adults. Methods: Population-based prospective cohort study of Australian adults 45 years of age and older followed by record-linkage to laboratory-confirmed influenza, pertussis, and nontyphoidal salmonella notifications, hospitalization records, and antibiotic dispensing data from January 1, 2009 to December 31, 2015. Proportions of those with infections who were prescribed antibiotics were estimated, and characteristics associated with antibiotic prescribing were examined. Results: There were 1,056 influenza, 151 pertussis, and 334 nontyphoidal salmonella cases in the cohort eligible for analysis. Antibiotics were dispensed in 56.2% (594/1,056) of influenza, 78.8% (119/151) of pertussis, and 39.5% (132/334) of nontyphoidal salmonella cases within the ±10-day window around the infection onset date. The likelihood of antibiotic dispensing did not differ according to most participant characteristics examined, including whether cases had an associated hospitalization, their age, and recorded comorbidities. Macrolides were the predominant class of antibiotics dispensed for pertussis (79%), whereas both beta-lactams (36.3%) and macrolides (35.4%) were used for cases of influenza. There was no dominant antibiotic class dispensed among those with nontyphoidal salmonella. Conclusions: Given concerns regarding increasing antibiotic resistance, the high proportion of adults with influenza and nontyphoidal salmonella cases dispensed antibiotics indicate the need for further strengthening of antimicrobial stewardship by raising education and awareness of guidelines for managing these infections.

Effectiveness of hospital-wide methicillin-resistant Staphylococcus aureus (MRSA) infection control policies differs by ward specialty.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of preventable nosocomial infections and is endemic in hospitals worldwide. The effectiveness of infection control policies varies significantly across hospital settings. The impact of the hospital context towards the rate of nosocomial MRSA infections and the success of infection control is understudied. We conducted a modelling study to evaluate several infection control policies in surgical, intensive care, and medical ward specialties, each with distinct ward conditions and policies, of a tertiary public hospital in Sydney, Australia. We reconfirm hand hygiene as the most successful policy and find it to be necessary for the success of other policies. Active screening for MRSA, patient isolation in single-bed rooms, and additional staffing were found to be less effective. Across these ward specialties, MRSA transmission risk varied by 13% and reductions in the prevalence and nosocomial incidence rate of MRSA due to infection control policies varied by up to 45%. Different levels of infection control were required to reduce and control nosocomial MRSA infections for each ward specialty. Infection control policies and policy targets should be specific for the ward and context of the hospital. The model we developed is generic and can be calibrated to represent different ward settings and pathogens transmitted between patients indirectly through health care workers. This can aid the timely and cost effective design of synergistic and context specific infection control policies.

Impact of a web-based personally controlled health management system on influenza vaccination and health services utilization rates: a randomized controlled trial.

OBJECTIVE: To assess the impact of a web-based personally controlled health management system (PCHMS) on the uptake of seasonal influenza vaccine and primary care service utilization among university students and staff. MATERIALS AND METHODS: A PCHMS called Healthy.me was developed and evaluated in a 2010 CONSORT-compliant two-group (6-month waitlist vs PCHMS) parallel randomized controlled trial (RCT) (allocation ratio 1:1). The PCHMS integrated an untethered personal health record with consumer care pathways, social forums, and messaging links with a health service provider. RESULTS: 742 university students and staff met inclusion criteria and were randomized to a 6-month waitlist (n=372) or the PCHMS (n=370). Amongst the 470 participants eligible for primary analysis, PCHMS users were 6.7% (95% CI: 1.46 to 12.30) more likely than the waitlist to receive an influenza vaccine (waitlist: 4.9% (12/246, 95% CI 2.8 to 8.3) vs PCHMS: 11.6% (26/224, 95% CI 8.0 to 16.5); χ(2)=7.1, p=0.008). PCHMS participants were also 11.6% (95% CI 3.6 to 19.5) more likely to visit the health service provider (waitlist: 17.9% (44/246, 95% CI 13.6 to 23.2) vs PCHMS: 29.5% (66/224, 95% CI: 23.9 to 35.7); χ(2)=8.8, p=0.003). A dose-response effect was detected, where greater use of the PCHMS was associated with higher rates of vaccination (p=0.001) and health service provider visits (p=0.003). DISCUSSION: PCHMS can significantly increase consumer participation in preventive health activities, such as influenza vaccination. CONCLUSIONS: Integrating a PCHMS into routine health service delivery systems appears to be an effective mechanism for enhancing consumer engagement in preventive health measures. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000386033. http://www.anzctr.org.au/trial_view.aspx?id=335463.

Protocol for a randomised controlled trial examining the impact of a web-based personally controlled health management system on the uptake of influenza vaccination rates.

BACKGROUND: Online social networking and personally controlled health management systems (PCHMS) offer a new opportunity for developing innovative interventions to prevent diseases of public health concern (e.g., influenza) but there are few comparative studies about patterns of use and impact of these systems. METHODS/DESIGN: A 2010 CONSORT-compliant randomised controlled trial with a two-group parallel design will assess the efficacy of a web-based PCHMS called Healthy.me in facilitating the uptake of influenza vaccine amongst university students and staff. Eligible participants are randomised either to obtain access to Healthy.me or a 6-month waitlist. Participants complete pre-study, post-study and monthly surveys about their health and utilisation of health services. A post-study clinical audit will be conducted to validate self-reports about influenza vaccination and visits to the university health service due to influenza-like illness (ILI) amongst a subset of participants. 600 participants older than 18 years with monthly access to the Internet and email will be recruited. Participants who (i) discontinue the online registration process; (ii) report obtaining an influenza vaccination in 2010 before the commencement of the study; or (iii) report being influenced by other participants to undertake influenza vaccination will be excluded from analysis. The primary outcome measure is the number of participants obtaining influenza vaccination during the study. Secondary outcome measures include: number of participants (i) experiencing ILI symptoms, (ii) absent from or experiencing impairment in work or study due to ILI symptoms, (iii) using health services or medications due to ILI symptoms; (iv) expressing positive or negative attitudes or experiences towards influenza vaccination, via their reasons of receiving (or not receiving) influenza vaccine; and (v) their patterns of usage of Healthy.me (e.g., frequency and timing of hits, duration of access, uptake of specific functions). DISCUSSION: This study will provide new insights about the utility of online social networking and PCHMS for public health and health promotion. It will help to assess whether a web-based PCHMS, with connectivity to a health service provider, containing information and self-management tools, can improve the uptake of preventive health services amongst university students and staff. TRIAL REGISTRATION: ACTRN12610000386033 (Australian New Zealand Clinical Trials Registry).

Influenza outbreak during Sydney World Youth Day 2008: the utility of laboratory testing and case definitions on mass gathering outbreak containment.

BACKGROUND: Influenza causes annual epidemics and often results in extensive outbreaks in closed communities. To minimize transmission, a range of interventions have been suggested. For these to be effective, an accurate and timely diagnosis of influenza is required. This is confirmed by a positive laboratory test result in an individual whose symptoms are consistent with a predefined clinical case definition. However, the utility of these clinical case definitions and laboratory testing in mass gathering outbreaks remains unknown. METHODS AND RESULTS: An influenza outbreak was identified during World Youth Day 2008 in Sydney. From the data collected on pilgrims presenting to a single clinic, a Markov model was developed and validated against the actual epidemic curve. Simulations were performed to examine the utility of different clinical case definitions and laboratory testing strategies for containment of influenza outbreaks. Clinical case definitions were found to have the greatest impact on averting further cases with no added benefit when combined with any laboratory test. Although nucleic acid testing (NAT) demonstrated higher utility than indirect immunofluorescence antigen or on-site point-of-care testing, this effect was lost when laboratory NAT turnaround times was included. The main benefit of laboratory confirmation was limited to identification of true influenza cases amenable to interventions such as antiviral therapy. CONCLUSIONS: Continuous re-evaluation of case definitions and laboratory testing strategies are essential for effective management of influenza outbreaks during mass gatherings.

Rolling circle amplification and multiplex allele-specific PCR for rapid detection of katG and inhA gene mutations in Mycobacterium tuberculosis.

The aim of the study was to compare a novel, rolling circle amplification (RCA) assay for detection of common isoniazid (INH) resistance mutations in Mycobacterium tuberculosis with a multiplex allele-specific PCR (MAS-PCR) and sequencing of katG and the fabG1-inhA promoter region. One or more mutations were identified by RCA, MAS-PCR, and sequencing in 21 (68%), 22 (71%), and 23 (74%), respectively, of 31 epidemiologically unrelated INH-resistant isolates, and in none of 8 INH-susceptible isolates. The RCA assay is a rapid, inexpensive, and practical screening method for INH resistance in M. tuberculosis in countries with high prevalence of INH resistance.

Utility of genotyping of Mycobacterium tuberculosis in the contact investigation: a decision analysis.

The objective of this study was to compare the traditional tuberculosis contact-tracing strategy with a two-stage strategy, in low prevalence countries. We compared the utility of contact tracing of pulmonary tuberculosis patients using a single interview (Strategy I) with that of two-stage strategies, namely traditional 'stone-in the pond' contact tracing (strategy II) and a strategy involving second interviews of patients whose Mycobacterium tuberculosis isolates are genotypically clustered (Strategy III). Factors affecting the utility and impact of each were explored using sensitivity analysis of probabilistic decision trees and a quantitative Markov simulation. Contact tracing using Strategy III demonstrated a higher utility and a 12% lower probability of secondary infection being missed compared with Strategy II. The threshold level, at which a change, from a traditional to a two-stage contact tracing strategy is indicated, is when the rate of clustering is 4% or more. The utility of Strategy III is optimal when the probability of detecting new epidemiological links is more than 10%. Strategy III allows detection of 58% of infected patients within 2 years after exposure compared with Strategy II and Strategy I which will detect 47% and 32% of infected contacts within 2 years, respectively. Strategy III allows detection of 58% of infected patients within 2 years after exposure, compared with 32% and 47% for Strategies I and II, respectively. There is a linear relationship between the rate of clustering of isolates and the probability of secondary cases being prevented by the use of Strategy III. A two-stage tuberculosis contact tracing strategy, based on clustering of genetically related M. tuberculosis isolates, should improve identification of epidemiologic links and prevent more cases of secondary infections in low prevalence settings and so augment traditional contact tracing. The main factors affecting utilities were the likelihood of new epidemiological links being identified after the second interview and the local rate of clustering of M. tuberculosis isolates.

Which clinical decisions benefit from automation? A task complexity approach.

This paper describes a model for analysing medical decision making tasks and evaluation of their suitability for automation. The overall approach focuses on the assessment of decision complexity and possible reduction of human effort by automated decision support. The approach consists of five subsequent steps: (1) selection of the domain and relevant tasks; (2) evaluation of the knowledge complexity for tasks selected; (3) selection of potentially most cognitively demanding task; (4) assessment of unaided and aided effort requirements for this task accomplishment; and (5) selection of computational tools to achieve this complexity reduction. The model described allows for task automation without lowering of decision quality.