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AbstractStreptococcus pneumoniaeis a leading cause of invasive disease in infants, especially in low-income settings. Asymptomatic carriage in the nasopharynx is a prerequisite for disease, and the duration of carriage is an important consideration in modelling transmission dynamics and vaccine response. Existing studies of carriage duration variability are based at the serotype level only, and do not probe variation within lineages or fully quantify interactions with other environmental factors.Here we developed a model to calculate the duration of carriage episodes from longitudinal swab data. By combining these results with whole genome sequence data we estimate that pneumococcal genomic variation accounted for 63% of the phenotype variation, whereas host traits accounted for less than 5%. We further partitioned this heritability into both lineage and locus effects, and quantified the amount attributable to the largest sources of variation in carriage duration: serotype (17%), drug-resistance (9%) and other significant locus effects (7%). For the locus effects, a genome-wide association study identified 16 loci which may have an effect on carriage duration independent of serotype. Hits at a genome-wide level of significance were to prophage sequences, suggesting infection by such viruses substantially affects carriage duration.These results show that both serotype and non-serotype specific effects alter carriage duration in infants and young children and are more important than other environmental factors such as host genetics. This has implications for models of pneumococcal competition and antibiotic resistance, and leads the way for the analysis of heritability of complex bacterial traits.Significance statementOther than serotype, the genetic determinants of pneumococcal carriage duration are unknown. In this study we used longitudinal sampling to measure the duration of carriage in infants, and searched for any associated variation in the pan-genome. While we found that the pathogen genome explains most of the variability in duration, serotype did not fully account for this. Recent theoretical work has proposed the existence of alleles which alter carriage duration to explain the puzzle of continued coexistence of antibiotic-resistant and sensitive strains. Here we have shown that these alleles do exist in a natural population, and also identified candidates for the loci which fulfil this role. Together these findings have implications for future modelling of pneumococcal epidemiology and resistance.
\n \n\n \n \nIntroductionScrub typhus is a neglected tropical disease with an estimated 1 million cases annually. The Asia-Pacific region is an endemic area for scrub typhus, especially in Thailand.MethodsBetween June 2018 and December 2019, 31 patients with acute undifferentiated febrile illness (AUFI) were recruited for clinical trials and tested positive by a scrub typhus IgM RDT.ResultsOf the 17 buffy coat patient samples tested by 47kDa real-time PCR and 56kDa type-specific antigen (TSA) nested PCR, 94% (16/17) were positive, and of the 11 patients that presented with eschar lesions, 100% (11/11) of the eschar samples were confirmed positive. Genetic analysis of the 560 bp partial 56-kDa TSA gene demonstrated that most Orientia tsutsugamushi (Ot) infections were with Karp, Gilliam, Taiwan, P23, and CM606-like strains.DiscussionThis is the second occasion that the CM606-like and P23-like strains were reported in northern Thailand (first reported in 2011 and 2013, respectively). This study demonstrates that 1) the eschar remains the most reliable biological sample for PCR diagnosis of scrub typhus and 2) Northwestern Thailand has significant diversity of Ot strains, which underlines the requirement for ongoing surveillance to increase our understanding of Ot diversity to ensure accurate diagnostics and treatment.
\n \n\n \n \nAbstract\nBackground\nDengue is a mosquito-borne disease that causes over 300 million infections worldwide each year with no specific treatment available. Effective surveillance systems are needed for outbreak detection and resource allocation. Spatial cluster detection methods are commonly used, but no general guidance exists on the most appropriate method for dengue surveillance. Therefore, a comprehensive study is needed to assess different methods and provide guidance for dengue surveillance programs.\n\nMethods\nTo evaluate the effectiveness of different cluster detection methods for dengue surveillance, we selected and assessed commonly used methods: Getis Ord $${G}_{i}^{*}$$\n\nG\n\ni\n\n\n\n\u2217\n\n\n, Local Moran, SaTScan, and Bayesian modeling. We conducted a simulation study to compare their performance in detecting clusters, and applied all methods to a case study of dengue surveillance in Thailand in 2019 to further evaluate their practical utility.\n\nResults\nIn the simulation study, Getis Ord $${G}_{i}^{*}$$\n\nG\n\ni\n\n\n\n\u2217\n\n\n and Local Moran had similar performance, with most misdetections occurring at cluster boundaries and isolated hotspots. SaTScan showed better precision but was less effective at detecting inner outliers, although it performed well on large outbreaks. Bayesian convolution modeling had the highest overall precision in the simulation study. In the dengue case study in Thailand, Getis Ord $${G}_{i}^{*}$$\n\nG\n\ni\n\n\n\n\u2217\n\n\n and Local Moran missed most disease clusters, while SaTScan was mostly able to detect a large cluster. Bayesian disease mapping seemed to be the most effective, with adaptive detection of irregularly shaped disease anomalies.\n\nConclusions\nBayesian modeling showed to be the most effective method, demonstrating the best accuracy in adaptively identifying irregularly shaped disease anomalies. In contrast, SaTScan excelled in detecting large outbreaks and regular forms. This study provides empirical evidence for the selection of appropriate tools for dengue surveillance in Thailand, with potential applicability to other disease control programs in similar settings.\n
\n \n\n \n \nIntroductionFever commonly leads to healthcare seeking and hospital admission in sub-Saharan Africa and Asia. There is only limited guidance for clinicians managing non-malarial fevers, which often results in inappropriate treatment for patients. Furthermore, there is little evidence for estimates of disease burden, or to guide empirical therapy, control measures, resource allocation, prioritisation of clinical diagnostics or antimicrobial stewardship. The Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE) study seeks to address these information gaps.Methods and analysisFIEBRE investigates febrile illness in paediatric and adult outpatients and inpatients using standardised clinical, laboratory and social science protocols over a minimum 12-month period at five sites in sub-Saharan Africa and Southeastern and Southern Asia. Patients presenting with fever are enrolled and provide clinical data, pharyngeal swabs and a venous blood sample; selected participants also provide a urine sample. Laboratory assessments target infections that are treatable and/or preventable. Selected point-of-care tests, as well as blood and urine cultures and antimicrobial susceptibility testing, are performed on site. On day 28, patients provide a second venous blood sample for serology and information on clinical outcome. Further diagnostic assays are performed at international reference laboratories. Blood and pharyngeal samples from matched community controls enable calculation of AFs, and surveys of treatment seeking allow estimation of the incidence of common infections. Additional assays detect markers that may differentiate bacterial from non-bacterial causes of illness and/or prognosticate illness severity. Social science research on antimicrobial use will inform future recommendations for fever case management. Residual samples from participants are stored for future use.Ethics and disseminationEthics approval was obtained from all relevant institutional and national committees; written informed consent is obtained from all participants or parents/guardians. Final results will be shared with participating communities, and in open-access journals and other scientific fora. Study documents are available online (https://doi.org/10.17037/PUBS.04652739).
\n \n\n \n \nBACKGROUND: Improving breastfeeding rates is one of the most cost-effective ways to prevent infant deaths, but most of the world falls far below WHO recommended breastfeeding practices. Confident, informed healthcare workers are an important resource to promote breastfeeding, but healthcare workers are at risk of early breastfeeding cessation themselves. Culture, ethnicity and socio-economic status impact breastfeeding rates with some of the highest and lowest rates in Southeast Asia reported from Thailand. This study explores the relationship between workplace determinants of breastfeeding, personal breastfeeding outcomes for healthcare workers, and the breastfeeding care healthcare workers provide their patients. METHODS: This study used a sequential exploratory design guided by a conceptual framework based on social ecological/ecological psychology models. Participants came from four clinical sites in Northern Thailand, from ethnically Burman or Karen communities with high breastfeeding rates, and Thai communities with low breastfeeding rates. In-depth interviews (July 2020-November 2020) were followed by a quantitative survey (November 2020-July 2021) derived from validated questionnaires (Australian Breastfeeding Knowledge and Attitudes Questionnaire and the Workplace Breastfeeding Support Scale) with minor local adaptations. RESULTS: Interviews highlighted the beneficial effects of supportive workplace policies, the importance of physical spaces to facilitate proximity between mothers and infants, and the problem of low milk production. Meeting the WHO recommended practices of exclusive breastfeeding to 6 months or total breastfeeding to 2 years or more was more common in sites with higher levels of breastfeeding support (aOR 7.3, 95%CI 1.8, 29.1 for exclusive breastfeeding). Exclusive breastfeeding was also higher when staff set breastfeeding goals (aOR 4.4, 95%CI 1.7, 11.5). Staff who were able to see their infants during the work day were less likely to terminate breastfeeding because of work (aOR 0.3, 95%CI 0.1, 0.8). Staff who met both WHO recommendations themselves were more likely to report high levels of confidence caring for breastfeeding patients (aOR 2.6, 95%CI 1.1, 6.4). CONCLUSIONS: Workplace protections including supportive maternity leave policies and child-friendly spaces can improve breastfeeding outcomes for healthcare workers. These improved outcomes are then passed on to patients who benefit from healthcare workers who are more confident and attentive to breastfeeding problems.
\n \n\n \n \nAbstractStreptococcus pneumoniae (pneumococcus) is a nasopharyngeal commensal and respiratory pathogen. This study characterises the immunoglobulin G (IgG) repertoire recognising pneumococci from birth to 24 months old (mo) in a prospectively-sampled cohort of 63 children using a panproteome array. IgG levels are highest at birth, due to transplacental transmission of maternal antibodies. The subsequent emergence of responses to individual antigens exhibit distinct kinetics across the cohort. Stable differences in the strength of individuals\u2019 responses, correlating with maternal IgG concentrations, are established by 6 mo. By 12 mo, children develop unique antibody profiles that are boosted by re-exposure. However, some proteins only stimulate substantial responses in adults. Integrating genomic data on nasopharyngeal colonisation demonstrates rare pneumococcal antigens can elicit strong IgG levels post-exposure. Quantifying such responses to the diverse core loci (DCL) proteins is complicated by cross-immunity between variants. In particular, the conserved N terminus of DCL protein zinc metalloprotease B provokes the strongest early IgG responses. DCL proteins\u2019 ability to inhibit mucosal immunity likely explains continued pneumococcal carriage despite hosts\u2019 polyvalent antibody repertoire. Yet higher IgG levels are associated with reduced incidence, and severity, of pneumonia, demonstrating the importance of the heterogeneity in response strength and kinetics across antigens and individuals.
\n \n\n \n \nBackgroundScrub typhus is an understudied vector-borne bacterial infection.MethodsWe tested archived fever samples for scrub typhus seropositivity to begin charting its geographic distribution in Indonesia. We analysed 1033 serum samples from three sites. IgM and IgG enzyme-linked immunosorbent assay (ELISA) against Orientia tsutsugamushi was performed using Karp, Kato, Gilliam, TA 716 antigens. To determine the cutoff in the absence of a presumed unexposed population and gold standard tests, we identified the visual inflection point, performed change point analysis, and used finite mixture models.ResultsThe optical density cutoff values used for IgM and IgG were 0.49 and 0.13, respectively. Across all sites, IgM seropositivity was 4.6% (95% CI: 3.4 to 6.0%) while IgG seropositivity was 4.4% (95% CI: 3.3 to 5.8%). The overall seropositivity across sites was 8.8% (95% CI: 8.1 to 11.7%). The overall seropositivity for Jambi, Denpasar, Tabanan were 9.7% (95% CI: 7.0 to 13.3%), 8.0% (95% CI: 5.7 to 11.0%), 9.0% (95% CI: 6.1 to 13.0%), respectively.ConclusionsWe conclude that O. tsutsugamushi exposure in humans occurred at all sites analysed and could be the cause of illness in some cases. Though it was not the main cause of acute fever in these locations, it is still important to consider scrub typhus in cases not responding to beta-lactam antibiotics. Future seroprevalence surveys and testing for scrub typhus in acute febrile illness studies will be essential to understand its distribution and burden in Indonesia.
\n \n\n \n \nAbstract\n\nBackground\nMalaria continues to pose a significant burden in endemic countries, many of which lack access to molecular surveillance. Insights from malaria cases in travellers returning to non-endemic areas can provide valuable data to inform endemic country programmes. To evaluate the potential for novel global insights into malaria, we examined epidemiological and molecular data from imported malaria cases to Australia.\n\n\nMethods\nWe analysed malaria cases reported in Australia from 2012 to 2022 using National Notifiable Disease Surveillance System data. Molecular data on imported malaria cases were obtained from literature searches.\n\n\nResults\nBetween 2012 and 2022, 3204 malaria cases were reported in Australia. Most cases (69%) were male and 44% occurred in young adults aged 20\u201339\u00a0years. Incidence rates initially declined between 2012 and 2015, then increased until 2019. During 2012\u20132019, the incidence in travellers ranged from 1.34 to 7.71 per 100\u2009000 trips. Cases were primarily acquired in Sub-Saharan Africa (n\u2009=\u20091433; 45%), Oceania (n\u2009=\u2009569; 18%) and Southern and Central Asia (n\u2009=\u2009367; 12%). The most common countries of acquisition were Papua New Guinea (n\u2009=\u2009474) and India (n\u2009=\u2009277). Plasmodium falciparum accounted for 58% (1871/3204) of cases and was predominantly acquired in Sub-Saharan Africa, and Plasmodium vivax accounted for 32% (1016/3204), predominantly from Oceania and Asia. Molecular studies of imported malaria cases to Australia identified genetic mutations and deletions associated with drug resistance and false-negative rapid diagnostic test results, and led to the establishment of reference genomes for P. vivax and Plasmodium malariae.\n\n\nConclusions\nOur analysis highlights the continuing burden of imported malaria into Australia. Molecular studies have offered valuable insights into drug resistance and diagnostic limitations, and established reference genomes. Integrating molecular data into national surveillance systems could provide important infectious disease intelligence to optimize treatment guidelines for returning travellers and support endemic country surveillance programmes.\n
\n \n\n \n \nIn remote communities, diagnosis of G6PD deficiency is challenging. We assessed the impact of modified test procedures and delayed testing for the point-of-care diagnostic STANDARD G6PD (SDBiosensor, RoK), and evaluated recommended cut-offs. We tested capillary blood from fingerpricks (Standard Method) and a microtainer (BD, USA; Method 1), venous blood from a vacutainer (BD, USA; Method 2), varied sample application methods (Methods 3), and used micropipettes rather than the test\u2019s single-use pipette (Method 4). Repeatability was assessed by comparing median differences between paired measurements. All methods were tested 20 times under laboratory conditions on three volunteers. The Standard Method and the method with best repeatability were tested in Indonesia and Nepal. In Indonesia 60 participants were tested in duplicate by both methods, in Nepal 120 participants were tested in duplicate by either method. The adjusted male median (AMM) of the Biosensor Standard Method readings was defined as 100% activity. In Indonesia, the difference between paired readings of the Standard and modified methods was compared to assess the impact of delayed testing. In the pilot study repeatability didn\u2019t differ significantly (p = 0.381); Method 3 showed lowest variability. One Nepalese participant had <30% activity, one Indonesian and 10 Nepalese participants had intermediate activity (\u226530% to <70% activity). Repeatability didn\u2019t differ significantly in Indonesia (Standard: 0.2U/gHb [IQR: 0.1\u20130.4]; Method 3: 0.3U/gHb [IQR: 0.1\u20130.5]; p = 0.425) or Nepal (Standard: 0.4U/gHb [IQR: 0.2\u20130.6]; Method 3: 0.3U/gHb [IQR: 0.1\u20130.6]; p = 0.330). Median G6PD measurements by Method 3 were 0.4U/gHb (IQR: -0.2 to 0.7, p = 0.005) higher after a 5-hour delay compared to the Standard Method. The definition of 100% activity by the Standard Method matched the manufacturer-recommended cut-off for 70% activity. We couldn\u2019t improve repeatability. Delays of up to 5 hours didn\u2019t result in a clinically relevant difference in measured G6PD activity. The manufacturer\u2019s recommended cut-off for intermediate deficiency is conservative.
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