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IntroductionFever 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.
\n \n\n \n \nAbstract\nBackground\nAchieving meaningful consent can be challenging, particularly in contexts of diminished literacy, yet is a vital part of participant protection in global health research.\n\nMethod\nWe explored the challenges and potential solutions of achieving meaningful consent through a qualitative study in a predominantly hill tribe ethnic minority population in northern Thailand, a culturally distinctive population with low literacy. Semi-structured interviews were conducted with 37 respondents who had participated in scrub typhus clinical research, their family members, researchers and other key informants. A thematic analysis was conducted.\n\nResults\nOur analysis identified four interrelated themes surrounding participants\u2019 ability to give consent: varying degrees of research understanding, limitations of using informal translators, issues impacting decisions to join research, and voluntariness of consent. Suggestions for achieving more meaningful consent included the use of formal translators and community engagement with research populations.\n\nConclusions\nParticipant\u2019s agency in decision making to join research should be supported, but research information needs to be communicated to potential participants in a way that they can understand. We found that improved understanding about the study and its potential benefits and harms goes beyond literacy or translation and requires attention to social and cultural factors.\n
\n \n\n \n \nThe soluble urokinase plasminogen activator receptor (suPAR) has been proposed as a biomarker for risk stratification of patients presenting with acute infections. However, most studies evaluating suPAR have used platform-based assays, the accuracy of which may differ from point-of-care tests capable of informing timely triage in settings without established laboratory capacity. Using samples and data collected during a prospective cohort study of 425 patients presenting with moderate Covid-19 to two hospitals in India, we evaluated the analytical performance and prognostic accuracy of a commercially-available rapid diagnostic test (RDT) for suPAR, using an enzyme-linked immunosorbent assay (ELISA) as the reference standard. Our hypothesis was that the suPAR RDT might be useful for triage of patients presenting with moderate Covid-19 irrespective of its analytical performance when compared with the reference test. Although agreement between the two tests was limited (bias = -2.46 ng/mL [95% CI = -2.65 to -2.27 ng/mL]), prognostic accuracy to predict supplemental oxygen requirement was comparable, whether suPAR was used alone (area under the receiver operating characteristic curve [AUC] of RDT = 0.73 [95% CI = 0.68 to 0.79] vs. AUC of ELISA = 0.70 [95% CI = 0.63 to 0.76]; p = 0.12) or as part of a published multivariable prediction model (AUC of RDT-based model = 0.74 [95% CI = 0.66 to 0.83] vs. AUC of ELISA-based model = 0.72 [95% CI = 0.64 to 0.81]; p = 0.78). Lack of agreement between the RDT and ELISA in our cohort warrants further investigation and highlights the importance of assessing candidate point-of-care tests to ensure management algorithms reflect the assay that will ultimately be used to inform patient care. Availability of a quantitative point-of-care test for suPAR opens the door to suPAR-guided risk stratification of patients with Covid-19 and other acute infections in settings with limited laboratory capacity.
\n \n\n \n \n\nBackground\nEarly access to correct diagnosis and appropriate treatment is essential for malaria elimination, and in Cambodia this relies on village malaria workers (VMWs). Decreasing malaria transmission leave VMWs with diminished roles. Activities related to the control of other health conditions could keep these community health workers relevant.\n\n\nMethods\nDuring 2022, 120 VMWs attended training at local health centres on four health education packages: 1. hygiene and sanitation; 2. disease surveillance; 3. management of mild illness; 4. vaccination and antenatal care. All training and evaluation sessions were documented through meeting minutes, and 19 focus group discussions (FGDs) were conducted among VMWs and health centre personnel. Audio-records of FGDs were transcribed and translated in English and underwent thematic analysis.\n\n\nResults\nVMWs reported strong interest in the training and welcomed the expansion of their roles thus assuring their continued relevance. VMWs prioritized disease surveillance and management of mild illness among the available training packages because these topics were seen as most relevant. While training was considered comprehensible and important, the low literacy among VMWs was an impediment suggesting training materials need to be delivered visually. Since VMWs have limited resources, incentives could ensure that VMWs are motivated to undertake additional roles and responsibilities.\n\n\nConclusions\nThe transformation of VMWs into community health workers with roles beyond malaria is a promising approach for sustaining health care provision in remote areas. Training needs to consider the low scientific literacy, time constraints and limited resources of VMWs.\n
\n \n\n \n \nAccurate and reliable guidelines for referral of children from resource-limited primary care settings are lacking. We identified three practicable paediatric severity scores (the Liverpool quick Sequential Organ Failure Assessment (LqSOFA), the quick Pediatric Logistic Organ Dysfunction-2, and the modified Systemic Inflammatory Response Syndrome) and externally validated their performance in young children presenting with acute respiratory infections (ARIs) to a primary care clinic located within a refugee camp on the Thailand-Myanmar border. This secondary analysis of data from a longitudinal birth cohort study consisted of 3010 ARI presentations in children aged\u2009\u2264\u200924\u00a0months. The primary outcome was receipt of supplemental oxygen. We externally validated the discrimination, calibration, and net-benefit of the scores, and quantified gains in performance that might be expected if they were deployed as simple clinical prediction models, and updated to include nutritional status and respiratory distress. 104/3,010 (3.5%) presentations met the primary outcome. The LqSOFA score demonstrated the best discrimination (AUC 0.84; 95% CI 0.79-0.89) and achieved a sensitivity and specificity\u2009>\u20090.80. Converting the scores into clinical prediction models improved performance, resulting in\u2009~\u200920% fewer unnecessary referrals and\u2009~\u200930-50% fewer children incorrectly managed in the community. The LqSOFA score is a promising triage tool for young children presenting with ARIs in resource-limited primary care settings. Where feasible, deploying the score as a simple clinical prediction model might enable more accurate and nuanced risk stratification, increasing applicability across a wider range of contexts.
\n \n\n \n \nBackgroundFever is a common reason to seek healthcare in Southeast Asia, and the decline of malaria has complexified how is perceived, and what actions are taken towards it. We investigated the concept of fever and the determinants influencing health-seeking behaviours among migrants on the Thai-Myanmar border, where rapid economic development collides with precarious political and socio-economic conditions.MethodsWe implemented a mixed-methods study between August to December 2019. Phase I used a qualitative approach, with in-depth interviews and focus group discussions. Phase II used a quantitative approach with a close-ended questionnaire based on Phase I findings. A conditional inference tree (CIT) model first identified geographic and socio-demographic determinants, which were then tested using a logistic regression model.ResultsFever corresponded to a high diversity of conceptions, symptoms and believed causes. Self-medication was the commonest behaviour at fever onset. If fever persisted, migrants primarily sought care in humanitarian cost-free clinics (45.5%, 92/202), followed by private clinics (43.1%, 87/202), health posts (36.1%, 73/202), public hospitals (33.7%, 68/202) and primary care units (30, 14.9%). The qualitative analysis identified distance and legal status as key barriers for accessing health care. The quantitative analysis further investigated determinants influencing health-seeking behaviour: living near a town where a cost-free clinic operated was inversely associated with seeking care at health posts (adjusted odds ratio [aOR], 0.40, 95% confidence interval [95% CI] [0.19-0.86]), and public hospital attendance (aOR 0.31, 95% CI [0.14-0.67]). Living further away from the nearest town was associated with health posts attendance (aOR 1.05, 95% CI [1.00-1.10] per 1\u00a0km). Having legal status was inversely associated with cost-free clinics attendance (aOR 0.27, 95% CI [0.10-0.71]), and positively associated with private clinic and public hospital attendance (aOR 2.56, 95% CI [1.00-6.54] and 5.15, 95% CI [1.80-14.71], respectively).ConclusionsFever conception and believed causes are context-specific and should be investigated prior to any intervention. Distance to care and legal status were key determinants influencing health-seeking behaviour. Current economic upheavals are accelerating the unregulated flow of undocumented migrants from Myanmar to Thailand, warranting further inclusiveness and investments in the public health system.
\n \n\n \n \nReliable tools to inform outpatient management of childhood pneumonia in resource-limited settings are needed. We investigated the value added by biomarkers of the host infection response to the performance of the Liverpool quick Sequential Organ Failure Assessment score (LqSOFA), for triage of children presenting with pneumonia to a primary care clinic in a refugee camp on the Thailand-Myanmar border. 900 consecutive presentations of children aged\u2009\u2264\u200924\u00a0months meeting WHO pneumonia criteria were included. The primary outcome was receipt of supplemental oxygen. We compared discrimination of a clinical risk score (LqSOFA) to markers of endothelial injury (Ang-1, Ang-2, sFlt-1), immune activation (CHI3L1, IP-10, IL-1ra, IL-6, IL-8, IL-10, sTNFR-1, sTREM-1), and inflammation (CRP, PCT), and quantified the net benefit of including biomarkers alongside LqSOFA. We evaluated the differential contribution of LqSOFA and host biomarkers to the diagnosis and prognosis of pneumonia severity. 49/900 (5.4%) presentations met the primary outcome. Discrimination of LqSOFA and Ang-2, the best performing biomarker, were comparable (AUC 0.82 [95% CI 0.76-0.88] and 0.81 [95% CI 0.74-0.87] respectively). Combining Ang-2 with LqSOFA improved discrimination (AUC 0.91; 95% CI 0.87-0.94; p\u2009
\n \n\n \n \nBackground Dengue is the most common and widespread mosquito-borne arboviral disease globally estimated to cause >390 million infections and >20,000 deaths annually. There are no effective preventive drugs and the newly introduced vaccines are not yet available. Control of dengue transmission still relies primarily on mosquito vector control. Although most vector control methods currently used by national dengue control programs may temporarily reduce mosquito populations, there is little evidence that they affect transmission. There is an urgent need for innovative, participatory, effective, and locally adapted approaches for sustainable vector control and monitoring in which students can be particularly relevant contributors and to demonstrate a clear link between vector reduction and dengue transmission reduction, using tools that are inexpensive and easy to use by local communities in a sustainable manner. Methods Here we describe a cluster randomized controlled trial to be conducted in 46 school catchment areas in two townships in Yangon, Myanmar. The outcome measures are dengue cases confirmed by rapid diagnostic test in the townships, dengue incidence in schools, entomological indices, knowledge, attitudes and practice, behavior, and engagement. Conclusions The trial involves middle school students that positions them to become actors in dengue knowledge transfer to their communities and take a leadership role in the delivery of vector control interventions and monitoring methods. Following this rationale, we believe that students can become change agents of decentralized vector surveillance and sustainable disease control in line with recent new paradigms in integrated and participatory vector surveillance and control. This provides an opportunity to operationalize transdisciplinary research towards sustainable health development. Due to the COVID-19 pandemic and political instability in Myanmar the project has been terminated by the donor, but the protocol will be helpful for potential future implementation of the project in Myanmar and/or elsewhere. Registration: This trial was registered in the ISRCTN Registry on 31 May 2022 (https://doi.org/10.1186/ISRCTN78254298).
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