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The current early childhood caries (ECC) case definition contains a substantial degree of clinical heterogeneity, and to address this, we sought to identify clinical subtypes of the disease. We used tooth surface-level dental caries experience from a discovery and 3 replication community-based cohorts of 3-to-5-year-old children (N=226,471). We identified five disease subtypes with distinct patterns of caries lesion intraoral distribution that largely replicated across cohorts. These subtypes were associated with established caries risk factors (e.g., history of nighttime bottle-feeding), showed familial concordance and microbiome differences, and predicted dental caries experience 7 years after subtype assignment. Notably, classification of children in these subgroups can be achieved by inspecting small sets of easily examinable tooth surfaces with reasonable accuracy. Collectively, our findings provide evidence for generalizable and clinically recognizable subtypes of ECC. Etiology, targeted prevention, and optimal management of these subtypes should be systematically investigated in future studies.

Microbiome studies are revealing complex microbiota in biofilm-mediated human diseases commonly linked with specific bacterial pathogens. Streptococcus mutans has been implicated as the primary pathogen in childhood dental caries (tooth decay). While the role of polymicrobial communities is appreciated, it remains unclear whether other microorganisms are active contributors, inactive cohabitants, or interact with known pathogens such as S. mutans. Here, we integrate multi-omics of human dental plaque (biofilm) from two community-based samples of preschool-age children in a discovery-validation pipeline involving bioinformatics, laboratory, and in vivo experimental approaches to identify disease-relevant inter-species interactions. In metagenomics and metatranscriptomics analyses among 416 preschool-age children, we identify 16 taxa strongly associated with childhood caries. Using multiscale imaging, virulence assays, microcalorimetry, and computational analyses, we investigate biofilm formation dynamics, microscale spatial arrangement, and metabolic activity by Selenomonas sputigena, Prevotella salivae and Leptotrichia wadei either individually or with S. mutans. Notably, we discover that the flagellated S. sputigena, a subgingival anaerobe with previously unknown role in supragingival biofilm virulence, becomes trapped in foreign streptococcal exoglucans, loses its motility but actively proliferates to build a honeycomb-like multicellular superstructure encapsulating S. mutans and enhances acidogenesis. Rodent model experiments reveal a previously unrecognized ability of S. sputigena to colonize supragingival tooth surfaces. While incapable of causing caries on its own, S. sputigena exacerbates the disease severity in vivo when co-infected with S. mutans, causing extensive lesions on tooth enamel. Our data reveal a pathobiont from a disparate habitat in a prevalent disease that cooperates with a known pathogen to build a unique 3D spatial structure and heighten biofilm virulence—which may be relevant to other polymicrobial diseases.

Community water fluoridation is an important component of oral health promotion, as fluoride exposure is a well-documented dental caries-preventive agent. Direct measurements of domestic water fluoride content provide valuable information regarding individuals’ fluoride exposure and thus caries risk; however, they are logistically challenging to carry out at a large scale in oral health research. This article describes the development and evaluation of a novel method for the imputation of missing domestic water fluoride concentration data informed by spatial autocorrelation. The context is a state-wide epidemiologic study of pediatric oral health in North Carolina, where domestic water fluoride concentration information was missing for approximately 75% of study participants with clinical data on dental caries. A new machine-learning-based imputation method that combines partitioning around medoids clustering and random forest classification (PAMRF) is developed and implemented. Imputed values are filtered according to allowable error rates or target sample size, depending on the requirements of each application. In leave-one-out cross-validation and simulation studies, PAMRF outperforms four existing imputation approaches—two conventional spatial interpolation methods (i.e., inverse-distance weighting, IDW and universal kriging, UK) and two supervised learning methods (k-nearest neighbors, KNN and classification and regression trees, CART). The inclusion of multiply imputed values in the estimation of the association between fluoride concentration and dental caries prevalence resulted in essentially no change in PAMRF estimates but substantial gains in precision due to larger effective sample size. PAMRF is a powerful new method for the imputation of missing fluoride values where geographical information exists.

ObjectivesTo test whether postulated subtypes of early childhood caries (ECC) are predictive of subsequent caries experience in a population-based cohort of Swedish children.MethodsThe study included children aged between 3 and 5 years at study entry with dental records available for at least 5 years of follow-up. Dental record data were retrieved from the Swedish Quality Registry for Caries and Periodontal disease (SKaPa) for the initial and follow-up visits. Participants who had ECC at study entry were assigned to one of five ECC subtypes (termed classes 1 to 5) using latent class modelling of tooth surface-level caries experience. Subsequent experience of caries was assessed using the decayed, missing, and filled surfaces indices (dmfs/DMFS) at follow-up visits, and compared between ECC subtypes using logistic and negative binomial regression modelling.ResultsThe study included 128,355 children who had 3 or more dental visits spanning at least 5 years post baseline. Of these children, 31,919 had caries at the initial visit. Baseline ECC subtype was associated with differences in subsequent disease experience. As an example, 83% of children who had a severe form of ECC at age 5 went on to have caries in the permanent dentition by the end of the study, compared to 51% of children who were caries-free at age 5 (adjusted odds ratio of 4.9 for new disease at their third follow-up).ConclusionsECC subtypes assigned at a baseline visit are associated with differences in subsequent caries experience in both primary and permanent teeth. This suggests that the development and future validation of an ECC classification can be used in addition to current prediction tools to help identify children at high risk of developing new caries lesions throughout childhood and adolescence.

Introduction: Noma (cancrum oris) is a devastating opportunistic infection resulting in severe tissue destruction that affects mouth and oro-facial structures. There are substantial gaps in our current knowledge and understanding of its aetiology, pathogenesis, prevention and treatment efficacy, as well as its distribution and burden. Although observed worldwide, the disease impacts the most vulnerable and marginalised populations, and is most reported in young children from sub-Saharan Africa. Noma often presents alongside conditions of extreme poverty, malnutrition and poor environmental sanitation. This protocol paper outlines the methodology for a systematic review planned to exhaustively synthesize the findings of the available noma literature. The project aims to generate an account of the present state of knowledge about the various aspects of noma to aid in framing effective strategies and interventions to curb this disease which disproportionately afflicts the poorest in society. Methods and analysis: The following databases have been searched by a medical librarian from database inception to 7 December 2022: OVID (MEDLINE/ Embase/ CAB abstracts/ Global Health), Scopus, Web of Science, African Index Medicus, African Journals Online: Health, French language search: Pascal, ClinicalTrials.gov, and WHO ICTRP. All primary research studies reporting on patients of any age diagnosed with noma will be eligible for inclusion in the review, including clinical trials, cohort studies, case-control, cross-sectional, other observational studies, case studies and case series. Data will be extracted from included studies to analyse the current evidence-based knowledge on the distribution, risk factors, microbiology, prevention and treatment modalities, and outcomes of noma. Ethics and dissemination: Results of this systematic review will be published in a peer-reviewed journal upon completion. PROSPERO Registration: CRD42019124839 (08/03/2019)

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

In this cross-sectional, community-based study among a multi-ethnic sample of preschool-age children in North Carolina, United States, we sought to quantify the association between guardians’ self-reported oral health and their children’s oral health and determine whether race/ethnicity and education level modify these associations. We used questionnaire (n = 7852) responses about caregivers’ and their children’s oral health and clinical examination-derived (n = 6243) early childhood caries (ECC) status defined at the ICDAS ≥ 3 caries lesion detection threshold. We used multi-level mixed-effects generalized linear models to examine the associations between the guardians’ reported oral health and their children’s reported and clinically determined oral health among the entire sample and within strata of race/ethnicity, guardians’ education, and children’s dental home. The guardians’ and their children’s reported fair/poor oral health (FPOH) were 32% and 15%, respectively, whereas 54% of the children had ECC and 36% had unrestored disease. The guardians’ FPOH was strongly associated with their children’s FPOH (average marginal effect (AME) = +19 percentage points (p.p.); 95% CI = 17–21), and this association was most pronounced among Hispanics, lower-educated guardians, and children without a dental home. Similar patterns, but smaller-in-magnitude associations, were found for the guardians’ FPOH and their children’s clinically determined ECC (AME = +9 p.p.; 95% CI = 6–12) and unrestored disease (AME = +7 p.p.; 95% CI = 4–9). The study’s findings support a strong association between guardians’ and their children’s reported and clinically determined oral health and implicate ethnicity, education, and having a dental home as factors possibly modifying the magnitude of these associations.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite notable anthropometric variability with ancestry proportions, and a high burden of growth stunting and overweight/obesity in Hispanic/Latino populations. This address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults, to identify and fine-map common genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,769) and validated our findings in 9 additional studies (HISLA Stage 2, n=9,336). We conducted a trans-ethnic GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one novel BMI locus, as well two novel BMI signals and another novel height signal, each within established anthropometric loci. In our trans-ethnic meta- analysis, we identified three additional novel BMI loci, one novel height locus, and one novel WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI. We replicated >60 established anthropometric loci in Hispanic/Latino populations at genome-wide significance—representing up to 30% of previously-reported index SNP anthropometric associations. Trans-ethnic meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our novel findings demonstrate that future studies may also benefit from leveraging differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Objective In this cross-sectional study in a large community-based sample of preschool-age children, we sought to identify distinct clusters of modifiable early childhood oral health-related behaviours (OHBs) and quantify their association with clinical and parent-reported measures of early childhood oral health. Methods We relied upon a questionnaire (n = 8033; 11% in Spanish) and clinical oral health data (n = 6404; early childhood caries [ECC] prevalence = 54%] collected in the context of an epidemiologic study of early childhood oral health among 3- to 5-year-old children in North Carolina. Latent class analysis was used to identify clusters of modifiable OHBs based on parents' responses to 6 questionnaire items pertaining to their children's oral hygiene, diet and dental home. The optimal number of clusters was determined based on measures of model fit and interpretability. We examined associations of OHB clusters with clinical and parent-reported child oral health status (ie, ECC prevalence, severity and proportion with untreated disease) using bivariate association tests and multivariable regression modelling with marginal effects estimation accounting for clustered data. We used Mplus v.8.6 (Muthen & Muthen, Los Angeles, CA, USA) and Stata v.16.1 (StataCorp, College Station, TX, USA) for data analyses. Results We identified 2 OHB clusters, a favourable (74%) and an unfavourable (26%) one. Children in the favourable OHB cluster had better oral hygiene practices (ie, tooth brushing frequency and fluoridated toothpaste use), lower consumption frequency of sugar-containing snacks and beverages, less frequent reports of night-time bottle-feeding history and a higher likelihood of a dental home. Children in the unfavourable cluster had significantly higher ECC prevalence (57% vs 53%), caries burden (mean dmfs = 9.3 vs 7.6), untreated disease (43% vs 33%) and worse parent-reported oral health status than the favourable cluster. Conclusions Our findings demonstrate the importance and utility of clustering common, modifiable ECC risk factors in population studies - health promotion efforts may centre on groups of people rather than individual behavioural risk factors.

Background: Aspiration community-acquired pneumonia (ACAP) and community-acquired pneumonia (CAP) in patients with aspiration risk factors (AspRFs) are infections associated with anaerobes, but limited evidence suggests their pathogenic role. Research Question: What are the aspiration risk factors, microbiology patterns, and empiric anti-anaerobic use in patients hospitalized with CAP? Study Design and Methods: This is a secondary analysis of GLIMP, an international, multicenter, point-prevalence study of adults hospitalized with CAP. Patients were stratified into three groups: (1) ACAP, (2) CAP/AspRF+ (CAP with AspRF), and (3) CAP/AspRF- (CAP without AspRF). Data on demographics, comorbidities, microbiological results, and anti-anaerobic antibiotics were analyzed in all groups. Patients were further stratified in severe and nonsevere CAP groups. Results: We enrolled 2,606 patients with CAP, of which 193 (7.4%) had ACAP. Risk factors independently associated with ACAP were male, bedridden, underweight, a nursing home resident, and having a history of stroke, dementia, mental illness, and enteral tube feeding. Among non-ACAP patients, 1,709 (70.8%) had CAP/AspRF+ and 704 (29.2%) had CAP/AspRF-. Microbiology patterns including anaerobes were similar between CAP/AspRF-, CAP/AspRF+ and ACAP (0.0% vs 1.03% vs 1.64%). Patients with severe ACAP had higher rates of total gram-negative bacteria (64.3% vs 44.3% vs 33.3%, P =.021) and lower rates of total gram-positive bacteria (7.1% vs 38.1% vs 50.0%, P 50% in all groups) independent of AspRFs or ACAP received specific or broad-spectrum anti-anaerobic coverage antibiotics. Interpretation: Hospitalized patients with ACAP or CAP/AspRF+ had similar anaerobic flora compared with patients without aspiration risk factors. Gram-negative bacteria were more prevalent in patients with severe ACAP. Despite having similar microbiological flora between groups, a large proportion of CAP patients received anti-anaerobic antibiotic coverage.

Early childhood caries (ECC) is an aggressive form of dental caries occurring in the first five years of life. Despite its prevalence and consequences, little progress has been made in its prevention and even less is known about individuals&rsquo, susceptibility or genomic risk factors. The genome-wide association study (GWAS) of ECC (&ldquo, ZOE 2.0&rdquo, ) is a community-based, multi-ethnic, cross-sectional, genetic epidemiologic study seeking to address this knowledge gap. This paper describes the study&rsquo, s design, the cohort&rsquo, s demographic profile, data domains, and key oral health outcomes. Between 2016 and 2019, the study enrolled 8059 3&ndash, 5-year-old children attending public preschools in North Carolina, United States. Participants resided in 86 of the state&rsquo, s 100 counties and racial/ethnic minorities predominated&mdash, for example, 48% (n = 3872) were African American, 22% white, and 20% (n = 1611) were Hispanic/Latino. Seventy-nine percent (n = 6404) of participants underwent clinical dental examinations yielding ECC outcome measures&mdash, ECC (defined at the established caries lesion threshold) prevalence was 54% and the mean number of decayed, missing, filled surfaces due to caries was eight. Nearly all (98%) examined children provided sufficient DNA from saliva for genotyping. The cohort&rsquo, s community-based nature and rich data offer excellent opportunities for addressing important clinical, epidemiologic, and biological questions in early childhood.

Background In the absence of definitive diagnosis, healthcare providers are likely to prescribe empirical antibacterials to those who test negative for malaria. This problem is of critical importance in Southern Asia (SA) and South-eastern Asia (SEA) where high levels of antimicrobial consumption and high prevalence of antimicrobial resistance have been reported. To improve management and guide further diagnostic test development, better understanding is needed of the true causative agents of fever and their geographical variability. Methods We conducted a systematic review of published literature (1980–2015) to characterise the spectrum of pathogens causing non-malarial febrile illness in SA and SEA. We searched six databases in English and French languages: MEDLINE, EMBASE, Global Health (CABI) database, WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. Results A total of 29,558 records from 19 countries in SA and SEA were screened, of which 2410 (8.1%) met the selection criteria. Bacterial aetiologies were reported in 1235 (51.2%) articles, viral in 846 (35.1%), parasitic in 132 (5.5%), and fungal in 54 (2.2%), and 143 (6.0%) articles reported more than one pathogen group. In descending order of frequency, Salmonella Typhi, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and coagulase negative Staphylococcus were the commonly reported bacteria, while dengue virus, chikungunya virus, Japanese encephalitis virus, hepatitis B virus, and hepatitis C virus were common viral pathogens reported. Reports of rarely reported or emerging pathogens included a case report of Borrelia burgdorferi (Lyme disease) in India in 2010 and reports of Nipah virus in Singapore and India. Conclusions This review summarises the reported non-malaria pathogens that may cause febrile illness in SA and SEA. The findings emphasise the need of standardising the reporting of aetiological studies to develop effective, evidence-based fever management and improved surveillance. Research and development of diagnostic tools would benefit from up-to-date epidemiological reporting of the regional diversities of non-malaria fever aetiologies. Trial registration PROSPERO registration, CRD42016049281

Additional file 1. Further results

Additional file 3. Assessment of risk of bias

Additional file 1.

Background The availability of reliable point-of-care tests for malaria has heralded a paradigm shift in the management of febrile illnesses away from presumptive antimalarial therapy. In the absence of a definitive diagnosis, health care providers are more likely to prescribe empirical antimicrobials to those who test negative for malaria. To improve management and guide further test development, better understanding is needed of the true causative agents and their geographic variability. Methods A systematic review of published literature was undertaken to characterise the spectrum of pathogens causing non-malaria febrile illness in Africa (1980–2015). Literature searches were conducted in English and French languages in six databases: MEDLINE, EMBASE, Global Health (CABI), WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. A number of published articles (rather than incidence or prevalence) reporting a given pathogen were presented. Results A total of 16,523 records from 48 African countries were screened, of which 1065 (6.4%) met selection criteria. Bacterial infections were reported in 564 (53.0%) records, viral infections in 374 (35.1%), parasitic infections in 47 (4.4%), fungal infections in nine (0.8%), and 71 (6.7%) publications reported more than one pathogen group. Age range of the study population was not specified in 233 (21.9%) publications. Staphylococcus aureus (18.2%), non-typhoidal Salmonella (17.3%), and Escherichia coli (15.4%) were the commonly reported bacterial infections whereas Rift Valley fever virus (7.4%), yellow fever virus (7.0%), and Ebola virus (6.7%) were the most commonly reported viral infections. Dengue virus infection, previously not thought to be widespread in Africa, was reported in 54 (5.1%) of articles. Conclusions This review summarises the published reports of non-malaria pathogens that may cause febrile illness in Africa. As the threat of antimicrobial resistance looms, knowledge of the distribution of infectious agents causing fever should facilitate priority setting in the development of new diagnostic tools and improved antimicrobial stewardship. Trial registration PROSPERO, CRD42016049281

Background There is a pressing need to understand better the extent and distribution of antimicrobial resistance on a global scale, to inform development of effective interventions. Collation of datasets for meta-analysis, mathematical modelling and temporo-spatial analysis is hampered by the considerable variability in clinical sampling, variable quality in laboratory practice and inconsistencies in antimicrobial susceptibility testing and reporting. Methods The Microbiology Investigation Criteria for Reporting Objectively (MICRO) checklist was developed by an international working group of clinical and laboratory microbiologists, infectious disease physicians, epidemiologists and mathematical modellers. Results In keeping with the STROBE checklist, but applicable to all study designs, MICRO defines items to be included in reports of studies involving human clinical microbiology data. It provides a concise and comprehensive reference for clinicians, researchers, reviewers and journals working on, critically appraising, and publishing clinical microbiology datasets. Conclusions Implementation of the MICRO checklist will enhance the quality and scientific reporting of clinical microbiology data, increasing data utility and comparability to improve surveillance, grade data quality, facilitate meta-analyses and inform policy and interventions from local to global levels. Electronic supplementary material The online version of this article (10.1186/s12916-019-1301-1) contains supplementary material, which is available to authorized users.

Epidemiological investigations of early childhood oral health rely upon the collection of high-quality clinical measures of health and disease. However, ascertainment of valid and accurate clinical measures presents unique challenges among young, preschool-age children. The paper presents a clinical research protocol for the conduct of oral epidemiological examinations among children, implemented in ZOE 2.0, a large-scale population-based genetic epidemiologic study of early childhood caries (ECC). The protocol has been developed for the collection of information on tooth surface-level dental caries experience and tooth-level developmental defects of the enamel in the primary dentition. Dental caries experience is recorded using visual criteria modified from the International Caries Detection and Assessment System (ICDAS), and measurement of developmental defects is based upon the modified Clarkson and O'Mullane Developmental Defects of the Enamel Index. After a dental prophylaxis (toothbrushing among all children and flossing as needed), children's teeth are examined by trained and calibrated examiners in community locations, using portable dental equipment, compressed air, and uniform artificial light and magnification conditions. Data are entered directly onto a computer using a custom Microsoft Access-based data entry application. The ZOE 2.0 clinical protocol has been implemented successfully for the conduct of over 6000 research examinations to date, contributing phenotype data to downstream genomics and other "omics" studies of ECC and DDE, as well as traditional clinical and epidemiologic dental research.

Background– Antimicrobial resistance (AMR) poses a colossal threat to global health and incurs high economic costs to society. Economic evaluations of antimicrobials and interventions such as diagnostics and vaccines that affect their consumption rarely include the costs of AMR, resulting in sub-optimal policy recommendations. We estimate the economic cost of AMR per antibiotic consumed, stratified by drug class and national income level.Methods– The model is comprised of three components: correlation coefficients between human antibiotic consumption and subsequent resistance; the economic costs of AMR for five key pathogens; and consumption data for antibiotic classes driving resistance in these organisms. These were used to calculate the economic cost of AMR per antibiotic consumed for different drug classes, using data from Thailand and the United States (US) to represent low/middle and high-income countries.Results– The correlation coefficients between consumption of antibiotics that drive resistance in S. aureus, E. coli, K. pneumoniae, A. baumanii, and P. aeruginosa and resistance rates were 0.37, 0.27, 0.35, 0.45, and 0.52, respectively. The total economic cost of AMR due to resistance in these five pathogens was $0.5 billion and $2.8 billion in Thailand and the US, respectively. The cost of AMR associated with the consumption of one standard unit (SU) of antibiotics ranged from $0.1 for macrolides to $0.7 for quinolones, cephalosporins and broad-spectrum penicillins in the Thai context. In the US context, the cost of AMR per SU of antibiotic consumed ranged from $0.1 for carbapenems to $0.6 for quinolones, cephalosporins and broad spectrum penicillins.Conclusion– The economic costs of AMR per antibiotic consumed were considerable, often exceeding their purchase cost. Differences between Thailand and the US were apparent, corresponding with variation in the overall burden of AMR and relative prevalence of different pathogens. Notwithstanding their limitations, use of these estimates in economic evaluations can make better-informed policy recommendations regarding interventions that affect antimicrobial consumption and those aimed specifically at reducing the burden of AMR.

Background Increasing evidence is becoming available on the aetiology and management of fevers in Asia; the importance of these fevers has increased with the decline in the incidence of malaria. Aims To conduct a narrative review of the epidemiology and management of fevers in South and South-East Asia and to highlight gaps in our knowledge that impair evidence-based health policy decisions. Sources A narrative review of papers published since 2012 on developments in fever epidemiology, diagnosis and treatment in South and South-East Asia. The papers that the authors felt were pivotal, from their personal perspectives, are discussed. Content We identified 100 studies. Among the 30 studies (30%)—including both children and adults—that investigated three or more pathogens, the most frequently reported fever aetiology was dengue (reported by 15, 50%), followed by leptospirosis (eight, 27%), scrub typhus (seven, 23%) and Salmonella serovar Typhi (six, 20%). Among four studies investigating three or more pathogens in children, dengue and Staphylococcus aureus were the most frequent, followed by non-typhoidal Salmonella spp, Streptococcus pneumoniae , Salmonella serovar Typhi, and Orientia tsutsugamushi . Increased awareness is needed that rickettsial pathogens are common but do not respond to cephalosporins, and that alternative therapies, such as tetracyclines, are required. Implications Many key gaps remain, and consensus guidelines for study design are needed to aid comparative understanding of the epidemiology of fevers. More investment in developing accurate and affordable diagnostic tests for rural Asia and independent evaluation of those already on the market are needed. Treatment algorithms, including simple biomarker assays, appropriate for empirical therapy of fevers in different areas of rural Asia should be a major aim of fever research. Enhanced antimicrobial resistance (AMR) surveillance and openly accessible databases of geography-specific AMR data would inform policy on empirical and specific therapy. More investment in innovative strategies facilitating infectious disease surveillance in remote rural communities would be an important component of poverty reduction and improving public health.

BACKGROUND\ud There is a high risk of occupational exposure to tuberculosis among healthcare workers in endemic countries. Regular screening for tuberculosis among healthcare workers is not carried out in Nepal. Infection control measures are also not routinely implemented. The aim of this study was to determine the prevalence of active tuberculosis among staff/students at Patan Hospital.\ud \ud METHODS\ud Participants were given a self-administered questionnaire and invited to undergo chest radiography. Cases were scored and reviewed based on predetermined criteria, and presumptive tuberculosis cases were invited to undergo sputum smear and culture. Participants were categorized according to the extent of patient contact and asked about history of tuberculosis medication.\ud \ud RESULTS\ud Among 560 participants, 76.8% had direct contact with patients. Fifty-eight (10.4%) gave history of cough >2 weeks. Based on symptom history and chest radiography, 20.0% (n=112) cases were reviewed, and 12.5% (n=14) of those reviewed had sputum tested for acid-fast bacilli. One participant had culture-positive tuberculosis. Fifty participants (8.9%) reported tuberculosis in the past, among which 42.0% (n=21) occurred after employment at Patan Hospital and 42.0% before joining Patan Hospital. Security staff, radiology technicians and ward cleaning staff had the highest proportion of cases with a history of tuberculosis.History of tuberculosis medication had no relation with age, sex, education, body mass index and smoking.The incidence rate of tuberculosis at Patan Hospital was 3.6 per 1000 person-years.\ud \ud CONCLUSIONS\ud Overall incidence of tuberculosis among healthcare workers is noteworthy. However, this study suggests when symptomatic tuberculosis occurs in healthcare worker at Patan Hospital, it is diagnosed and there is not a large pool of undiagnosed tuberculosis.

Background Salmonella serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A), the causative agents of enteric fever, have been routinely isolated organisms from the blood of febrile patients in the Kathmandu Valley since the early 1990s. Susceptibility against commonly used antimicrobials for treating enteric fever has gradually changed throughout South Asia since this time, posing serious treatment challenges. Here, we aimed to longitudinally describe trends in the isolation of Salmonella enterica and assess changes in their antimicrobial susceptibility in Kathmandu over a 23-year period. Methods We conducted a retrospective analysis of standardised microbiological data from April 1992 to December 2014 at a single healthcare facility in Kathmandu, examining time trends of Salmonella-associated bacteraemia and the corresponding antimicrobial susceptibility profiles of the isolated organisms. Results Over 23 years there were 30,353 positive blood cultures. Salmonella enterica accounted for 65.4% (19,857/30,353) of all the bacteria positive blood cultures. S. Typhi and S. Paratyphi A were the dominant serovars, constituting 68.5% (13,592/19,857) and 30.5% (6,057/19,857) of all isolated Salmonellae. We observed (i) a peak in the number of Salmonella-positive cultures in 2002, a year of heavy rainfall and flooding in the Kathmandu Valley, followed by a decline toward pre-flood baseline by 2014, (ii) an increase in the proportion of S. Paratyphi in all Salmonella-positive cultures between 1992 and 2014, (iii) a decrease in the prevalence of MDR for both S. Typhi and S. Paratyphi, and (iv) a recent increase in fluoroquinolone non-susceptibility in both S. Typhi and S. Paratyphi isolates. Conclusions Our work describes significant changes in the epidemiology of Salmonella enterica in the Kathmandu Valley during the last quarter of a century. We highlight the need to examine current treatment protocols for enteric fever and suggest a change from fluoroquinolone monotherapy to combination therapies of macrolides or cephalosporins along with older first-line antimicrobials that have regained their efficacy., Author summary Aiming to understand the epidemiology and changing patterns of the Salmonella enterica serovars Typhi and Paratyphi A within a single healthcare facility in Kathmandu, we retrospectively analysed 23 years of microbiological blood culture data. From 224,741 blood cultures performed, 30,353 were confirmed to be positive for pathogenic bacteria, of which Salmonella enterica accounted for 65.4% (19,857/30,353) of all the bacteria positive blood cultures. S. Typhi and S. Paratyphi A were the dominant serovars, constituting 68.5% (13,592/19,857) and 30.5% (6,057/19,857) of all isolated Salmonellae. We observed that S. Typhi and S. Paratyphi A remained the leading cause of bacterial febrile illness since the 1990s. Additionally, antimicrobial resistance is a major public health challenge, and resistance against the antimicrobials most commonly used for treating enteric fever has developed over the last two decades. In this analysis we were able to document a decrease in the number of Salmonella-positive cultures from 2002 to 2014 and an increase in the proportion of S. Paratyphi A in all Salmonella-positive cultures between 1992 and 2014. Concurrently, we also observed a decrease in MDR for S. Typhi and S. Paratyphi and a recent increase in fluoroquinolone non-susceptibility in both serovars.

Summary Background Because treatment with third-generation cephalosporins is associated with slow clinical improvement and high relapse burden for enteric fever, whereas the fluoroquinolone gatifloxacin is associated with rapid fever clearance and low relapse burden, we postulated that gatifloxacin would be superior to the cephalosporin ceftriaxone in treating enteric fever. Methods We did an open-label, randomised, controlled, superiority trial at two hospitals in the Kathmandu valley, Nepal. Eligible participants were children (aged 2–13 years) and adult (aged 14–45 years) with criteria for suspected enteric fever (body temperature ≥38·0°C for ≥4 days without a focus of infection). We randomly assigned eligible patients (1:1) without stratification to 7 days of either oral gatifloxacin (10 mg/kg per day) or intravenous ceftriaxone (60 mg/kg up to 2 g per day for patients aged 2–13 years, or 2 g per day for patients aged ≥14 years). The randomisation list was computer-generated using blocks of four and six. The primary outcome was a composite of treatment failure, defined as the occurrence of at least one of the following: fever clearance time of more than 7 days after treatment initiation; the need for rescue treatment on day 8; microbiological failure (ie, blood cultures positive for Salmonella enterica serotype Typhi, or Paratyphi A, B, or C) on day 8; or relapse or disease-related complications within 28 days of treatment initiation. We did the analyses in the modified intention-to-treat population, and subpopulations with either confirmed blood-culture positivity, or blood-culture negativity. The trial was powered to detect an increase of 20% in the risk of failure. This trial was registered at ClinicalTrials.gov, number NCT01421693, and is now closed. Findings Between Sept 18, 2011, and July 14, 2014, we screened 725 patients for eligibility. On July 14, 2014, the trial was stopped early by the data safety and monitoring board because S Typhi strains with high-level resistance to ciprofloxacin and gatifloxacin had emerged. At this point, 239 were in the modified intention-to-treat population (120 assigned to gatifloxacin, 119 to ceftriaxone). 18 (15%) patients who received gatifloxacin had treatment failure, compared with 19 (16%) who received ceftriaxone (hazard ratio [HR] 1·04 [95% CI 0·55–1·98]; p=0·91). In the culture-confirmed population, 16 (26%) of 62 patients who received gatifloxacin failed treatment, compared with four (7%) of 54 who received ceftriaxone (HR 0·24 [95% CI 0·08–0·73]; p=0·01). Treatment failure was associated with the emergence of S Typhi exhibiting resistance against fluoroquinolones, requiring the trial to be stopped. By contrast, in patients with a negative blood culture, only two (3%) of 58 who received gatifloxacin failed treatment versus 15 (23%) of 65 who received ceftriaxone (HR 7·50 [95% CI 1·71–32·80]; p=0·01). A similar number of non-serious adverse events occurred in each treatment group, and no serious events were reported. Interpretation Our results suggest that fluoroquinolones should no longer be used for treatment of enteric fever in Nepal. Additionally, under our study conditions, ceftriaxone was suboptimum in a high proportion of patients with culture-negative enteric fever. Since antimicrobials, specifically fluoroquinolones, are one of the only routinely used control measures for enteric fever, the assessment of novel diagnostics, new treatment options, and use of existing vaccines and development of next-generation vaccines are now a high priority. Funding Wellcome Trust and Li Ka Shing Foundation.

BACKGROUND: Antibiotic resistance is a major global health problem and pathogens such as meticillin-resistant Staphylococcus aureus (MRSA) have become of particular concern in the management of lower respiratory tract infections. However, few data are available on the worldwide prevalence and risk factors for MRSA pneumonia. We aimed to determine the point prevalence of MRSA pneumonia and identify specific MRSA risk factors in community-dwelling patients hospitalised with pneumonia.METHODS: We did an international, multicentre study of community-dwelling, adult patients admitted to hospital with pneumonia who had microbiological tests taken within 24 h of presentation. We recruited investigators from 222 hospitals in 54 countries to gather point-prevalence data for all patients admitted with these characteristics during 4 days randomly selected during the months of March, April, May, and June in 2015. We assessed prevalence of MRSA pneumonia and associated risk factors through logistic regression analysis.FINDINGS: 3702 patients hospitalised with pneumonia were enrolled, with 3193 patients receiving microbiological tests within 24 h of admission, forming the patient population. 1173 (37%) had at least one pathogen isolated (culture-positive population). The overall prevalence of confirmed MRSA pneumonia was 3·0% (n=95), with differing prevalence between continents and countries. Three risk factors were independently associated with MRSA pneumonia: previous MRSA infection or colonisation (odds ratio 6·21, 95% CI 3·25-11·85), recurrent skin infections (2·87, 1·10-7·45), and severe pneumonia disease (2·39, 1·55-3·68).INTERPRETATION: This multicountry study shows low prevalence of MRSA pneumonia and specific MRSA risk factors among community-dwelling patients hospitalised with pneumonia.FUNDING: None.

Tuberculous meningitis (TBM) remains the most dangerous form of tuberculosis with high mortality and potential complications. The prompt diagnosis and treatment of this condition remains a key for better prognosis. A 39-year-old woman presented with severe headache, fever, nausea and vomiting, with a history of headache for a month. On examination, confusion, neck rigidity, ptosis and upward plantar reflexes were present. After 7 days of empiric treatment without resolution of her symptoms, she had another spinal tap performed. The diagnosis of TBM was performed by the GeneXpert MTB/RIF assay from her cerebrospinal fluid (CSF). Antitubercular chemotherapy was started. The patient subsequently improved. Where available, the GeneXpert assay should be used immediately in CSF samples of patients suspected of TBM as an adjunct to clinical algorithms to increase the chance of a prompt diagnosis and treatment.

To the Editor—We read with great interest the recent article by Meltzer et al, “A Large Outbreak of Salmonella Paratyphi A Infection Among Israeli Travelers to Nepal” [1], and we would like to raise a few issues. The authors made the point that randomized controlled trials (RCTs) are difficult to conduct in developing countries. However, in Nepal, over the last decade we have carried out a series of RCTs for the treatment of uncomplicated enteric fever [2–4]. Despite being constrained by limited infrastructure and research funding, we have made this a possibility by employing a novel design and method of carrying out RCTs for enteric fever, where we have formed a team of community health auxiliaries to visit patients at their homes where the treatments are administered and follow-up parameters measured. We have systematically evaluated several treatment options for the treatment of enteric fever in both adults and children, including an ongoing trial using intravenous medication. In fact, the trial currently under way, due to conclude soon, has ceftriaxone as one of its treatment arms. Such trials could also be adapted and carried out in other settings where the disease is endemic and would avert the difficulties of carrying out trials that the authors profess. Given the rapid emergence of resistance to commonly used antimicrobials against enteric fever, it is important to consistently carry out RCTs to determine the most optimum therapy, that which employs the shortest and simplest regimens to effectively cure the disease, and making use of novel methods might be the best way to do so in a setting such as ours beset by this neglected disease. As difficult as it is to conduct such trials to the level of accepted standards, we would also like to point out that comparisons or documentation of treatment regimens, although not necessarily based on a randomized study, can also be immensely useful and practicable for quickly discerning and reporting failing treatments. However, in this study the treatment recommendations are based on the effects of the drugs on only 1 strain with a singular susceptibility pattern, whereas it must be borne in mind that in any endemic setting there are a multitude of strains and susceptibility patterns in play [5] that would have differing resistance to both ceftriaxone and azithromycin. Also, the effect of azithromycin seen may be a solitary effect as shown in other studies [6, 7] and not a synergistic one with ceftriaxone. Therefore, basing treatment regimens solely on comparisons presented in this study may not be appropriate. It is also difficult to accurately diagnose enteric fever, and blood culture is positive in only 40%–60% of presumptive cases [8]. There indeed must have been other travelers returning from Nepal who had similar clinical features and needed the same courses of antimicrobials but whose blood cultures did not grow any organism. The proper identification of the subset of culture-negative patients is also immensely important. Given the good surveillance system in Israel, the report would have been more informative if the authors had included these patients as well.

Camphor is usually used in the USA to repel insects, but it is widely used in other countries as an herb. We report the case of a 52-year-old previously healthy Nepali man who ingested approximately 10 g of pure camphor with therapeutic intention. He developed grand mal seizures, and was evaluated in an emergency room. He failed to recall the camphor ingestion initially, and was treated with phenytoin for new-onset idiopathic seizures. Examining physicians only later found out about his camphor ingestion. Finding the cause of new-onset seizures is often challenging for emergency room physicians, internists and neurologists. In addition to other well-reported causes of secondary seizures, herbal medications and supplements must also be explored.

Background: In many rural areas at risk for enteric fever, there are few data on Salmonella enterica serotypes Typhi (S. Typhi) and Paratyphi (S. Paratyphi) incidence, due to limited laboratory capacity for microbiologic culture. Here, we describe an approach that permits recovery of the causative agents of enteric fever in such settings. This approach involves the use of an electricity-free incubator based upon use of phase-change materials. We compared this against conventional blood culture for detection of typhoidal Salmonella. Methodology/Principal Findings: Three hundred and four patients with undifferentiated fever attending the outpatient and emergency departments of a public hospital in the Kathmandu Valley of Nepal were recruited. Conventional blood culture was compared against an electricity-free culture approach. Blood from 66 (21.7%) patients tested positive for a Gram-negative bacterium by at least one of the two methods. Sixty-five (21.4%) patients tested blood culture positive for S. Typhi (30; 9.9%) or S. Paratyphi A (35; 11.5%). From the 65 individuals with culture-confirmed enteric fever, 55 (84.6%) were identified by the conventional blood culture and 60 (92.3%) were identified by the experimental method. Median time-to-positivity was 2 days for both procedures. The experimental approach was falsely positive due to probable skin contaminants in 2 of 239 individuals (0.8%). The percentages of positive and negative agreement for diagnosis of enteric fever were 90.9% (95% CI: 80.0%–97.0%) and 96.0% (92.7%–98.1%), respectively. After initial incubation, Salmonella isolates could be readily recovered from blood culture bottles maintained at room temperature for six months. Conclusions/Significance: A simple culture approach based upon a phase-change incubator can be used to isolate agents of enteric fever. This approach could be used as a surveillance tool to assess incidence and drug resistance of the etiologic agents of enteric fever in settings without reliable local access to electricity or local diagnostic microbiology laboratories., Boston Children's Hospital (Frederick H. Lovejoy Fund), Harvard Global Health Institute, National Institute of Allergy and Infectious Diseases (U.S.) (Grant AI100023), National Institute of Allergy and Infectious Diseases (U.S.) (Grant AI077883)

Details of microbiology datasets from South and South East Asia included in the review. For each study, the antimicrobial susceptibility guideline details are summarised along with deviations from expected reporting for four bug-drug combinations: Klebsiella pneumoniae-ampicillin; Salmonella sp.-gentamicin; Staphylococcus aureus-beta-lactams; and Streptococcus pneumoniae-penicillin. The Staphylococcus aureus-beta-lactams combination includes any penicillin, cephalosporin or carbapenem apart from penicillinase-labile drugs (benzylpenicillin, phenoxymethylpenicillin, amoxicillin, ampicillin). (PDF 489 kb)

Details of microbiology datasets from South and South East Asia included in the review. For each study, the antimicrobial susceptibility guideline details are summarised along with deviations from expected reporting for four bug-drug combinations: Klebsiella pneumoniae-ampicillin; Salmonella sp.-gentamicin; Staphylococcus aureus-beta-lactams; and Streptococcus pneumoniae-penicillin. The Staphylococcus aureus-beta-lactams combination includes any penicillin, cephalosporin or carbapenem apart from penicillinase-labile drugs (benzylpenicillin, phenoxymethylpenicillin, amoxicillin, ampicillin). (PDF 489 kb)