Comparative efficacy of low-dose versus standard-dose azithromycin for patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea

Marks, Michael; Mitjà, Oriol; Bottomley, Christian; Kwakye, Cynthia; Houinei, Wendy; Bauri, Mathias; Adwere, Paul; Abdulai, Abdul Aziz; Dua, Fredrick; Boateng, Laud; Wangi, James; Ohene, Sally-Ann; Wangnapi, Regina; Simpson, Shirley V.; Miag, Helen; Addo, Kennedy Kwasi; Basing, Laud Anthony; Danavall, Damien; Huang, Kai; Pillay, Allan; Ballard, Ronald C.; Solomon, Anthony W.; Chen, Cheng Y.; Bieb, Sibauk; Adu‐Sarkodie, Yaw; Mabey, David; Asiedu, Kingsley; Hounei, Wendy; Ohene, Sayy-Ann; Bieb, Sivuak V; Agana, Nsire; Ampadu, Edwin; Amponsah-Achiano, Kwame; Bediako, Asare; Biredu, Michael; Faried, Kyei; Iddrisu, Ahmed; Kotey, Nana Konama; Yeboah, George Ny; El-Duah, Philip; Phillips, Richard Odame; Binka, Fred; Nyonator, Frank; Zunuo, Anthony; Ackumey, Mercy A; Amanor, Ivy Brago; Bnosu, Christian; Frischmann, Sieghard; Lammie, Patrick J.; Martin, Diana L.; Ye, Tun; Christophel, Eva; Tiendrébéogo, Alexandre; Vestergard, Lasse; Bassat, Quique; Abdad, Yazid; Dima, H; Kotty, Bethuel; Mamore, Kaiok; Manup, Walerius; Olowau, Benson; Agyei, Enoch O; Agyemang, David; Ako, Ebenezer Padi; Antwi, Prince; Darko, Jane; Darko, Ophelia O; Darko, Phylis; Duodu, Bertha; Jabasi, Daniel; Karim, Fuseini L; Koomson, Obed K; Labri, Bernard A; Nartey, John; Tamatey, Randsford; Yirenkyi, Benjamin; Arhin, Mercy; Biney, Frank; Danso, Juliana O; Dei, Martin A; Djan, Moses; Sasu, Samuel; Solomon, Brefo A; Torvinya, Victor; Amankwaah, Hagar; Baffoe, James; Keteku, Lydia; Kondobala, Kofi; Lomotey, Rita Dede; Nartey, Augustina A; Oppong, Paul; Quainoo, Millicent A; Abotsi, Theophilus; Agebshie, Dzighordi; Ameamu, Amos; Angwaawie, Paul; Ayibor, Rose; Mwingmendeli, Margaret; Nakodia, John; Nambagyira, Amatus; Nanga, Dominic; Tetteh, Nichola; Wanaom, Augustine

doi:10.1016/s2214-109x(18)30023-8

Cited by 22 publications

(26 citation statements)

References 28 publications

(47 reference statements)

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“…( d .1) Quantification of fold-change TGFBR3 protein expression levels normalized to GAPDH. e - g Immunofluorescence staining of wildtype (top) and YAP2-5SA-ΔC 54 mouse skin showing phospho-SMAD3 (green) and YAP (Red) protein expression. h - j Immunofluorescence staining of wildtype (top) and YAP2-5SA-ΔC 54 mice skin showing PLAU (green) and YAP (red) protein expression in YAP2-5SA-ΔC epidermis.…”

Section: Resultsmentioning

confidence: 99%

“…e - g Immunofluorescence staining of wildtype (top) and YAP2-5SA-ΔC 54 mouse skin showing phospho-SMAD3 (green) and YAP (Red) protein expression. h - j Immunofluorescence staining of wildtype (top) and YAP2-5SA-ΔC 54 mice skin showing PLAU (green) and YAP (red) protein expression in YAP2-5SA-ΔC epidermis. k Western blots detecting PLAU (55 KDa) and GAPDH (37 KDa) in protein lysates of wildtype and YAP2-5SA-ΔC skin ( N = 3).…”

Section: Resultsmentioning

confidence: 99%

“… a-c Immunofluorescence staining of wildtype (top) and YAP2-5SA-ΔC 54 mouse skin showing TGFBR3 (green) and YAP (red) protein expression in YAP2-5SA-ΔC epidermis. d Western blots detecting TGFBR3 (100 KDa) and GAPDH (37 KDa) in protein lysates of wildtype and YAP2-5SA-ΔC skin (N = 3).…”

Section: Resultsmentioning

confidence: 99%

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Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation

et al. 2018

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Yes-associated protein (YAP) is a mechanosensor protein and a downstream effector of the Hippo kinase pathway, which controls organ growth, cell proliferation, survival, maintenance and regeneration. Unphosphorylated YAP translocates to the nucleus where it acts as a cofactor of primarily the TEAD transcription factors to activate target gene transcription and cell proliferation. Perturbed YAP activation results in tumorigenesis. The pathways downstream of activated YAP that drive cell proliferation remain relatively unexplored. In this study, we employed YAP2-5SA-∆C transgenic mice, which overexpress a mildly activated YAP mutant protein in basal keratinocytes leading to increased proliferation of the epidermal stem/progenitor cell populations. We performed massively-parallel sequencing of skin biopsy mRNA (RNA-Seq) and found dysregulation of 1491 genes in YAP2-5SA-∆C skin, including many with roles in cell activation and proliferation. Furthermore, we found that 150 of these dysregulated genes harbored YAP/TEAD binding motifs in the 3′ UTR, suggesting that these may be direct YAP/TEAD target genes in the control of epidermal regeneration. Further validation and functional characterization assays identified Plau and Tgfbr3 as prime candidate genes that may be activated by epidermal YAP activity in the mouse skin in vivo to promote keratinocyte proliferation. This study provides novel insights into the mechanisms regulated by YAP that control tissue homeostasis, and in particular in conditions where YAP is aberrantly activated such as in neoplastic and regenerative skin disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation

et al. 2018

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“…A map of the study districts and their location in Ghana(19) Sample and Data collection:Patients (both genders) with clinically diagnosed yaws lesions were actively selected from the recruitment sites (schools and communities).A full medical history, study site information including GPS coordinates, demographic data including communities of residence and clinical assessment, were performed and all information recorded onto a standardized Patient Record Form. Each of the clinically diagnosed children were screened using the DPP ® Syphilis Screen & Confirm Assay (Chembio Diagnostic Systems Inc. Medford, NY) as described by Causer et al (12), Samples for PCR were collected by swabbing ulcerative lesions and scrapping from papilloma of DPP positive participants to confirm Treponema pallidum subsp pertenue.…”

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confidence: 99%

Mapping of yaws endemicity in Ghana; Lessons to strengthen the planning and implementation of yaws eradication

Law

Djan

et al. 2020

Preprint

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Yaws caused by Treponema pallidum subsp pertenue is a disease of poverty and affects communities where basic socio-economic amenities are lacking. With results showing that single dose azithromycin is effective in the treatment of yaws, the World Health Organisation introduced the Morges strategy with the intent to eradicate yaws by 2020. Ghana is one of the countries with the most yaws cases globally, and the National Yaws Eradication Program in Ghana intends to conduct Mass Drug Administration (MDA) of endemic communities in line with the Total Community Treatment plan of the Morges strategy. It is therefore important to map out endemic communities to ensure that MDA is both effective and financially efficient. Children with suspected yaws lesions were actively selected from the recruitment sites (schools and communities). A full medical history, study site information including GPS coordinates, demographic data including communities of residence and clinical assessment were taken. Each of the clinically diagnosed children were screened using the DPP Syphilis Screen & Confirm Assay (DPP). Samples for PCR were collected by swabbing ulcerative lesions of participants and tested for Treponema pallidum subsp pertenue and Haemophilus ducreyi DNA. In all, 625 children with a median age of 10 years were recruited into the study. While 401(64.2%) were DPP positive, only 141 of them had Treponema pallidum subsp pertenue DNA (TPE_DNA) accounting for 22.6% of those who were clinically diagnosed. Based on the DPP results, yaws was endemic in all the 4 study sites with participants from 88 communities in 13 districts in 4 regions in Ghana. There was no statistically significant difference between the various districts in terms of DPP results (x2=0.9364, p= 0.817) and 154 (24.6%) of those clinically diagnosed as yaws were positive for Haemophilus ducreyi DNA. Our study shows that communities endemic for yaws are also endemic for Haemophilus ducreyi i. Most yaws endemic communities were found at the border of other districts and regions. It is recommended that MDA should not only target endemic communities, but it should also target entire endemic districts as well as neighbouring districts in order to be effective.

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“…The serological cure rate in patients with active yaws was slightly lower in the low-dose arm. In patients with latent yaws the serological cure rate was equivalent with both doses of azithromycin [ 36 ]. Taken together with observational data, this suggests that low-dose azithromycin is also effective in the treatment of yaws, although the 30 mg/kg dose remains the standard of care.…”

Section: Azithromycin-based Treatmentmentioning

confidence: 99%

Advances in the Treatment of Yaws

Marks

2018

TropicalMed

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Yaws is one of the three endemic treponematoses and is recognised by the World Health Organization as a neglected tropical disease. Yaws is currently reported in 15 countries in the Pacific, South-East Asia, West and Central Africa, predominantly affects children, and results in destructive lesions of the skin and soft tissues. For most of the twentieth century penicillin-based treatment was the standard of care and resistance to penicillin has still not been described. Recently, oral azithromycin has been shown to be an effective treatment for yaws, facilitating renewed yaws eradication efforts. Resistance to azithromycin is an emerging threat and close surveillance will be required as yaws eradication efforts are scaled up globally.

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Comparative efficacy of low-dose versus standard-dose azithromycin for patients with yaws: a randomised non-inferiority trial in Ghana and Papua New Guinea

Abstract: Coalition for Operational Research on Neglected Tropical Diseases.

Cited by 22 publications

References 28 publications

Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation

Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation

Mapping of yaws endemicity in Ghana; Lessons to strengthen the planning and implementation of yaws eradication

Advances in the Treatment of Yaws

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