85 results on '"Burr SE"'
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2. Mass drug administration with azithromycin for trachoma elimination and the population structure of Streptococcus pneumoniae in the nasopharynx
- Author
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Gladstone, RA, Bojang, E, Hart, J, Harding-Esch, EM, Mabey, D, Sillah, A, Bailey, RL, Burr, SE, Roca, A, Bentley, SD, Holland, MJ, Gladstone, RA, Bojang, E, Hart, J, Harding-Esch, EM, Mabey, D, Sillah, A, Bailey, RL, Burr, SE, Roca, A, Bentley, SD, and Holland, MJ more...
- Abstract
OBJECTIVE: Mass drug administration (MDA) with azithromycin for trachoma elimination reduces nasopharyngeal carriage of Streptococcus pneumoniae in the short term. We evaluated S. pneumoniae carried in the nasopharynx before and after a round of azithromycin MDA to determine whether MDA was associated with changes in pneumococcal population structure and resistance. METHODS: We analysed 514 pneumococcal whole genomes randomly selected from nasopharyngeal samples collected in two Gambian villages that received three annual rounds of MDA for trachoma elimination. The 514 samples represented 293 participants, of which 75% were children aged 0-9 years, isolated during three cross-sectional surveys (CSSs) conducted before the third round of MDA (CSS-1) and at 1 (CSS-2) and 6 (CSS-3) months after MDA. Bayesian Analysis of Population Structure (BAPS) was used to cluster related isolates by capturing variation in the core genome. Serotype and multilocus sequence type were inferred from the genotype. Antimicrobial resistance determinants were identified from assemblies, including known macrolide resistance genes. RESULTS: Twenty-seven BAPS clusters were assigned. These consisted of 81 sequence types (STs). Two BAPS clusters not observed in CSS-1 (n = 109) or CSS-2 (n = 69), increased in frequency in CSS-3 (n = 126); BAPS20 (8.73%, p 0.016) and BAPS22 (7.14%, p 0.032) but were not associated with antimicrobial resistance. Macrolide resistance within BAPS17 increased after treatment (CSS-1 n = 0/6, CSS-2/3 n = 5/5, p 0.002) and was carried on a mobile transposable element that also conferred resistance to tetracycline. DISCUSSION: Limited changes in pneumococcal population structure were observed after the third round of MDA, suggesting treatment had little effect on the circulating lineages. An increase in macrolide resistance within one BAPS highlights the need for antimicrobial resistance surveillance in treated villages. more...
- Published
- 2021
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3. Fecal biomarkers of environmental enteric dysfunction and the gut microbiota of rural Malawian children: An observational study.
- Author
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Chaima, D, Pickering, H, Hart, JD, Burr, SE, Maleta, KM, Kalua, K, Bailey, RL, Holland, MJ, Chaima, D, Pickering, H, Hart, JD, Burr, SE, Maleta, KM, Kalua, K, Bailey, RL, and Holland, MJ
- Abstract
Environmental enteric dysfunction (EED) is a subclinical condition of the gut characterized by changes in morphology and function with underlying chronic inflammatory responses. This study characterized composition and diversity of the gut microbiota in rural Malawian children with and without signs of EED. Fecal samples were collected from children aged 1-59 months. Neopterin, myeloperoxidase and alpha-1 antitrypsin concentrations were quantified by ELISA and combined to form a composite EED score using principal component analysis. DNA was extracted from fecal samples and V4-16S rRNA gene sequencing was used to characterize the gut microbiota. The concentrations of all three biomarkers decreased with increasing age, which is consistent with other studies of children living in similar low-income settings. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. Increased alpha diversity was associated with a reduction in neopterin concentration. Microbiota composition was different between fecal samples with low and high composite EED scores; increased abundance of Succinivibrio was associated with reduced composite EED scores. more...
- Published
- 2021
4. Effects of Biannual Azithromycin Mass Drug Administration on Malaria in Malawian Children: A Cluster-Randomized Trial
- Author
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Hart, JD, Samikwa, L, Sikina, F, Kalua, K, Keenan, JD, Lietman, TM, Burr, SE, Bailey, RL, Hart, JD, Samikwa, L, Sikina, F, Kalua, K, Keenan, JD, Lietman, TM, Burr, SE, and Bailey, RL
- Abstract
Reductions in malaria morbidity have been reported following azithromycin mass drug administration (MDA) for trachoma. The recent Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) trial reported a reduction in child mortality following biannual azithromycin MDA. Here, we investigate the effects of azithromycin MDA on malaria at the MORDOR-Malawi study site. A cluster-randomized double-blind placebo-controlled trial, with 15 clusters per arm, was conducted. House-to-house census was updated biannually, and azithromycin or placebo syrup was distributed to children aged 1-59 months for a total of four biannual distributions. At baseline, 12-month, and 24-month follow-up visits, a random sample of 1,200 children was assessed for malaria with thick and thin blood smears and hemoglobin measurement. In the community-level analysis, there was no difference in the prevalence of parasitemia (1.0% lower in azithromycin-treated communities; 95% CI: -8.2 to 6.1), gametocytemia (0.7% lower in azithromycin-treated communities; 95% CI: -2.8 to 1.5), or anemia (1.7% lower in azithromycin-treated communities; 95% CI: -8.1 to 4.6) between placebo and azithromycin communities. Further interrogation of the data at the individual level, both per-protocol (including only those who received treatment 6 months previously) and by intention-to-treat, did not identify differences in parasitemia between treatment arms. In contrast to several previous reports, this study did not show an effect of azithromycin MDA on malaria parasitemia at the community or individual levels. more...
- Published
- 2020
5. Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity
- Author
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Last, AR, Pickering, H, Roberts, Ch, Coll, F, Phelan, J, Burr, SE, Cassama, E, Nabicassa, M, Seth-Smith, HMB, Hadfield, J, Cutcliffe, LT, Clarke, IN, Mabey, DCW, Bailey, RL, Clark, TG, Thomson, NR, and Holland, MJ more...
- Subjects
lcsh:QH426-470 ,Population ,lcsh:Medicine ,Chlamydia trachomatis ,Genomics ,Single-nucleotide polymorphism ,Biology ,medicine.disease_cause ,Genome ,Pathogenesis ,03 medical and health sciences ,Intergenic region ,medicine ,Genome-wide association analysis ,education ,Disease severity ,030304 developmental biology ,Trachoma ,Pathogen genomic diversity ,0303 health sciences ,education.field_of_study ,030306 microbiology ,lcsh:R ,Single nucleotide polymorphisms ,medicine.disease ,3. Good health ,lcsh:Genetics ,Immunology - Abstract
Chlamydia trachomatis(Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide. UsingCtwhole genome sequences obtained directly from conjunctival swabs, we studiedCtgenomic diversity and associations betweenCtgenetic polymorphisms with ocular localization and disease severity in a treatment-naïve trachoma-endemic population in Guinea Bissau, West Africa. All sequences fall within the T2 ocular clade phylogenetically. This is consistent with the presence of the characteristic deletion intrpAresulting in a truncated non-functional protein and the ocular tyrosine repeat regions present intarPassociated with ocular tissue localization. We have identified twenty-oneCtnon-synonymous single nucleotide polymorphisms (SNPs) associated with ocular localization, including SNPs withinpmpD(OR=4.07,p*=0.001) andtarP(OR=0.34,p*=0.009). Eight SNPs associated with disease severity were found inyjfH (rlmB)(OR=0.13,p*=0.037),CTA0273(OR=0.12,p*=0.027),trmD(OR=0.12,p*=0.032),CTA0744(OR=0.12,p*=0.041),glgA(OR=0.10,p*=0.026),alaS(OR=0.10,p*=0.032),pmpE(OR=0.08,p*=0.001) and the intergenic regionCTA0744-CTA0745(OR=0.13,p*=0.043). This study demonstrates the extent of genomic diversity within a naturally circulating population of ocularCt, and the first to describe novel genomic associations with disease severity. These findings direct investigation of host-pathogen interactions that may be important in ocularCtpathogenesis and disease transmission. more...
- Published
- 2018
6. Pgp3 seroprevalence and associations with active trachoma and ocular Chlamydia trachomatis infection in Malawi: cross-sectional surveys in six evaluation units
- Author
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Ngondi, JM, Burr, SE, Hart, J, Samikwa, L, Chaima, D, Cooley, G, Martin, D, Masika, M, Solomon, AW, Bailey, RL, Kalua, K, Ngondi, JM, Burr, SE, Hart, J, Samikwa, L, Chaima, D, Cooley, G, Martin, D, Masika, M, Solomon, AW, Bailey, RL, and Kalua, K more...
- Abstract
BACKGROUND: Following one to five years of antibiotic mass drug administration (MDA) for the elimination of trachoma as a public health problem, programmes must conduct impact surveys to inform decisions on whether MDA is still needed. These decisions are currently based on the prevalence of trachomatous inflammation-follicular (TF), which, after MDA, correlates poorly with prevalence of ocular Chlamydia trachomatis infection. METHODOLOGY/PRINCIPAL FINDINGS: Impact surveys in six evaluation units (EUs) of Malawi were used as a platform to explore associations between the prevalence of TF, ocular C. trachomatis infection and anti-Pgp3 antibodies one year after the third annual round of MDA. Participants were examined for trachoma using the World Health Organization simplified grading system. Ocular swabs and dried blood spots (DBS) were collected from children aged 1-9 years. Swabs were tested for C. trachomatis DNA using GeneXpert. DBS were assayed for anti-Pgp3 antibodies using ELISA. EU-level prevalence of TF in children aged 1-9 years ranged from 4.7% (95% CI 3.4-6.3) to 7.2% (95% CI 5.8-8.9). Prevalence of C. trachomatis infection in children ranged from 0.1% (95% CI 0.0-0.6) to 0.7% (95% CI 0.3-1.3) while Pgp3 seroprevalence ranged from 6.9% (95% CI 5.4-8.6) to 12.0% (95% CI 10.1-14.0) and increased with age. CONCLUSIONS/SIGNIFICANCE: Based on current global policy, the prevalence of TF indicates that a further year of antibiotic MDA is warranted in four of six EUs yet the very low levels of infection cast doubt on the universal applicability of TF-based cut-offs for antibiotic MDA. Pgp3 seroprevalence was similar to that reported following MDA in other settings that have reached the elimination target however the predictive value of any particular level of seropositivity with respect to risk of subsequent infection recrudescence is, as yet, unknown. more...
- Published
- 2019
7. Population-based analysis of ocularChlamydia trachomatisin trachoma-endemic West African communities identifies genomic markers of disease severity
- Author
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Last, AR, Pickering, H, Roberts, Ch, Coll, F, Phelan, J, Burr, SE, Cassama, E, Nabicassa, M, Seth-Smith, HMB, Hadfield, J, Cutcliffe, LT, Clarke, IN, Mabey, DCW, Bailey, RL, Clark, TG, Thomson, NR, and Holland, MJ more...
- Abstract
Chlamydia trachomatis(Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide. UsingCtwhole genome sequences obtained directly from conjunctival swabs, we studiedCtgenomic diversity and associations betweenCtgenetic polymorphisms with ocular localization and disease severity in a treatment-naïve trachoma-endemic population in Guinea Bissau, West Africa. All sequences fall within the T2 ocular clade phylogenetically. This is consistent with the presence of the characteristic deletion intrpAresulting in a truncated non-functional protein and the ocular tyrosine repeat regions present intarPassociated with ocular tissue localization. We have identified twenty-oneCtnon-synonymous single nucleotide polymorphisms (SNPs) associated with ocular localization, including SNPs withinpmpD(OR=4.07,p*=0.001) andtarP(OR=0.34,p*=0.009). Eight SNPs associated with disease severity were found inyjfH (rlmB)(OR=0.13,p*=0.037),CTA0273(OR=0.12,p*=0.027),trmD(OR=0.12,p*=0.032),CTA0744(OR=0.12,p*=0.041),glgA(OR=0.10,p*=0.026),alaS(OR=0.10,p*=0.032),pmpE(OR=0.08,p*=0.001) and the intergenic regionCTA0744-CTA0745(OR=0.13,p*=0.043). This study demonstrates the extent of genomic diversity within a naturally circulating population of ocularCt, and the first to describe novel genomic associations with disease severity. These findings direct investigation of host-pathogen interactions that may be important in ocularCtpathogenesis and disease transmission. more...
- Published
- 2017
8. Cross-Sectional Surveys of the Prevalence of Follicular Trachoma and Trichiasis in The Gambia: Has Elimination Been Reached?
- Author
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Burr, SE, Sillah, A, Sanou, AS, Wadagni, AC, Hart, J, Harding-Esch, EM, Kanyi, S, and Bailey, RL
- Subjects
Bacterial Diseases ,Adult ,Male ,Rural Population ,Census ,Trichiasis ,lcsh:Arctic medicine. Tropical medicine ,Eye Diseases ,Adolescent ,lcsh:RC955-962 ,Sexually Transmitted Diseases ,Surgical and Invasive Medical Procedures ,Research and Analysis Methods ,Global Health ,Blindness ,Chlamydia Infection ,Geographical Locations ,Ocular System ,Risk Factors ,Surveys and Questionnaires ,Medicine and Health Sciences ,Prevalence ,Humans ,Public and Occupational Health ,Child ,Trachoma ,Survey Research ,lcsh:Public aspects of medicine ,Ophthalmic Procedures ,Biology and Life Sciences ,Infant ,lcsh:RA1-1270 ,Tropical Diseases ,Ophthalmology ,Infectious Diseases ,Cross-Sectional Studies ,Research Design ,Child, Preschool ,People and Places ,Africa ,Eyes ,Gambia ,Female ,Anatomy ,Head ,Research Article ,Neglected Tropical Diseases - Abstract
Background The Gambia’s National Eye Health Programme has made a concerted effort to reduce the prevalence of trachoma. The present study had two objectives. The first was to conduct surveillance following mass drug administrations to determine whether The Gambia has reached the World Health Organization’s (WHO) criteria for trachoma elimination, namely a prevalence of trachomatous inflammation—follicular (TF) of less than 5% in children aged 1 to 9 years. The second was to determine the prevalence of trichiasis (TT) cases unknown to the programme and evaluate whether these meet the WHO criteria of less than 0.1% in the total population. Methodology/Principal Findings Three cross-sectional surveys were conducted between 2011 and 2013 to determine the prevalence of TF and TT in each of nine surveillance zones. Each zone was of similar size, with a population of 60,000 to 90,000, once urban settlements were excluded. Trachoma grading was carried out according to the WHO’s simplified trachoma grading system. The prevalence of TF in children aged 1 to 9 years was less than 5% in each surveillance zone at each of the three surveys. The prevalence of TT cases varied by zone from 0 to 1.7% of adults greater than 14 years while the prevalence of TT cases unknown to the country’s National Eye Health Programme was estimated at 0.15% total population. Conclusions/Significance The Gambia has reached the elimination threshold for TF in children. Further work is needed to bring the number of unknown TT cases below the elimination threshold., Author Summary Trachoma, the world’s leading infectious cause of blindness, is caused by ocular infection with the bacterium Chlamydia trachomatis. The Gambia, situated in West Africa, has implemented all facets of the World Health Organization-recommended SAFE strategy for trachoma control including surgery to correct the in-turning of eyelashes (trichiasis), mass drug administration with antibiotics, promotion of facial hygiene and environmental improvements. In 2011, The Gambia’s National Eye Health Programme began three years of rolling surveys to determine the prevalence of trachoma in the country and to evaluate whether trachoma elimination has been reached. The results suggest the country has reached the elimination threshold for trachoma in children (less than 5% prevalence) but that more work needs to be done to reduce the prevalence of trichiasis in adults. more...
- Published
- 2016
9. Evaluation of a Chlamydia trachomatis-specific, commercial, real-time PCR for use with ocular swabs
- Author
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Pickering, H, primary, Holland, MJ, additional, Last, AR, additional, Burton, MJ, additional, and Burr, SE, additional
- Published
- 2018
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10. Population-based analysis of ocularChlamydia trachomatisin trachoma-endemic West African communities identifies genomic markers of disease severity
- Author
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Last, AR, primary, Pickering, H, additional, Roberts, Ch, additional, Coll, F, additional, Phelan, J, additional, Burr, SE, additional, Cassama, E, additional, Nabicassa, M, additional, Seth-Smith, HMB, additional, Hadfield, J, additional, Cutcliffe, LT, additional, Clarke, IN, additional, Mabey, DCW, additional, Bailey, RL, additional, Clark, TG, additional, Thomson, NR, additional, and Holland, MJ, additional more...
- Published
- 2017
- Full Text
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11. Short-term increase in prevalence of nasopharyngeal carriage of macrolide-resistant Staphylococcus aureus following mass drug administration with azithromycin for trachoma control
- Author
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Bojang, E, Jafali, J, Perreten, V, Hart, J, Harding-Esch, EM, Sillah, A, Mabey, DCW, Holland, MJ, Bailey, RL, Roca, A, Burr, SE, Bojang, E, Jafali, J, Perreten, V, Hart, J, Harding-Esch, EM, Sillah, A, Mabey, DCW, Holland, MJ, Bailey, RL, Roca, A, and Burr, SE more...
- Abstract
BACKGROUND: Mass drug administration (MDA) with azithromycin is a corner-stone of trachoma control however it may drive the emergence of antimicrobial resistance. In a cluster-randomized trial (Clinical trial gov NCT00792922), we compared the reduction in the prevalence of active trachoma in communities that received three annual rounds of MDA to that in communities that received a single treatment round. We used the framework of this trial to carry out an opportunistic study to investigate if the increased rounds of treatment resulted in increased prevalence of nasopharyngeal carriage of macrolide-resistant Staphylococcus aureus. Three cross-sectional surveys were conducted in two villages receiving three annual rounds of MDA (3 × treatment arm). Surveys were conducted immediately before the third round of MDA (CSS-1) and at one (CSS-2) and six (CSS-3) months after MDA. The final survey also included six villages that had received only one round of MDA 30 months previously (1 × treatment arm). RESULTS: In the 3 × treatment arm, a short-term increase in prevalence of S. aureus carriage was seen following MDA from 24.6% at CSS-1 to 38.6% at CSS-2 (p < 0.001). Prevalence fell to 8.8% at CSS-3 (p < 0.001). A transient increase was also seen in prevalence of carriage of azithromycin resistant (AzmR) strains from 8.9% at CSS-1 to 34.1% (p < 0.001) in CSS-2 and down to 7.3% (p = 0.417) in CSS-3. A similar trend was observed for prevalence of carriage of macrolide-inducible-clindamycin resistant (iMLSB) strains. In CSS-3, prevalence of carriage of resistant strains was higher in the 3 × treatment arm than in the 1 × treatment (AzmR 7.3% vs. 1.6%, p = 0.010; iMLSB 5.8% vs. 0.8%, p < 0.001). Macrolide resistance was attributed to the presence of msr and erm genes. CONCLUSIONS: Three annual rounds of MDA with azithromycin were associated with a short-term increase in both the prevalence of nasopharyngeal carriage of S. aureus and prevalence of carriage of AzmR and iMLSB S. au more...
- Published
- 2017
12. Cross-Sectional Surveys of the Prevalence of Follicular Trachoma and Trichiasis in The Gambia: Has Elimination Been Reached?
- Author
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Ngondi, JM, Burr, SE, Sillah, A, Sanou, AS, Wadagni, AC, Hart, J, Harding-Esch, EM, Kanyi, S, Bailey, RL, Ngondi, JM, Burr, SE, Sillah, A, Sanou, AS, Wadagni, AC, Hart, J, Harding-Esch, EM, Kanyi, S, and Bailey, RL more...
- Abstract
BACKGROUND: The Gambia's National Eye Health Programme has made a concerted effort to reduce the prevalence of trachoma. The present study had two objectives. The first was to conduct surveillance following mass drug administrations to determine whether The Gambia has reached the World Health Organization's (WHO) criteria for trachoma elimination, namely a prevalence of trachomatous inflammation-follicular (TF) of less than 5% in children aged 1 to 9 years. The second was to determine the prevalence of trichiasis (TT) cases unknown to the programme and evaluate whether these meet the WHO criteria of less than 0.1% in the total population. METHODOLOGY/PRINCIPAL FINDINGS: Three cross-sectional surveys were conducted between 2011 and 2013 to determine the prevalence of TF and TT in each of nine surveillance zones. Each zone was of similar size, with a population of 60,000 to 90,000, once urban settlements were excluded. Trachoma grading was carried out according to the WHO's simplified trachoma grading system. The prevalence of TF in children aged 1 to 9 years was less than 5% in each surveillance zone at each of the three surveys. The prevalence of TT cases varied by zone from 0 to 1.7% of adults greater than 14 years while the prevalence of TT cases unknown to the country's National Eye Health Programme was estimated at 0.15% total population. CONCLUSIONS/SIGNIFICANCE: The Gambia has reached the elimination threshold for TF in children. Further work is needed to bring the number of unknown TT cases below the elimination threshold. more...
- Published
- 2016
13. Non-Participation during Azithromycin Mass Treatment for Trachoma in The Gambia: Heterogeneity and Risk Factors
- Author
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Vinetz, JM, Edwards, T, Allen, E, Harding-Esch, EM, Hart, J, Burr, SE, Holland, MJ, Sillah, A, West, SK, Mabey, D, Bailey, R, Vinetz, JM, Edwards, T, Allen, E, Harding-Esch, EM, Hart, J, Burr, SE, Holland, MJ, Sillah, A, West, SK, Mabey, D, and Bailey, R more...
- Abstract
BACKGROUND: There is concern that untreated individuals in mass drug administration (MDA) programs for neglected tropical diseases can reduce the impact of elimination efforts by maintaining a source of transmission and re-infection. METHODOLOGY/PRINCIPAL FINDINGS: Treatment receipt was recorded against the community census during three MDAs with azithromycin for trachoma in The Gambia, a hypo-endemic setting. Predictors of non-participation were investigated in 1-9 year olds using random effects logistic regression of cross-sectional data for each MDA. Two types of non-participators were identified: present during MDA but not treated (PNT) and eligible for treatment but absent during MDA (EBA). PNT and EBA children were compared to treated children separately. Multivariable models were developed using baseline data and validated using year one and two data, with a priori adjustment for previous treatment status. Analyses included approximately 10000 children at baseline and 5000 children subsequently. There was strong evidence of spatial heterogeneity, and persistent non-participation within households and individuals. By year two, non-participation increased significantly to 10.4% overall from 6.2% at baseline, with more, smaller geographical clusters of non-participating households. Multivariable models suggested household level predictors of non-participation (increased time to water and household head non-participation for both PNT and EBA; increased household size for PNT status only; non-inclusion in a previous trachoma examination survey and younger age for EBA only). Enhanced coverage efforts did not decrease non-participation. Few infected children were detected at year three and only one infected child was EBA previously. Infected children were in communities close to untreated endemic areas with higher rates of EBA non-participation during MDA. CONCLUSIONS/SIGNIFICANCE: In hypo-endemic settings, with good coverage and no association between non-participa more...
- Published
- 2014
14. Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control
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Burr, SE, Hart, J, Edwards, T, Harding-Esch, EM, Holland, MJ, Mabey, DCW, Sillah, A, Bailey, RL, Burr, SE, Hart, J, Edwards, T, Harding-Esch, EM, Holland, MJ, Mabey, DCW, Sillah, A, and Bailey, RL
- Abstract
BACKGROUND: Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed. METHODS: Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms. RESULTS: No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms. CONCLUSIONS: Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status. more...
- Published
- 2014
15. Conjunctival MicroRNA Expression in Inflammatory Trachomatous Scarring
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Vinetz, JM, Derrick, T, Roberts, CH, Rajasekhar, M, Burr, SE, Joof, H, Makalo, P, Bailey, RL, Mabey, DCW, Burton, MJ, Holland, MJ, Vinetz, JM, Derrick, T, Roberts, CH, Rajasekhar, M, Burr, SE, Joof, H, Makalo, P, Bailey, RL, Mabey, DCW, Burton, MJ, and Holland, MJ more...
- Abstract
PURPOSE: Trachoma is a fibrotic disease of the conjunctiva initiated by Chlamydia trachomatis infection. This blinding disease affects over 40 million people worldwide yet the mechanisms underlying its pathogenesis remain poorly understood. We have investigated host microRNA (miR) expression in health (N) and disease (conjunctival scarring with (TSI) and without (TS) inflammation) to determine if these epigenetic differences are associated with pathology. METHODS: We collected two independent samples of human conjunctival swab specimens from individuals living in The Gambia (n = 63 & 194). miR was extracted, and we investigated the expression of 754 miR in the first sample of 63 specimens (23 N, 17 TS, 23 TSI) using Taqman qPCR array human miRNA genecards. Network and pathway analysis was performed on this dataset. Seven miR that were significantly differentially expressed between different phenotypic groups were then selected for validation by qPCR in the second sample of 194 specimens (93 N, 74 TS, 22 TSI). RESULTS: Array screening revealed differential expression of 82 miR between N, TS and TSI phenotypes (fold change >3, p<0.05). Predicted mRNA targets of these miR were enriched in pathways involved in fibrosis and epithelial cell differentiation. Two miR were confirmed as being differentially expressed upon validation by qPCR. miR-147b is significantly up-regulated in TSI versus N (fold change = 2.3, p = 0.03) and miR-1285 is up-regulated in TSI versus TS (fold change = 4.6, p = 0.005), which was consistent with the results of the qPCR array. CONCLUSIONS: miR-147b and miR-1285 are up-regulated in inflammatory trachomatous scarring. Further investigation of the function of these miR will aid our understanding of the pathogenesis of trachoma. more...
- Published
- 2013
16. Mass Treatment with Azithromycin for Trachoma: When Is One Round Enough? Results from the PRET Trial in The Gambia
- Author
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Vinetz, JM, Harding-Esch, EM, Sillah, A, Edwards, T, Burr, SE, Hart, JD, Joof, H, Laye, M, Makalo, P, Manjang, A, Molina, S, Sarr-Sissoho, I, Quinn, TC, Lietman, T, Holland, MJ, Mabey, D, West, SK, Bailey, R, Vinetz, JM, Harding-Esch, EM, Sillah, A, Edwards, T, Burr, SE, Hart, JD, Joof, H, Laye, M, Makalo, P, Manjang, A, Molina, S, Sarr-Sissoho, I, Quinn, TC, Lietman, T, Holland, MJ, Mabey, D, West, SK, and Bailey, R more...
- Abstract
BACKGROUND: The World Health Organization has recommended three rounds of mass drug administration (MDA) with antibiotics in districts where the prevalence of follicular trachoma (TF) is ≥10% in children aged 1-9 years, with treatment coverage of at least 80%. For districts at 5-10% TF prevalence it was recommended that TF be assessed in 1-9 year olds in each community within the district, with three rounds of MDA provided to any community where TF≥10%. Worldwide, over 40 million people live in districts whose TF prevalence is estimated to be between 5 and 10%. The best way to treat these districts, and the optimum role of testing for infection in deciding whether to initiate or discontinue MDA, are unknown. METHODS: In a community randomized trial with a factorial design, we randomly assigned 48 communities in four Gambian districts, in which the prevalence of trachoma was known or suspected to be above 10%, to receive annual mass treatment with expected coverage of 80-89% ("Standard"), or to receive an additional visit in an attempt to achieve coverage of 90% or more ("Enhanced"). The same 48 communities were randomised to receive mass treatment annually for three years ("3×"), or to have treatment discontinued if Chlamydia trachomatis (Ct) infection was not detected in a sample of children in the community after mass treatment (stopping rule("SR")). Primary outcomes were the prevalence of TF and of Ct infection in 0-5 year olds at 36 months. RESULTS: The baseline prevalence of TF and of Ct infection in the target communities was 6.5% and 0.8% respectively. At 36 months the prevalence of TF was 2.8%, and that of Ct infection was 0.5%. No differences were found between the arms in TF or Ct infection prevalence either at baseline (Standard-3×: TF 5.6%, Ct 0.7%; Standard-SR: TF 6.1%, Ct 0.2%; Enhanced-3×: TF 7.4%, Ct 0.9%; and Enhanced-SR: TF 6.2%, Ct 1.2%); or at 36 months (Standard-3×: TF 2.3%, Ct 1.0%; Standard-SR TF 2.5%, Ct 0.2%; Enhanced-3× TF 3.0%, Ct 0.2%; an more...
- Published
- 2013
17. Association between Ocular Bacterial Carriage and Follicular Trachoma Following Mass Azithromycin Distribution in The Gambia
- Author
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Ngondi, JM, Burr, SE, Hart, JD, Edwards, T, Baldeh, I, Bojang, E, Harding-Esch, EM, Holland, MJ, Lietman, TM, West, SK, Mabey, DCW, Sillah, A, Bailey, RL, Ngondi, JM, Burr, SE, Hart, JD, Edwards, T, Baldeh, I, Bojang, E, Harding-Esch, EM, Holland, MJ, Lietman, TM, West, SK, Mabey, DCW, Sillah, A, and Bailey, RL more...
- Abstract
BACKGROUND: Trachoma, caused by ocular Chlamydia trachomatis infection, is the leading infectious cause of blindness, but its prevalence is now falling in many countries. As the prevalence falls, an increasing proportion of individuals with clinical signs of follicular trachoma (TF) is not infected with C. trachomatis. A recent study in Tanzania suggested that other bacteria may play a role in the persistence of these clinical signs. METHODOLOGY/PRINCIPAL FINDINGS: We examined associations between clinical signs of TF and ocular colonization with four pathogens commonly found in the nasopharnyx, three years after the initiation of mass azithromycin distribution. Children aged 0 to 5 years were randomly selected from 16 Gambian communities. Both eyes of each child were examined and graded for trachoma according to the World Health Organization (WHO) simplified system. Two swabs were taken from the right eye: one swab was processed for polymerase chain reaction (PCR) using the Amplicor test for detection of C. trachomatis DNA and the second swab was processed by routine bacteriology to assay for the presence of viable Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Prevalence of TF was 6.2% (96/1538) while prevalence of ocular C. trachomatis infection was 1.0% (16/1538). After adjustment, increased odds of TF were observed in the presence of C. trachomatis (OR = 10.4, 95%CI 1.32-81.2, p = 0.03), S. pneumoniae (OR = 2.14, 95%CI 1.03-4.44, p = 0.04) and H. influenzae (OR = 4.72, 95% CI 1.53-14.5, p = 0.01). CONCLUSIONS/SIGNIFICANCE: Clinical signs of TF can persist in communities even when ocular C. trachomatis infection has been controlled through mass azithromycin distribution. In these settings, TF may be associated with ocular colonization with bacteria commonly carried in the nasopharnyx. This may affect the interpretation of impact surveys and the determinations of thresholds for discontinuing mass drug administra more...
- Published
- 2013
18. Association of Type III secretion genes with virulence of Aeromonas salmonicida subsp. salmonicida
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Burr, SE, primary, Wahli, T, additional, Segner, H, additional, Pugovkin, D, additional, and Frey, J, additional
- Published
- 2003
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19. Azithromycin mass drug administration for reducing child mortality in Malawi
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Hart, JD, Bailey, RL, and Burr, SE
- Abstract
BACKGROUND: Child mortality has decreased considerably in recent years but more than one in ten children still die before their fifth birthday in several African countries. The MORDOR study investigated whether azithromycin mass drug administration (MDA) reduces child mortality in three countries in Africa. The study described within this thesis was conducted at the MORDOR-Malawi site and aims to provide additional detail on potential mechanisms of effect of the intervention; macrolide resistance; and cost-effectiveness. METHODS: The study involved cluster randomisation of communities in Mangochi District, Malawi, to biannual azithromycin or placebo MDA. Household visits were conducted to update the census and perform verbal autopsies (VAs) to assess causes of death. Indicators related to healthcare access; malaria risk; and water, sanitation and hygiene were measured. Nasopharyngeal samples were collected to assess macrolide resistance. Cost data were collected for one complete round of fieldwork. RESULTS: The study included 334 clusters. The mortality rate ratio in azithromycin-treated compared to placebo-treated communities was 0.91 (95%CI: 0.79–1.05); P=0.20. There was evidence for an effect of the intervention in infants aged 1-5 months: 0.70 (95%CI: 0.50-0.99); P=0.04; but not in older age groups. The VA analyses suggested possible effects on pneumonia, HIV/AIDS and diarrhoea mortality. The intervention was highly cost-effective according to the WHO’s willingness-to-pay thresholds, costing $898 per death averted. At the 12-month and 24-month follow-up rounds, macrolide resistance in Streptococcus pneumoniae was higher in the azithromycin group compared to placebo. CONCLUSION: The mortality findings at the MORDOR-Malawi site could be explained by the broad spectrum of activity of azithromycin against gut and respiratory organisms, including non-vaccine pneumococcal serotypes and other aetiological causes of pneumonia, sepsis and meningitis. Azithromycin MDA is a feasible short-term intervention to reduce child mortality, whilst longer term sustainable health system improvements are pursued. Vigilance of antibiotic resistance is required. more...
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- 2022
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20. Characterization of the fecal microbiota of rural Malawian children, associations with biomarkers of environmental enteric dysfunction and the impact of a mass drug administration program
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Chaima, D, Holland, MJ, and Burr, SE
- Abstract
Environmental Enteric Dysfunction (EED) is a subclinical condition of the gut characterized by changes in gut morphology and function with underlying chronic inflammatory responses. EED affects more than two-thirds of young children living in low-income settings. EED has been linked with growth faltering in young children living in low-income settings, however, the mechanisms by which EED impacts growth are not well defined. A proposed pathway suggests that ingestion of enteric pathogens and toxins, through contaminated food and water, changes gut microbiota composition and function. This results in intestinal inflammation and changes in the intestinal epithelium structure. There is limited data examining the association between the gut microbiota and EED. The present work was nested in a cluster-randomized trial of mass drug administration of azithromycin and was carried out to characterize composition and diversity of the gut microbiota in rural Malawian children with and without signs of EED. The work also tested for associations between the gut microbiota and stunting. Proteins were extracted from fecal samples and used for the quantification, by ELISA, of neopterin, myeloperoxidase and alpha-1 antitrypsin, which are biomarkers of intestinal inflammation and permeability that have been proposed as potential proxies of EED. Concentrations of the three biomarkers were combined to form a proxy EED score using principal component analysis. Total genomic DNA was also extracted from the fecal samples for V4-16SrRNA sequencing and for species-specific PCR to determine intestinal carriage of bacteria that have previously been shown to be associated with growth in a mouse model. All three biomarkers decreased with age. Faecalibacterium prausnitzii and Dorea formicigenerans were prevalent in over 70% of children while Bifidobacterium longum was the least prevalent of the bacteria assayed. No associations were found between fecal biomarkers of EED or intestinal bacteria carriage and stunting, however, intestinal carriage of D. formicigenerans was associated with normal biomarker concentration. Increased fecal microbiota diversity was associated with a reduction in neopterin concentration. Increased abundance of Succinivibrio was associated with reduced EED scores. Mass treatment with azithromycin appeared to have no long-term impact on alpha diversity of fecal samples but was weakly associated with increased abundance of Prevotella at 24-months follow-up. A negative correlation between age and the three biomarkers of EED was found and confirms trends shown in other children living in similar low-income settings. The association between D. formicigenerans and normal biomarker concentration suggests a potential beneficial role of the bacterium in gut health. An increase in microbiota diversity is potentially associated with reduced intestinal inflammation, but larger studies are needed to confirm this. The association between Succinivibrio and biomarkers of EED shown here is consistent with recent data from another study conducted in Malawi. Succinivibrio plays a role in fiber-degradation and metabolites of fiber-degradation have been shown to inhibit intestinal colonization by pathogenic bacteria, therefore, further studies are needed to investigate the significance of this bacterium in EED. Mass treatment with azithromycin may have long-lasting effects on the abundance of defined bacterial taxa but not overall microbiota diversity. more...
21. Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.
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Monko TR, Tripp EH, Burr SE, Gunderson KN, Lanier LM, Georgieff MK, and Bastian TW
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- Humans, Rats, Child, Animals, Mice, Parvalbumins metabolism, Parvalbumins pharmacology, mu-Crystallins, Neurons metabolism, Thyroid Hormones, Hippocampus metabolism, Iron metabolism, Adenosine Triphosphate metabolism, Gene Expression, Iodide Peroxidase metabolism, Iodide Peroxidase pharmacology, Neurogranin metabolism, Iron Deficiencies
- Abstract
Background: Developing neurons have high thyroid hormone and iron requirements to support their metabolically demanding growth. Early-life iron and thyroid-hormone deficiencies are prevalent and often coexist, and each independently increases risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid-hormone concentrations and impairs thyroid hormone-responsive gene expression in the neonatal rat brain, but it is unclear whether the effect is cell-intrinsic., Objectives: This study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons., Methods: Iron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 d in vitro (DIV). At 11DIV and 18DIV, thyroid hormone-regulated gene messenger ribonucleic acid (mRNA)concentrations indexing thyroid hormone homeostasis (Hairless, mu-crystallin, Type II deiodinase, solute carrier family member 1c1, and solute carrier family member 16a2) and neurodevelopment (neurogranin, Parvalbumin, and Krüppel-like factor 9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures, and gene expression and adenosine 5'-triphosphate (ATP) concentrations were quantified at 21DIV., Results: At 11DIV and 18DIV, neuronal iron deficiency decreased neurogranin, Parvalbumin, and mu-crystallin, and by 18DIV, solute carrier family member 16a2, solute carrier family member 1c1, Type II deiodinase, and Hairless were increased, suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal component analysis reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status. Iron repletion from 14-21DIV did not restore ATP concentration, and Principal component analysis suggests that, after iron repletion, cultures maintain a gene expression signature indicative of previous iron deficiency., Conclusions: These novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of the homeostatic response to acutely match neuronal energy production and growth signaling. However, the adaptation to iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency., Competing Interests: Conflict of interest The authors report no conflicts of interest., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2024
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22. Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons.
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Monko TR, Tripp EH, Burr SE, Gunderson KN, Lanier LM, Georgieff MK, and Bastian TW
- Abstract
Background: Developing neurons have high thyroid hormone and iron requirements to support their metabolism and growth. Early-life iron and thyroid hormone deficiencies are prevalent, often coexist, and increase the risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid hormone levels and impairs thyroid hormone-responsive gene expression in the neonatal rat brain., Objective: This study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons., Methods: Iron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 days in vitro (DIV). At 11DIV and 18DIV, mRNA levels for thyroid hormone-regulated genes indexing thyroid hormone homeostasis ( Hr, Crym, Dio2, Slco1c1, Slc16a2 ) and neurodevelopment ( Nrgn, Pvalb, Klf9 ) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures and gene expression and ATP levels were quantified at 21DIV., Results: At 11DIV and 18DIV, neuronal iron deficiency decreased Nrgn, Pvalb , and Crym , and by 18DIV, Slc16a2, Slco1c1, Dio2 , and Hr were increased; collectively suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal Component Analysis (PCA) reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status ( Tfr1 mRNA). Iron repletion from 14-21DIV restored neurodevelopmental genes, but not all thyroid hormone homeostatic genes, and ATP concentrations remained significantly altered. PCA clustering suggests that cultures replete with iron maintain a gene expression signature indicative of previous iron deficiency., Conclusions: These novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of homeostatic response to match neuronal energy production and growth signaling for these important metabolic regulators. However, iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency. more...
- Published
- 2023
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23. Biannual Administrations of Azithromycin and the Gastrointestinal Microbiome of Malawian Children: A Nested Cohort Study Within a Randomized Controlled Trial.
- Author
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Chaima D, Pickering H, Hart JD, Burr SE, Houghton J, Maleta K, Kalua K, Bailey RL, and Holland MJ
- Subjects
- Azithromycin therapeutic use, Bacteria genetics, Child, Child, Preschool, Cohort Studies, Humans, Infant, RNA, Ribosomal, 16S genetics, Gastrointestinal Microbiome genetics
- Abstract
Community-level mass treatment with azithromycin has been associated with a mortality benefit in children. However, antibiotic exposures result in disruption of the gut microbiota and repeated exposures may reduce recovery of the gut flora. We conducted a nested cohort study within the framework of a randomized controlled trial to examine associations between mass drug administration (MDA) with azithromycin and the gut microbiota of rural Malawian children aged between 1 and 59 months. Fecal samples were collected from the children at baseline and 6 months after two or four biannual rounds of azithromycin treatment. DNA was extracted from fecal samples and V4-16S rRNA sequencing used to characterize the gut microbiota. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. There were no associations between azithromycin treatment and changes in alpha diversity, however, four biannual rounds of treatment were associated with increased abundance of Prevotella . The lack of significant changes in gut microbiota after four biannual treatments supports the use of mass azithromycin treatment to reduce mortality in children living in low- and middle-income settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chaima, Pickering, Hart, Burr, Houghton, Maleta, Kalua, Bailey and Holland.) more...
- Published
- 2022
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24. Prevalence of nasopharyngeal Streptococcus pneumoniae carriage and resistance to macrolides in the setting of azithromycin mass drug administration: analysis from a cluster-randomised controlled trial in Malawi, 2015-17.
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Hart JD, Samikwa L, Meleke H, Burr SE, Cornick J, Kalua K, and Bailey RL
- Subjects
- Anti-Bacterial Agents pharmacology, Child, Drug Resistance, Bacterial, Humans, Macrolides therapeutic use, Malawi epidemiology, Mass Drug Administration, Prevalence, Streptococcus pneumoniae, Azithromycin therapeutic use, Trachoma drug therapy
- Abstract
Background: Azithromycin mass drug administration (MDA) could reduce child mortality. However, macrolide resistance, which has generally been reported to develop after whole-community MDA for trachoma control, is a concern, and it has less commonly been studied in the context of treating children to reduce mortality. Here, we report on macrolide resistance after biannual azithromycin MDA at the Malawi site of the MORDOR study., Methods: In the MORDOR cluster-randomised trial in Malawi, 30 communities in Mangochi District were randomly selected. Communities were randomly assigned to receive azithromycin or placebo by simple randomisation without stratification. Children aged 1-59 months were administered azithromycin 20 mg/kg or placebo as an oral suspension biannually for a total of four treatments in 2015-17. 1200 children (40 children per community) were randomly selected for nasopharyngeal swabs at baseline, 12 months (6 months after the second treatment visit), and 24 months (6 months after the fourth treatment visit). Samples were processed to culture Streptococcus pneumoniae . The primary outcome was the proportion of S pneumoniae isolates exhibiting macrolide resistance at 12 months and 24 months, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02048007., Findings: At baseline, 3467 (76%) of 4541 eligible children in the azithromycin group and 3107 (72%) of 4308 eligible children in the placebo group were treated. 564 nasopharyngeal swabs were taken from the azithromycin group and 563 from the placebo group, with similar numbers of swabs taken at 12 months and 24 months. In both groups at baseline, carriage of S pneumoniae was greater than 85% and the proportion of strains resistant to macrolides was 28%. At the 12-month follow-up, macrolide resistance was higher in the azithromycin group (36·9%, 95% CI 32·5-41·2) than in the placebo group (21·6%, 17·7-25·4; OR 2·26, 95% CI 1·46-3·49; p=0·0002). At 24 months, macrolide resistance remained higher in the azithromycin group (43·9%, 39·2-48·5) compared with placebo (32·8%, 28·5-37·1; OR 1·66, 1·15-2·40; p=0·0069)., Interpretation: These findings support previous evidence from trachoma MDA programmes and suggest that monitoring of macrolide resistance should remain a key component of azithromycin interventions for reducing child mortality., Funding: Bill & Melinda Gates Foundation., Competing Interests: We declare no competing interests., (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.) more...
- Published
- 2022
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25. Fecal biomarkers of environmental enteric dysfunction and the gut microbiota of rural Malawian children: An observational study.
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Chaima D, Pickering H, Hart JD, Burr SE, Maleta KM, Kalua K, Bailey RL, and Holland MJ
- Abstract
Environmental enteric dysfunction (EED) is a subclinical condition of the gut characterized by changes in morphology and function with underlying chronic inflammatory responses. This study characterized composition and diversity of the gut microbiota in rural Malawian children with and without signs of EED. Fecal samples were collected from children aged 1-59 months. Neopterin, myeloperoxidase and alpha-1 antitrypsin concentrations were quantified by ELISA and combined to form a composite EED score using principal component analysis. DNA was extracted from fecal samples and V4-16S rRNA gene sequencing was used to characterize the gut microbiota. The concentrations of all three biomarkers decreased with increasing age, which is consistent with other studies of children living in similar low-income settings. Firmicutes , Bacteroidetes , Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. Increased alpha diversity was associated with a reduction in neopterin concentration. Microbiota composition was different between fecal samples with low and high composite EED scores; increased abundance of Succinivibrio was associated with reduced composite EED scores., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).) more...
- Published
- 2021
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26. Mass drug administration with azithromycin for trachoma elimination and the population structure of Streptococcus pneumoniae in the nasopharynx.
- Author
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Gladstone RA, Bojang E, Hart J, Harding-Esch EM, Mabey D, Sillah A, Bailey RL, Burr SE, Roca A, Bentley SD, and Holland MJ
- Subjects
- Gambia epidemiology, Humans, Trachoma epidemiology, Trachoma microbiology, Azithromycin therapeutic use, Mass Drug Administration, Nasopharynx microbiology, Streptococcus pneumoniae drug effects, Trachoma prevention & control
- Abstract
Objective: Mass drug administration (MDA) with azithromycin for trachoma elimination reduces nasopharyngeal carriage of Streptococcus pneumoniae in the short term. We evaluated S. pneumoniae carried in the nasopharynx before and after a round of azithromycin MDA to determine whether MDA was associated with changes in pneumococcal population structure and resistance., Methods: We analysed 514 pneumococcal whole genomes randomly selected from nasopharyngeal samples collected in two Gambian villages that received three annual rounds of MDA for trachoma elimination. The 514 samples represented 293 participants, of which 75% were children aged 0-9 years, isolated during three cross-sectional surveys (CSSs) conducted before the third round of MDA (CSS-1) and at 1 (CSS-2) and 6 (CSS-3) months after MDA. Bayesian Analysis of Population Structure (BAPS) was used to cluster related isolates by capturing variation in the core genome. Serotype and multilocus sequence type were inferred from the genotype. Antimicrobial resistance determinants were identified from assemblies, including known macrolide resistance genes., Results: Twenty-seven BAPS clusters were assigned. These consisted of 81 sequence types (STs). Two BAPS clusters not observed in CSS-1 (n = 109) or CSS-2 (n = 69), increased in frequency in CSS-3 (n = 126); BAPS20 (8.73%, p 0.016) and BAPS22 (7.14%, p 0.032) but were not associated with antimicrobial resistance. Macrolide resistance within BAPS17 increased after treatment (CSS-1 n = 0/6, CSS-2/3 n = 5/5, p 0.002) and was carried on a mobile transposable element that also conferred resistance to tetracycline., Discussion: Limited changes in pneumococcal population structure were observed after the third round of MDA, suggesting treatment had little effect on the circulating lineages. An increase in macrolide resistance within one BAPS highlights the need for antimicrobial resistance surveillance in treated villages., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.) more...
- Published
- 2021
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27. Effects of Biannual Azithromycin Mass Drug Administration on Malaria in Malawian Children: A Cluster-Randomized Trial.
- Author
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Hart JD, Samikwa L, Sikina F, Kalua K, Keenan JD, Lietman TM, Burr SE, and Bailey RL
- Subjects
- Child Mortality, Child, Preschool, Double-Blind Method, Female, Humans, Infant, Malaria epidemiology, Malaria parasitology, Male, Mass Drug Administration, Parasitemia epidemiology, Parasitemia parasitology, Prevalence, Anemia epidemiology, Anti-Bacterial Agents administration & dosage, Azithromycin administration & dosage, Malaria drug therapy, Parasitemia drug therapy
- Abstract
Reductions in malaria morbidity have been reported following azithromycin mass drug administration (MDA) for trachoma. The recent Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) trial reported a reduction in child mortality following biannual azithromycin MDA. Here, we investigate the effects of azithromycin MDA on malaria at the MORDOR-Malawi study site. A cluster-randomized double-blind placebo-controlled trial, with 15 clusters per arm, was conducted. House-to-house census was updated biannually, and azithromycin or placebo syrup was distributed to children aged 1-59 months for a total of four biannual distributions. At baseline, 12-month, and 24-month follow-up visits, a random sample of 1,200 children was assessed for malaria with thick and thin blood smears and hemoglobin measurement. In the community-level analysis, there was no difference in the prevalence of parasitemia (1.0% lower in azithromycin-treated communities; 95% CI: -8.2 to 6.1), gametocytemia (0.7% lower in azithromycin-treated communities; 95% CI: -2.8 to 1.5), or anemia (1.7% lower in azithromycin-treated communities; 95% CI: -8.1 to 4.6) between placebo and azithromycin communities. Further interrogation of the data at the individual level, both per-protocol (including only those who received treatment 6 months previously) and by intention-to-treat, did not identify differences in parasitemia between treatment arms. In contrast to several previous reports, this study did not show an effect of azithromycin MDA on malaria parasitemia at the community or individual levels. more...
- Published
- 2020
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28. Pgp3 seroprevalence and associations with active trachoma and ocular Chlamydia trachomatis infection in Malawi: cross-sectional surveys in six evaluation units.
- Author
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Burr SE, Hart J, Samikwa L, Chaima D, Cooley G, Martin D, Masika M, Solomon AW, Bailey RL, and Kalua K
- Subjects
- Adolescent, Antigens, Bacterial genetics, Bacterial Proteins genetics, Child, Child, Preschool, Chlamydia trachomatis genetics, Cross-Sectional Studies, DNA, Bacterial, Female, Humans, Infant, Inflammation drug therapy, Malawi epidemiology, Male, Surveys and Questionnaires, Trachoma epidemiology, Anti-Bacterial Agents therapeutic use, Antigens, Bacterial immunology, Bacterial Proteins immunology, Chlamydia trachomatis immunology, Mass Drug Administration methods, Seroepidemiologic Studies, Trachoma drug therapy
- Abstract
Background: Following one to five years of antibiotic mass drug administration (MDA) for the elimination of trachoma as a public health problem, programmes must conduct impact surveys to inform decisions on whether MDA is still needed. These decisions are currently based on the prevalence of trachomatous inflammation-follicular (TF), which, after MDA, correlates poorly with prevalence of ocular Chlamydia trachomatis infection., Methodology/principal Findings: Impact surveys in six evaluation units (EUs) of Malawi were used as a platform to explore associations between the prevalence of TF, ocular C. trachomatis infection and anti-Pgp3 antibodies one year after the third annual round of MDA. Participants were examined for trachoma using the World Health Organization simplified grading system. Ocular swabs and dried blood spots (DBS) were collected from children aged 1-9 years. Swabs were tested for C. trachomatis DNA using GeneXpert. DBS were assayed for anti-Pgp3 antibodies using ELISA. EU-level prevalence of TF in children aged 1-9 years ranged from 4.7% (95% CI 3.4-6.3) to 7.2% (95% CI 5.8-8.9). Prevalence of C. trachomatis infection in children ranged from 0.1% (95% CI 0.0-0.6) to 0.7% (95% CI 0.3-1.3) while Pgp3 seroprevalence ranged from 6.9% (95% CI 5.4-8.6) to 12.0% (95% CI 10.1-14.0) and increased with age., Conclusions/significance: Based on current global policy, the prevalence of TF indicates that a further year of antibiotic MDA is warranted in four of six EUs yet the very low levels of infection cast doubt on the universal applicability of TF-based cut-offs for antibiotic MDA. Pgp3 seroprevalence was similar to that reported following MDA in other settings that have reached the elimination target however the predictive value of any particular level of seropositivity with respect to risk of subsequent infection recrudescence is, as yet, unknown., Competing Interests: The authors have declared that no competing interests exist. more...
- Published
- 2019
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29. Conjunctival Microbiome-Host Responses Are Associated With Impaired Epithelial Cell Health in Both Early and Late Stages of Trachoma.
- Author
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Pickering H, Palmer CD, Houghton J, Makalo P, Joof H, Derrick T, Goncalves A, Mabey DCW, Bailey RL, Burton MJ, Roberts CH, Burr SE, and Holland MJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents therapeutic use, Bacteria classification, Bacteria drug effects, Bacteria genetics, Case-Control Studies, Child, Child, Preschool, Chlamydia trachomatis, Cicatrix genetics, Conjunctival Diseases immunology, Conjunctival Diseases microbiology, Female, Gambia, Gene Expression, Host Microbial Interactions drug effects, Host Microbial Interactions genetics, Host Microbial Interactions immunology, Humans, Immunity, Innate, Infant, Interferon-gamma, Male, Middle Aged, Trachoma drug therapy, Trachoma genetics, Young Adult, Conjunctiva microbiology, Epithelial Cells microbiology, Microbiota drug effects, Microbiota genetics, Microbiota immunology, Trachoma immunology, Trachoma microbiology
- Abstract
Background: Trachoma, a neglected tropical disease, is the leading infectious cause of blindness and visual impairment worldwide. Host responses to ocular chlamydial infection resulting in chronic inflammation and expansion of non-chlamydial bacteria are hypothesized risk factors for development of active trachoma and conjunctival scarring. Methods: Ocular swabs from trachoma endemic populations in The Gambia were selected from archived samples for 16S sequencing and host conjunctival gene expression. We recruited children with active trachoma and adults with conjunctival scarring, alongside corresponding matched controls. Findings: In children, active trachoma was not associated with significant changes in the ocular microbiome. Haemophilus enrichment was associated with antimicrobial responses but not linked to active trachoma. Adults with scarring trachoma had a reduced ocular bacterial diversity compared to controls, with increased relative abundance of Corynebacterium . Increased abundance of Corynebacterium in scarring disease was associated with innate immune responses to the microbiota, dominated by altered mucin expression and increased matrix adhesion. Interpretation: In the absence of current Chlamydia trachomatis infection, changes in the ocular microbiome associate with differential expression of antimicrobial and inflammatory genes that impair epithelial cell health. In scarring trachoma, expansion of non-pathogenic bacteria such as Corynebacterium and innate responses are coincident, warranting further investigation of this relationship. Comparisons between active and scarring trachoma supported the relative absence of type-2 interferon responses in scarring, whilst highlighting a common suppression of re-epithelialization with altered epithelial and bacterial adhesion, likely contributing to development of scarring pathology. more...
- Published
- 2019
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30. Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity.
- Author
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Last AR, Pickering H, Roberts CH, Coll F, Phelan J, Burr SE, Cassama E, Nabicassa M, Seth-Smith HMB, Hadfield J, Cutcliffe LT, Clarke IN, Mabey DCW, Bailey RL, Clark TG, Thomson NR, and Holland MJ
- Subjects
- Conjunctiva pathology, Endemic Diseases, Genetic Markers, Guinea-Bissau, Humans, Likelihood Functions, Phenotype, Phylogeny, Polymorphism, Single Nucleotide genetics, Trachoma pathology, Whole Genome Sequencing, Chlamydia trachomatis genetics, Genome, Bacterial, Severity of Illness Index, Trachoma microbiology
- Abstract
Background: Chlamydia trachomatis (Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide. Ct strain-specific differences in clinical trachoma suggest that genetic polymorphisms in Ct may contribute to the observed variability in severity of clinical disease., Methods: Using Ct whole genome sequences obtained directly from conjunctival swabs, we studied Ct genomic diversity and associations between Ct genetic polymorphisms with ocular localization and disease severity in a treatment-naïve trachoma-endemic population in Guinea-Bissau, West Africa., Results: All Ct sequences fall within the T2 ocular clade phylogenetically. This is consistent with the presence of the characteristic deletion in trpA resulting in a truncated non-functional protein and the ocular tyrosine repeat regions present in tarP associated with ocular tissue localization. We have identified 21 Ct non-synonymous single nucleotide polymorphisms (SNPs) associated with ocular localization, including SNPs within pmpD (odds ratio, OR = 4.07, p* = 0.001) and tarP (OR = 0.34, p* = 0.009). Eight synonymous SNPs associated with disease severity were found in yjfH (rlmB) (OR = 0.13, p* = 0.037), CTA0273 (OR = 0.12, p* = 0.027), trmD (OR = 0.12, p* = 0.032), CTA0744 (OR = 0.12, p* = 0.041), glgA (OR = 0.10, p* = 0.026), alaS (OR = 0.10, p* = 0.032), pmpE (OR = 0.08, p* = 0.001) and the intergenic region CTA0744-CTA0745 (OR = 0.13, p* = 0.043)., Conclusions: This study demonstrates the extent of genomic diversity within a naturally circulating population of ocular Ct and is the first to describe novel genomic associations with disease severity. These findings direct investigation of host-pathogen interactions that may be important in ocular Ct pathogenesis and disease transmission. more...
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- 2018
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31. Evaluation of a Chlamydia trachomatis-specific, commercial, real-time PCR for use with ocular swabs.
- Author
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Pickering H, Holland MJ, Last AR, Burton MJ, and Burr SE
- Subjects
- Chlamydia trachomatis genetics, DNA, Bacterial genetics, Guinea-Bissau, Humans, Sensitivity and Specificity, Specimen Handling, Tanzania, Chlamydia trachomatis isolation & purification, Conjunctiva microbiology, Real-Time Polymerase Chain Reaction standards, Trachoma diagnosis
- Abstract
Background: Trachoma, the leading infectious cause of blindness worldwide, is caused by conjunctival Chlamydia trachomatis infection. Trachoma is diagnosed clinically by observation of conjunctival inflammation and/or scarring; however, there is evidence that monitoring C. trachomatis infection may be required for elimination programmes. There are many commercial and 'in-house' nucleic acid amplification tests for the detection of C. trachomatis DNA, but the majority have not been validated for use with ocular swabs. This study evaluated a commercial assay, the Fast-Track Vaginal swab kit, using conjunctival samples from trachoma-endemic areas. An objective, biostatistical-based method for binary classification of continuous PCR data was developed, to limit potential user-bias in diagnostic settings., Methods: The Fast-Track Vaginal swab assay was run on 210 ocular swab samples from Guinea-Bissau and Tanzania. Fit of individual amplification curves to exponential or sigmoid models, derivative and second derivative of the curves and final fluorescence value were examined for utility in thresholding for determining positivity. The results from the Fast-Track Vaginal swab assay were evaluated against a commercial test (Amplicor CT/NG) and a non-commercial test (in-house droplet digital PCR), both of whose performance has previously been evaluated., Results: Significant evidence of exponential amplification (R
2 > 0.99) and final fluorescence > 0.15 were combined for thresholding. This objective approach identified a population of positive samples, however there were a subset of samples that amplified towards the end of the cycling protocol (at or later than 35 cycles), which were less clearly defined. The Fast-Track Vaginal swab assay showed good sensitivity against the commercial (95.71) and non-commercial (97.18) tests. Specificity was lower against both (90.00 and 96.55, respectively)., Conclusions: This study defined a simple, automated protocol for binary classification of continuous, real-time qPCR data, for use in an end-point diagnostic test. This method identified a population of positive samples, however, as with manual thresholding, a subset of samples that amplified towards the end of the cycling program were less easily classified. When used with ocular swabs, the Fast-Track Vaginal swab assay had good sensitivity for C. trachomatis detection, but lower specificity than the commercial and non-commercial assays it was evaluated against, possibly leading to false positives. more...- Published
- 2018
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32. The impact of a single round of community mass treatment with azithromycin on disease severity and ocular Chlamydia trachomatis load in treatment-naïve trachoma-endemic island communities in West Africa.
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Last AR, Burr SE, Harding-Esch E, Cassama E, Nabicassa M, Roberts CH, Mabey DCW, Holland MJ, and Bailey RL
- Subjects
- Conjunctiva microbiology, Cross-Sectional Studies, Guinea-Bissau, Polymerase Chain Reaction, Severity of Illness Index, Trachoma microbiology, Treatment Outcome, Anti-Bacterial Agents administration & dosage, Azithromycin administration & dosage, Bacterial Load, Chlamydia trachomatis drug effects, Mass Drug Administration, Trachoma drug therapy, Trachoma pathology
- Abstract
Background: Trachoma, a neglected tropical disease, is caused by ocular infection with Chlamydia trachomatis (Ct). The World Health Organization (WHO) recommends three annual rounds of community mass drug treatment with azithromycin (MDA) if the prevalence of follicular trachoma in 1-9 year olds (TF
1-9 ) exceeds 10% at district level to achieve an elimination target of district-level TF1-9 below 5% after. To evaluate this strategy in treatment-naïve trachoma-endemic island communities in Guinea Bissau, we conducted a cross-sectional population-based trachoma survey on four islands. The upper tarsal conjunctivae of each participant were clinically assessed for trachoma and conjunctival swabs were obtained (n = 1507). We used a droplet digital PCR assay to detect Ct infection and estimate bacterial load. We visited the same households during a second cross-sectional survey and repeated the ocular examination and obtained conjunctival swabs from these households one year after MDA (n = 1029)., Results: Pre-MDA TF1-9 was 22.0% (136/618). Overall Ct infection prevalence (CtI) was 18.6% (25.4% in 1-9 year olds). Post-MDA (estimated coverage 70%), TF1-9 and CtI were significantly reduced (7.4% (29/394, P < 0.001) and 3.3% (34/1029, P < 0.001) (6.6% in 1-9 year olds, P < 0.001), respectively. Median ocular Ct load was reduced from 2038 to 384 copies/swab (P < 0.001). Following MDA cases of Ct infection were highly clustered (Moran's I 0.27, P < 0.001), with fewer clusters of Ct infection overall, fewer clusters of cases with high load infections and less severe disease., Conclusions: Despite a significant reduction in the number of clusters of Ct infection, mean Ct load, disease severity and presence of clusters of cases of high load Ct infection suggesting the beginning of trachoma control in isolated island communities, following a single round of MDA we demonstrate that transmission is still ongoing. These detailed data are useful in understanding the epidemiology of ocular Ct infection in the context of MDA and the tools employed may have utility in determining trachoma elimination and surveillance activities in similar settings. more...- Published
- 2017
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33. Does azithromycin given to women in labour decrease ocular bacterial infection in neonates? A double-blind, randomized trial.
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Burr SE, Camara B, Oluwalana C, Bojang E, Bottomley C, Bojang A, Bailey RL, D'Alessandro U, and Roca A
- Subjects
- Administration, Oral, Adult, Bacteria genetics, Bacteria isolation & purification, Conjunctivitis, Bacterial epidemiology, Conjunctivitis, Bacterial microbiology, DNA, Bacterial isolation & purification, DNA, Bacterial metabolism, Double-Blind Method, Female, Humans, Incidence, Infant, Newborn, Male, Odds Ratio, Parturition, Placebo Effect, Risk Factors, Staphylococcus aureus genetics, Staphylococcus aureus isolation & purification, Treatment Outcome, Young Adult, Azithromycin therapeutic use, Conjunctivitis, Bacterial prevention & control, Infectious Disease Transmission, Vertical prevention & control
- Abstract
Background: Vertical transmission can result in neonatal infection and disease. Reducing the transmission of bacterial pathogens from mother to infant may be an effective means of preventing neonatal infection, including bacterial conjunctivitis., Methods: In a double-blind, randomized trial, we assessed the effect of administering a single dose of oral azithromycin to women in labour on bacterial colonization of the neonate. A reduction in purulent neonatal conjunctivitis was a secondary objective of the trial. Ocular samples were collected from the lower fornix of infants presenting with clinical signs of purulent conjunctivitis during the first eight weeks of life. Incidence of purulent conjunctivitis was compared between trial arms. Bacterial infection was assessed using PCR and incidence of purulent conjunctivitis due to bacteria was also compared between arms., Results: Forty of 843 infants (4.7%) presented clinical signs of purulent conjunctivitis. No significant difference in incidence of purulent conjunctivitis was seen between azithromycin and placebo arms [4.3% (18/419) versus 5.2% (22/424), OR = 0.82, 95% CI (0.44,1.54), p = 0.628]. S. aureus was the most commonly identified pathogen, detected in 38% of cases. Incidence of purulent-conjunctivitis due to bacterial infection was lower in the azithromycin arm [1.2% (5/419) versus 3.8% (16/424), OR = 0.31, 95% CI (0.12-0.82), p = 0.025)]. The incidence of gram-positive bacteria was also lower in the azithromycin arm [1.0% (4/419) versus 3.3% (14/424), OR = 0.28, 95%CI (0.10-0.82), p = 0.029]., Conclusions: Oral azithromycin given to women during labour may have the potential to reduce the incidence of bacterial neonatal conjunctivitis., Trial Registration: ClinicalTrials.gov, identifier NCT01800942 , registration date 26 Feb 2013. more...
- Published
- 2017
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34. An outbreak of acute haemorrhagic conjunctivitis associated with coxsackievirus A24 variant in The Gambia, West Africa.
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Burr SE, Sillah A, Joof H, Bailey RL, and Holland MJ
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- Adult, Conjunctivitis, Acute Hemorrhagic virology, Enterovirus C, Human isolation & purification, Female, Gambia epidemiology, Humans, Male, Conjunctivitis, Acute Hemorrhagic epidemiology, Disease Outbreaks, Enterovirus C, Human pathogenicity
- Abstract
Objective: An outbreak of acute haemorrhagic conjunctivitis occurred in The Gambia, West Africa in 2011. Affected individuals presented with conjunctival haemorrhages, swelling and ocular discharge. In an effort to identify a causative agent of the disease, ocular swabs were taken from patients during the acute and convalescent phases. Total RNA was extracted from all samples and reverse-transcriptase PCR performed using primers specific for all enteroviruses. Resulting amplicons were sequenced and data compared to known sequences using the BLAST algorithm., Results: Forty-eight swabs were included in the analysis. Of these, 21 acute and 9 convalescent swabs (65% of the total) gave positive PCR results. Sequence analysis of the resulting amplicons indicated 99% sequence identity with coxsackievirus A24 variant identified during independent outbreaks of acute haemorrhagic conjunctivitis around the world and suggest the Gambian outbreak was due to this virus. more...
- Published
- 2017
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35. Serology reflects a decline in the prevalence of trachoma in two regions of The Gambia.
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Migchelsen SJ, Sepúlveda N, Martin DL, Cooley G, Gwyn S, Pickering H, Joof H, Makalo P, Bailey R, Burr SE, Mabey DCW, Solomon AW, and Roberts CH
- Subjects
- Adolescent, Adult, Anti-Bacterial Agents therapeutic use, Antibodies, Bacterial immunology, Child, Child, Preschool, Chlamydia trachomatis drug effects, Chlamydia trachomatis physiology, Cross-Sectional Studies, Female, Gambia epidemiology, Health Surveys methods, Health Surveys statistics & numerical data, Humans, Infant, Male, Prevalence, Serologic Tests, Trachoma blood, Trachoma microbiology, Young Adult, Antibodies, Bacterial blood, Antigens, Bacterial immunology, Chlamydia trachomatis immunology, Trachoma epidemiology
- Abstract
Trachoma is caused by Chlamydia trachomatis (Ct). It is targeted for global elimination as a public health problem. In 2014, a population-based cross-sectional study was performed in two previously trachoma-endemic areas of The Gambia. Participants of all ages from Lower River Region (LRR) (N = 1028) and Upper River Region (URR) (N = 840) underwent examination for trachoma and had blood collected for detection of antibodies against the Ct antigen Pgp3, by ELISA. Overall, 30 (1.6%) individuals had active trachoma; the prevalence in children aged 1-9 years was 3.4% (25/742) with no statistically significant difference in prevalence between the regions. There was a significant difference in overall seroprevalence by region: 26.2% in LRR and 17.1% in URR (p < 0.0001). In children 1-9 years old, seroprevalence was 4.4% in LRR and 3.9% in URR. Reversible catalytic models using information on age-specific seroprevalence demonstrated a decrease in the transmission of Ct infection in both regions, possibly reflecting the impact of improved access to water, health and sanitation as well as mass drug administration campaigns. Serological testing for antibodies to Ct antigens is potentially useful for trachoma programmes, but consideration should be given to the co-endemicity of sexually transmitted Ct infections. more...
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- 2017
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36. Genome-wide profiling of humoral immunity and pathogen genes under selection identifies immune evasion tactics of Chlamydia trachomatis during ocular infection.
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Pickering H, Teng A, Faal N, Joof H, Makalo P, Cassama E, Nabicassa M, Last AR, Burr SE, Rowland-Jones SL, Thomson NR, Roberts CH, Mabey DCW, Bailey RL, Hayward RD, de la Maza LM, and Holland MJ
- Subjects
- Antigens, Bacterial immunology, Child, Child, Preschool, Female, Gambia, Guinea-Bissau, Humans, Male, Chlamydia trachomatis immunology, Host-Pathogen Interactions, Immune Evasion, Immunity, Humoral, Selection, Genetic, Trachoma immunology
- Abstract
The frequency and duration of Chlamydia trachomatis (Ct) ocular infections decrease with age, suggesting development of partial immunity. However, there is a lack of clear correlates of immunity to Ct infection in humans. We screened sera from a cohort of Gambian children followed for six-months against a Ct-proteome microarray. At genome sequence level, we detected signatures of selection from a population of ocular Ct isolates from Guinea-Bissau. Together these approaches allowed us to highlight the focus of humoral responses and hypothesise new modes of pathogen immune evasion. Children who were susceptible to frequent and/or prolonged Ct infection had a less focussed antibody response, including preferential recognition of forty-two antigens. There was evidence of positive and purifying selection across the genome, but little balancing selection. In contrast, most antigens that were associated with susceptibility were under neutral selection. These data suggest an evasion strategy in which Ct presents a large panel of irrelevant antigens to the immune system to block or misdirect protective responses. Development of a focused immune response, possibly induced through vaccination, may be an effective strategy to promote protection to Ct infection. more...
- Published
- 2017
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37. Population-based prevalence survey of follicular trachoma and trachomatous trichiasis in the Casamance region of Senegal.
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Harding-Esch EM, Kadimpeul J, Sarr B, Sane A, Badji S, Laye M, Sillah A, Burr SE, MacLeod D, Last AR, Holland MJ, Mabey DC, and Bailey RL
- Subjects
- Adolescent, Anti-Bacterial Agents therapeutic use, Child, Child, Preschool, Cross-Sectional Studies, Drug Administration Schedule, Female, Health Promotion, Humans, Infant, Infant, Newborn, Male, Prevalence, Public Health, Risk Factors, Senegal epidemiology, Trachoma drug therapy, Trichiasis therapy, Trachoma epidemiology, Trichiasis epidemiology
- Abstract
Background: Trachoma, caused by ocular infection with Chlamydia trachomatis, is the leading infectious cause of blindness worldwide. We conducted the first population-based trachoma prevalence survey in the Casamance region of Senegal to enable the Senegalese National Eye Care Programme (NECP) to plan its trachoma control activities. The World Health Organization (WHO) guidelines state that any individual with trachomatous trichiasis (TT) should be offered surgery, but that surgery should be prioritised where the prevalence is >0.1%, and that districts and communities with a trachomatous inflammation, follicular (TF) prevalence of ≥10% in 1-9 year-olds should receive mass antibiotic treatment annually for a minimum of three years, along with hygiene promotion and environmental improvement, before re-assessing the prevalence to determine whether treatment can be discontinued (when TF prevalence in 1-9 year-olds falls <5%)., Methods: Local healthcare workers conducted a population-based household survey in four districts of the Bignona Department of Casamance region to estimate the prevalence of TF in 1-9 year-olds, and TT in ≥15 year-olds. Children's facial cleanliness (ocular and/or nasal discharge, dirt on the face, flies on the face) was measured at time of examination. Risk factor questionnaires were completed at the household level., Results: Sixty communities participated with a total censused population of 5580 individuals. The cluster-, age- and sex-adjusted estimated prevalence of TF in 1-9 year-olds was 2.5% (95% Confidence Interval (CI) 1.8-3.6) (38/1425) at the regional level and <5% in all districts, although the upper 95%CI exceeded 5% in all but one district. The prevalence of TT in those aged ≥15 years was estimated to be 1.4% (95%CI 1.0-1.9) (40/2744) at the regional level and >1% in all districts., Conclusion: With a prevalence <5%, TF does not appear to be a significant public health problem in this region. However, TF monitoring and surveillance at sub-district level will be required to ensure that elimination targets are sustained and that TF does not re-emerge as a public health problem. TT surgery remains the priority for trachoma elimination efforts in the region, with an estimated 1819 TT surgeries to conduct. more...
- Published
- 2017
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38. Short-term increase in prevalence of nasopharyngeal carriage of macrolide-resistant Staphylococcus aureus following mass drug administration with azithromycin for trachoma control.
- Author
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Bojang E, Jafali J, Perreten V, Hart J, Harding-Esch EM, Sillah A, Mabey DC, Holland MJ, Bailey RL, Roca A, and Burr SE
- Subjects
- Administration, Oral, Adolescent, Anti-Bacterial Agents therapeutic use, Carrier State epidemiology, Carrier State microbiology, Child, Cross-Sectional Studies, Drug Resistance, Bacterial, Female, Gambia epidemiology, Humans, Immunization Programs, Male, Microbial Sensitivity Tests, Nasopharyngitis drug therapy, Nasopharyngitis microbiology, Risk Factors, Specimen Handling methods, Staphylococcal Infections complications, Staphylococcal Infections drug therapy, Staphylococcal Infections epidemiology, Streptococcus pneumoniae drug effects, Trachoma complications, Azithromycin administration & dosage, Azithromycin therapeutic use, Macrolides therapeutic use, Methicillin-Resistant Staphylococcus aureus drug effects, Methicillin-Resistant Staphylococcus aureus pathogenicity, Nasopharynx microbiology, Prevalence, Trachoma drug therapy
- Abstract
Background: Mass drug administration (MDA) with azithromycin is a corner-stone of trachoma control however it may drive the emergence of antimicrobial resistance. In a cluster-randomized trial (Clinical trial gov NCT00792922), we compared the reduction in the prevalence of active trachoma in communities that received three annual rounds of MDA to that in communities that received a single treatment round. We used the framework of this trial to carry out an opportunistic study to investigate if the increased rounds of treatment resulted in increased prevalence of nasopharyngeal carriage of macrolide-resistant Staphylococcus aureus. Three cross-sectional surveys were conducted in two villages receiving three annual rounds of MDA (3 × treatment arm). Surveys were conducted immediately before the third round of MDA (CSS-1) and at one (CSS-2) and six (CSS-3) months after MDA. The final survey also included six villages that had received only one round of MDA 30 months previously (1 × treatment arm)., Results: In the 3 × treatment arm, a short-term increase in prevalence of S. aureus carriage was seen following MDA from 24.6% at CSS-1 to 38.6% at CSS-2 (p < 0.001). Prevalence fell to 8.8% at CSS-3 (p < 0.001). A transient increase was also seen in prevalence of carriage of azithromycin resistant (Azm
R ) strains from 8.9% at CSS-1 to 34.1% (p < 0.001) in CSS-2 and down to 7.3% (p = 0.417) in CSS-3. A similar trend was observed for prevalence of carriage of macrolide-inducible-clindamycin resistant (iMLSB ) strains. In CSS-3, prevalence of carriage of resistant strains was higher in the 3 × treatment arm than in the 1 × treatment (AzmR 7.3% vs. 1.6%, p = 0.010; iMLSB 5.8% vs. 0.8%, p < 0.001). Macrolide resistance was attributed to the presence of msr and erm genes., Conclusions: Three annual rounds of MDA with azithromycin were associated with a short-term increase in both the prevalence of nasopharyngeal carriage of S. aureus and prevalence of carriage of AzmR and iMLSB S. aureus., Trial Registration: This study was ancillary to the Partnership for the Rapid Elimination of Trachoma, ClinicalTrials.gov NCT00792922 , registration date November 17, 2008. more...- Published
- 2017
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39. Profiling and validation of individual and patterns of Chlamydia trachomatis-specific antibody responses in trachomatous trichiasis.
- Author
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Pickering H, Burr SE, Derrick T, Makalo P, Joof H, Hayward RD, and Holland MJ
- Subjects
- Adolescent, Adult, Aged, Blindness microbiology, Child, Female, Gambia epidemiology, Humans, Male, Middle Aged, Proteomics methods, Trachoma epidemiology, Trachoma microbiology, Trichiasis epidemiology, Trichiasis microbiology, Young Adult, Antibodies, Bacterial blood, Antibodies, Bacterial immunology, Chlamydia trachomatis immunology, Trachoma immunology, Trichiasis immunology
- Abstract
Background: Ocular Chlamydia trachomatis (Ct) infection causes trachoma, the leading infectious cause of blindness. A Ct D/UW3 proteome microarray and sera from Gambian adults with trachomatous trichiasis (TT) or healthy matched controls previously identified several novel antigens, which suggested differential recognition in adults with TT., Methods: We re-analysed this serological microarray data using more robust microarray analysis techniques accounting for typical problems associated with highly dimensional data. We examined the Ct-specific antibody profile concerning the overall diversity of responses, antigen expression stage and cellular localisation of antigens. We tested differentially recognised antigens by further serological testing of the screened sera and used larger independent sample sets for validation., Results: Antibody responses identified High-Performance on antigens expressed early and late in the Ct developmental cycle and those secreted or localised to the outer membrane. Eight antigens were preferentially recognised by scarred individuals and one antigen by healthy individuals. Three of these antigens, two associated with scarring (CT667 and CT706) and one healthy-associated (CT442), were not associated with the presence or absence of scarring following specific serological testing of the arrayed sera and sera from larger, independent case-control cohorts., Conclusions: This study identified focussed Ct-specific antibody profiles targeting proteins expressed during entry and exit from cells and localised to interact with the host. A small panel of antibody responses could discriminate between adults with and without TT in a trachoma-endemic community. Heterogenous responses in the independent validation of these antibody targets highlighted the need for large sample sizes, clearly defined clinical phenotypes and follow-up work. more...
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- 2017
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40. Inverse relationship between microRNA-155 and -184 expression with increasing conjunctival inflammation during ocular Chlamydia trachomatis infection.
- Author
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Derrick T, Last AR, Burr SE, Roberts CH, Nabicassa M, Cassama E, Bailey RL, Mabey DC, Burton MJ, and Holland MJ
- Subjects
- Blindness, Child, Child, Preschool, Conjunctiva parasitology, Down-Regulation, Female, Guinea-Bissau, Humans, Infant, Inflammation, Male, Trachoma parasitology, Up-Regulation, Chlamydia trachomatis immunology, Conjunctiva immunology, Gene Expression Regulation, MicroRNAs genetics, Trachoma immunology
- Abstract
Background: Trachoma, a preventable blinding eye disease, is initiated by ocular infection with Chlamydia trachomatis (Ct). We previously showed that microRNAs (miR) -147b and miR-1285 were up-regulated in inflammatory trachomatous scarring. During the initial stage of disease, follicular trachoma with current Ct infection, the differential expression of miR has not yet been investigated., Methods: Conjunctival samples were collected from 163 children aged 1-9 years old living in a trachoma-endemic region of Guinea Bissau, West Africa. Small RNA sequencing (RNAseq) was carried out on samples from five children with follicular trachoma and current Ct infection and five children with healthy conjunctivae and no Ct infection. Small RNAseq was also carried out on human epithelial cell lines infected with ocular Ct strains A2497 and isogenic plasmid-free A2497 in vitro. Results were validated by quantitative PCR (qPCR) in 163 clinical samples., Results: Differential expression of RNAseq data identified 12 miR with changes in relative expression during follicular trachoma, of which 9 were confirmed as differentially expressed by qPCR (miR-155, miR-150, miR-142, miR-181b, miR-181a, miR-342, miR-132, miR-4728 and miR-184). MiR-155 and miR-184 expression had a direct relationship with the degree of clinical inflammation. MiR-155 was up-regulated (OR = 2.533 ((95 % CI = 1.291-4.971); P = 0.0069) and miR-184 was down-regulated (OR = 0.416 ((95 % CI = 0.300-0.578); P = 1.61*10(-7)) as the severity of clinical inflammation increased. Differential miR expression was not detected in HEp-2 or HCjE epithelial cells 48 h post infection with Ct in vitro. HCjE cells, a conjunctival epithelial cell line, had a markedly different miR background expression compared to HEp-2 cells., Conclusions: In follicular trachoma, expression of miR-155 and miR-184 is correlated with the severity of inflammation. This likely reflects host regulation of the immune response and a prolonged period of wound healing following the clearance of Ct. Prolonged healing may be associated with subsequent development of scarring trachoma. more...
- Published
- 2016
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41. Design of an Immersion Vaccine Against Aeromonad Septicemia in Perch (Perca fluviatilis L.).
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Frey J, Burr SE, and Wahli T
- Subjects
- Aeromonas physiology, Animals, Antigens, Bacterial immunology, Vaccination, Aeromonas immunology, Bacterial Vaccines immunology, Perches microbiology
- Abstract
The production of an immersion vaccine and the vaccination procedure to immunize fry of perch (Perca fluviatilis L.) against pathogenic Aeromonas sobria that harbor a type III secretion system is described. The vaccine, based on chemically inactivated A. sobria, enables rapid vaccination of a large number of fish by immersion of fry in an aqueous vaccine suspension during 5 min, giving them high protection during fattening under open water conditions in a freshwater lake for at least 4 months. more...
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- 2016
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42. Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study.
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Roberts Ch, Franklin CS, Makalo P, Joof H, Sarr I, Mahdi OS, Sillah A, Bah M, Payne F, Jeffreys AE, Bottomley W, Natividad A, Molina-Gonzalez S, Burr SE, Preston M, Kwiatkowski D, Rockett KA, Clark TG, Burton MJ, Mabey DC, Bailey R, Barroso I, and Holland MJ more...
- Subjects
- Adult, Computational Biology methods, Conjunctivitis, Inclusion metabolism, Disease Susceptibility, Female, Fibrosis, Gene Ontology, Gene Regulatory Networks, Genomics methods, Humans, Male, Middle Aged, Models, Biological, Polymorphism, Single Nucleotide, Signal Transduction, Chlamydia trachomatis immunology, Conjunctivitis, Inclusion etiology, Conjunctivitis, Inclusion pathology, Genome-Wide Association Study, Immunity, Innate
- Abstract
Chlamydia trachomatis causes both trachoma and sexually transmitted infections. These diseases have similar pathology and potentially similar genetic predisposing factors. We aimed to identify polymorphisms and pathways associated with pathological sequelae of ocular Chlamydia trachomatis infections in The Gambia. We report a discovery phase genome-wide association study (GWAS) of scarring trachoma (1090 cases, 1531 controls) that identified 27 SNPs with strong, but not genome-wide significant, association with disease (5 × 10(-6) > P > 5 × 10(-8)). The most strongly associated SNP (rs111513399, P = 5.38 × 10(-7)) fell within a gene (PREX2) with homology to factors known to facilitate chlamydial entry to the host cell. Pathway analysis of GWAS data was significantly enriched for mitotic cell cycle processes (P = 0.001), the immune response (P = 0.00001) and for multiple cell surface receptor signalling pathways. New analyses of published transcriptome data sets from Gambia, Tanzania and Ethiopia also revealed that the same cell cycle and immune response pathways were enriched at the transcriptional level in various disease states. Although unconfirmed, the data suggest that genetic associations with chlamydial scarring disease may be focussed on processes relating to the immune response, the host cell cycle and cell surface receptor signalling. more...
- Published
- 2015
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43. Trachoma and Ocular Chlamydial Infection in the Era of Genomics.
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Derrick T, Roberts Ch, Last AR, Burr SE, and Holland MJ
- Subjects
- Animals, Epigenomics methods, Eye Infections genetics, Eye Infections microbiology, Genomics methods, Humans, Chlamydia trachomatis pathogenicity, Trachoma genetics
- Abstract
Trachoma is a blinding disease usually caused by infection with Chlamydia trachomatis (Ct) serovars A, B, and C in the upper tarsal conjunctiva. Individuals in endemic regions are repeatedly infected with Ct throughout childhood. A proportion of individuals experience prolonged or severe inflammatory episodes that are known to be significant risk factors for ocular scarring in later life. Continued scarring often leads to trichiasis and in-turning of the eyelashes, which causes pain and can eventually cause blindness. The mechanisms driving the chronic immunopathology in the conjunctiva, which largely progresses in the absence of detectable Ct infection in adults, are likely to be multifactorial. Socioeconomic status, education, and behavior have been identified as contributing to the risk of scarring and inflammation. We focus on the contribution of host and pathogen genetic variation, bacterial ecology of the conjunctiva, and host epigenetic imprinting including small RNA regulation by both host and pathogen in the development of ocular pathology. Each of these factors or processes contributes to pathogenic outcomes in other inflammatory diseases and we outline their potential role in trachoma. more...
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- 2015
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44. Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control.
- Author
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Burr SE, Hart J, Edwards T, Harding-Esch EM, Holland MJ, Mabey DC, Sillah A, and Bailey RL
- Subjects
- Child Health Services, Child, Preschool, Community Health Services, Female, Gambia, Humans, Infant, Male, Nutritional Status, Prevalence, Anthropometry, Anti-Bacterial Agents administration & dosage, Azithromycin administration & dosage, Trachoma prevention & control
- Abstract
Background: Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed., Methods: Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms., Results: No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms., Conclusions: Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status. more...
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- 2014
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45. The conjunctival microbiome in health and trachomatous disease: a case control study.
- Author
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Zhou Y, Holland MJ, Makalo P, Joof H, Roberts CH, Mabey DC, Bailey RL, Burton MJ, Weinstock GM, and Burr SE
- Abstract
Background: Trachoma, caused by Chlamydia trachomatis, remains the world's leading infectious cause of blindness. Repeated ocular infection during childhood leads to scarring of the conjunctiva, in-turning of the eyelashes (trichiasis) and corneal opacity in later life. There is a growing body of evidence to suggest non-chlamydial bacteria are associated with clinical signs of trachoma, independent of C. trachomatis infection., Methods: We used deep sequencing of the V1-V3 region of the bacterial 16S rRNA gene to characterize the microbiome of the conjunctiva of 220 residents of The Gambia, 105 with healthy conjunctivae and 115 with clinical signs of trachoma in the absence of detectable C. trachomatis infection. Deep sequencing was carried out using the Roche-454 platform. Sequence data were processed and analyzed through a pipeline developed by the Human Microbiome Project., Results: The microbiome of healthy participants was influenced by age and season of sample collection with increased richness and diversity seen in younger participants and in samples collected during the dry season. Decreased diversity and an increased abundance of Corynebacterium and Streptococcus were seen in participants with conjunctival scarring compared to normal controls. Abundance of Corynebacterium was higher still in adults with scarring and trichiasis compared to adults with scarring only., Conclusions: Our results indicate that changes in the conjunctival microbiome occur in trachomatous disease; whether these are a cause or a consequence is yet unknown. more...
- Published
- 2014
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46. Non-participation during azithromycin mass treatment for trachoma in The Gambia: heterogeneity and risk factors.
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Edwards T, Allen E, Harding-Esch EM, Hart J, Burr SE, Holland MJ, Sillah A, West SK, Mabey D, and Bailey R
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- Child, Child, Preschool, Female, Gambia epidemiology, Humans, Infant, Male, Risk Factors, Azithromycin administration & dosage, Azithromycin therapeutic use, Communicable Disease Control methods, Communicable Disease Control statistics & numerical data, Patient Compliance statistics & numerical data, Trachoma drug therapy, Trachoma epidemiology, Trachoma prevention & control
- Abstract
Background: There is concern that untreated individuals in mass drug administration (MDA) programs for neglected tropical diseases can reduce the impact of elimination efforts by maintaining a source of transmission and re-infection., Methodology/principal Findings: Treatment receipt was recorded against the community census during three MDAs with azithromycin for trachoma in The Gambia, a hypo-endemic setting. Predictors of non-participation were investigated in 1-9 year olds using random effects logistic regression of cross-sectional data for each MDA. Two types of non-participators were identified: present during MDA but not treated (PNT) and eligible for treatment but absent during MDA (EBA). PNT and EBA children were compared to treated children separately. Multivariable models were developed using baseline data and validated using year one and two data, with a priori adjustment for previous treatment status. Analyses included approximately 10000 children at baseline and 5000 children subsequently. There was strong evidence of spatial heterogeneity, and persistent non-participation within households and individuals. By year two, non-participation increased significantly to 10.4% overall from 6.2% at baseline, with more, smaller geographical clusters of non-participating households. Multivariable models suggested household level predictors of non-participation (increased time to water and household head non-participation for both PNT and EBA; increased household size for PNT status only; non-inclusion in a previous trachoma examination survey and younger age for EBA only). Enhanced coverage efforts did not decrease non-participation. Few infected children were detected at year three and only one infected child was EBA previously. Infected children were in communities close to untreated endemic areas with higher rates of EBA non-participation during MDA., Conclusions/significance: In hypo-endemic settings, with good coverage and no association between non-participation and infection, efforts to improve participation during MDA may not be required. Further research could investigate spatial hotspots of infection and non-participation in other low and medium prevalence settings before allocating resources to increase participation. more...
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- 2014
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47. Mass administration of azithromycin and Streptococcus pneumoniae carriage: cross-sectional surveys in the Gambia.
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Burr SE, Milne S, Jafali J, Bojang E, Rajasekhar M, Hart J, Harding-Esch EM, Holland MJ, Mabey DC, Sillah A, Bailey RL, and Roca A
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- Carrier State, Child, Child, Preschool, Cross-Sectional Studies, Drug Resistance, Bacterial, Female, Gambia epidemiology, Humans, Immunization Programs, Infant, Infant, Newborn, Male, Pneumococcal Vaccines administration & dosage, Prevalence, Risk Factors, Rural Population, Trachoma epidemiology, Anti-Bacterial Agents administration & dosage, Azithromycin administration & dosage, Nasopharynx microbiology, Streptococcus pneumoniae drug effects, Trachoma drug therapy
- Abstract
Objective: To evaluate the effect of repeated mass drug administration (MDA) of azithromycin in the Gambia on the nasopharyngeal carriage of Streptococcus pneumoniae and on the emergence of antibiotic-resistant strains., Methods: This study involved villages that participated in a cluster randomized trial comparing the effect of one versus three azithromycin MDA rounds on the prevalence of trachoma. Only villages in which most children received 7-valent pneumococcal conjugate vaccine were included. Three cross-sectional surveys were performed in two villages that received three annual MDA rounds: the first immediately before the third MDA round and the second and third, 1 and 6 months, respectively, after the third MDA round. The third survey also covered six villages that had received one MDA round 30 months previously. Pneumococcal carriage was assessed using nasopharyngeal swabs and azithromycin resistance was detected using the Etest., Findings: The prevalence of pneumococcal carriage decreased from 43.4% to 19.2% between the first and second surveys (P < 0.001) but rebounded by the third survey (45.8%; P = 0.591). Being a carrier at the first survey was a risk factor for being a carrier at the second (odds ratio: 3.71; P < 0.001). At the third survey, the prevalence of carriage was similar after one and three MDA rounds (50.3% versus 45.8%, respectively; P = 0.170), as was the prevalence of azithromycin resistance (0.3% versus 0.9%, respectively; P = 0.340)., Conclusion: Three azithromycin MDA rounds did not increase the prevalence of nasopharyngeal carriage of azithromycin-resistant S. pneumoniae strains compared with one round. more...
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- 2014
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48. Risk factors for active trachoma and ocular Chlamydia trachomatis infection in treatment-naïve trachoma-hyperendemic communities of the Bijagós Archipelago, Guinea Bissau.
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Last AR, Burr SE, Weiss HA, Harding-Esch EM, Cassama E, Nabicassa M, Mabey DC, Holland MJ, and Bailey RL
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- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Carrier State microbiology, Child, Child, Preschool, Conjunctiva microbiology, Cross-Sectional Studies, DNA, Bacterial genetics, DNA, Bacterial isolation & purification, Female, Guinea-Bissau epidemiology, Humans, Infant, Male, Middle Aged, Prevalence, Risk Factors, Sex Factors, Trachoma microbiology, Young Adult, Carrier State epidemiology, Chlamydia trachomatis isolation & purification, Trachoma epidemiology
- Abstract
Background: Trachoma, caused by ocular infection with Chlamydia trachomatis, is hyperendemic on the Bijagós Archipelago of Guinea Bissau. An understanding of the risk factors associated with active trachoma and infection on these remote and isolated islands, which are atypical of trachoma-endemic environments described elsewhere, is crucial to the implementation of trachoma elimination strategies., Methodology/principal Findings: A cross-sectional population-based trachoma prevalence survey was conducted on four islands. We conducted a questionnaire-based risk factor survey, examined participants for trachoma using the World Health Organization (WHO) simplified grading system and collected conjunctival swab samples for 1507 participants from 293 randomly selected households. DNA extracted from conjunctival swabs was tested using the Roche Amplicor CT/NG PCR assay. The prevalence of active (follicular and/or inflammatory) trachoma was 11% (167/1508) overall and 22% (136/618) in 1-9 year olds. The prevalence of C. trachomatis infection was 18% overall and 25% in 1-9 year olds. There were strong independent associations of active trachoma with ocular and nasal discharge, C. trachomatis infection, young age, male gender and type of household water source. C. trachomatis infection was independently associated with young age, ocular discharge, type of household water source and the presence of flies around a latrine., Conclusions/significance: In this remote island environment, household-level risk factors relating to fly populations, hygiene behaviours and water usage are likely to be important in the transmission of ocular C. trachomatis infection and the prevalence of active trachoma. This may be important in the implementation of environmental measures in trachoma control. more...
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- 2014
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49. Will droplet digital PCR become the test of choice for detecting and quantifying ocular Chlamydia trachomatis infection? Maybe.
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Roberts CH, Last A, Burr SE, Bailey RL, Mabey DC, and Holland MJ
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- Female, Humans, Male, Bacteriological Techniques methods, Chlamydia trachomatis isolation & purification, Polymerase Chain Reaction methods, Trachoma diagnosis, Trachoma microbiology
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- 2014
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50. Conjunctival scarring in trachoma is associated with the HLA-C ligand of KIR and is exacerbated by heterozygosity at KIR2DL2/KIR2DL3.
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Roberts CH, Molina S, Makalo P, Joof H, Harding-Esch EM, Burr SE, Mabey DC, Bailey RL, Burton MJ, and Holland MJ
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- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Chlamydia trachomatis immunology, Cicatrix immunology, Conjunctiva immunology, Female, Gambia, Genetic Association Studies, Genotype, Heterozygote, Humans, Infant, Killer Cells, Natural immunology, Ligands, Linkage Disequilibrium, Male, Middle Aged, Trachoma immunology, Trachoma pathology, Young Adult, Cicatrix pathology, Conjunctiva pathology, Genetic Predisposition to Disease, HLA-C Antigens immunology, Receptors, KIR2DL2 genetics, Receptors, KIR2DL3 genetics, Trachoma genetics
- Abstract
Background: Chlamydia trachomatis is globally the predominant infectious cause of blindness and one of the most common bacterial causes of sexually transmitted infection. Infections of the conjunctiva cause the blinding disease trachoma, an immuno-pathological disease that is characterised by chronic conjunctival inflammation and fibrosis. The polymorphic Killer-cell Immunoglobulin-like Receptors (KIR) are found on Natural Killer cells and have co-evolved with the Human Leucocyte Antigen (HLA) class I system. Certain genetic constellations of KIR and HLA class I polymorphisms are associated with a number of diseases in which modulation of the innate responses to viral and intracellular bacterial pathogens is central., Methodology: A sample of 134 Gambian pedigrees selected to contain at least one individual with conjunctival scarring in the F1 generation was used. Individuals (n = 830) were genotyped for HLA class I and KIR gene families. Family Based Association Tests and Case Pseudo-control tests were used to extend tests for transmission disequilibrium to take full advantage of the family design, genetic model and phenotype., Principle Findings: We found that the odds of trachomatous scarring increased with the number of genome copies of HLA-C2 (C1/C2 OR = 2.29 BHP-value = 0.006; C2/C2 OR = 3.97 BHP-value = 0.0004) and further increased when both KIR2DL2 and KIR2DL3 (C2/C2 OR = 5.95 BHP-value = 0.006) were present., Conclusions: To explain the observations in the context of chlamydial infection and trachoma we propose a two-stage model of response and disease that balances the cytolytic response of KIR expressing NK cells with the ability to secrete interferon gamma, a combination that may cause pathology. The data presented indicate that HLA-C genotypes are important determinants of conjunctival scarring in trachoma and that KIR2DL2/KIR2DL3 heterozygosity further increases risk of conjunctival scarring in individuals carrying HLA-C2. more...
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- 2014
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