@article {1636, title = {Azithromycin as adjunctive treatment for uncomplicated severe acute malnutrition (AMOUR): study protocol for a double-masked randomised controlled trial.}, journal = {BMJ Open}, volume = {15}, year = {2025}, month = {2025 Jul 01}, pages = {e104591}, abstract = {

INTRODUCTION: Amoxicillin is recommended for children with uncomplicated severe acute malnutrition (SAM). However, some trials have shown no difference in amoxicillin for nutritional recovery in children with SAM compared with placebo. In addition, amoxicillin treatment requires two times per day dosing for 7 days, which may influence adherence. Azithromycin is a broad-spectrum antibiotic that can be provided as a single dose and has reduced mortality in children aged 1-59 months when provided by mass drug administration. The AMOUR trial is designed to assess amoxicillin, azithromycin and placebo as part of outpatient treatment of uncomplicated SAM.

METHODS AND ANALYSIS: This double-masked randomised controlled trial will enrol 3000 children over 3 years in an individually randomised 1:1:1 allocation to azithromycin, amoxicillin or placebo arms and follow them for 12 months. Children eligible to enrol in the study will be aged 6-59 months and have uncomplicated non-oedematous SAM as defined by weight-for-height Z-score \<-3 SD and/or mid-upper arm circumference \<115 mm. Additionally, the children must not have received antibiotics in the past 7 days and have not received nutritional programme treatment for SAM in the 2 weeks before enrolling in the study. Each participant will receive a 7-day course of treatment or placebo based on the arm they were randomised to; 1 dose of azithromycin plus placebo for consistency in the number of doses, 7 days of amoxicillin or 7 days of placebo, with the first dose directly observed in all arms. The primary endpoint outcome will be weight gain defined by g/kg/day at 8 weeks. Mortality and relapse will be assessed at 8 weeks and 3 months, 6 months, 9 months and 12 months.

ETHICS AND DISSEMINATION: Ethical approval was obtained from the Institutional Review Board at the University of California, San Francisco (Protocol 23-39411) and the Comit{\'e} d{\textquoteright}Ethique pour la Recherche en Sant{\'e} in Ouagadougou, Burkina Faso (Protocol 2024-01-08). The results of this study will be disseminated to the Ministry of Health, community stakeholders and via peer-reviewed publications and academic conferences.

TRIAL REGISTRATION NUMBER: NCT06010719.

}, keywords = {Amoxicillin, Anti-Bacterial Agents, Azithromycin, Child, Preschool, Double-Blind Method, Female, Humans, Infant, Male, Randomized Controlled Trials as Topic, Severe Acute Malnutrition}, issn = {2044-6055}, doi = {10.1136/bmjopen-2025-104591}, author = {Bountogo, Mamadou and Zakane, Alphonse and Ouedraogo, Thierry A and Ouermi, Lucienne and Compaor{\'e}, Guillaume and Compaor{\'e}, Adama and Coulibaly, Boubacar and Koueta, Fla and Burroughs, Hadley R and Fetterman, Ian and La Mons, Jessica L and Lebas, Elodie and Doan, Thuy and Hsiang, Michelle and O{\textquoteright}Brien, Kieran Sunanda and Arnold, Benjamin and Sie, Ali and Oldenburg, Catherine E} } @article {1651, title = {Spillover of Azithromycin Mass Drug Administration and Child Survival: A Secondary Analysis of a Cluster-Randomized Clinical Trial.}, journal = {JAMA Netw Open}, volume = {8}, year = {2025}, month = {2025 Jul 01}, pages = {e2519693}, abstract = {

IMPORTANCE: World Health Organization guidelines on azithromycin mass drug administration for child survival target infants aged 1 to 11 months, although prior studies included those aged 1 to 59 months. The AVENIR trial suggested that infants aged 1 to 11 months have lower mortality if children aged 12 to 59 months in the same household are also included.

OBJECTIVE: To assess the possibility of a spillover effect by examining the association of azithromycin and mortality among children aged 1 to 11 months in subgroups defined by the presence of a child aged 12 to 59 months in the same household.

DESIGN, SETTING, AND PARTICIPANTS: This exploratory secondary analysis of the AVENIR (Azithromycine Pour la Vie des Enfants au Niger: Implementation et Recherche) adaptive cluster-randomized clinical trial was performed in 3000 rural and periurban communities in Niger. AVENIR communities were randomized to 3 arms and followed up for 2 years (November 24, 2020, to July 31, 2023). Study arms consisted of children aged 1 to 59 months receiving azithromycin (child arm); infants aged 1 to 11 months receiving azithromycin with placebo to children aged 12 to 59 months (infant arm); and children aged 1 to 59 months receiving placebo (placebo arm). Participants, investigators, data collectors, and data analysts were masked to randomization.

INTERVENTION: A single 20-mg/kg dose of oral azithromycin or placebo administered by study staff biannually.

MAIN OUTCOMES AND MEASURES: All-cause mortality in infants aged 1 to 11 months (deaths per 1000 person-years) measured through biannual census. Subgroups were defined by the presence of a child aged 12 to 59 months in the household recorded during the census.

RESULTS: After exclusions, 2883 communities and 98 969 infants aged 1 to 11 months were included in the analysis. Among the 23 770 infants in allocation 1 at baseline, mean (SD) age was 6.2 (3.1) months and 11 974 (50.4\%) were female. Mortality was 18.5 (95\% CI, 16.7-20.4) deaths per 1000 person-years in the child arm, 22.3 (95\% CI, 20.0-24.7) in the infant arm, and 23.9 (95\% CI, 21.6-26.2) in the placebo arm. The incidence rate ratio comparing mortality in the child and infant arms among children with an older sibling was 0.78 (95\% CI, 0.65-0.93) compared with 0.91 (95\% CI, 0.73-1.15; P = .26 for interaction) among those without. Comparing the infant and placebo arms, the incidence rate ratio among children with an older sibling was 0.96 (95\% CI, 0.81-1.14) compared with 0.90 (95\% CI, 0.71-1.12; P = .61 for interaction) among those without.

CONCLUSIONS AND RELEVANCE: In this secondary analysis of a cluster-randomized clinical trial, interaction for the presence of a older sibling was not statistically significant, but results were consistent with lower mortality among infants aged 1 to 11 months living with older, treated children.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04224987.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Cluster Analysis, Female, Humans, Infant, Infant Mortality, Male, Mass Drug Administration, Niger}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2025.19693}, author = {Arzika, Ahmed M and Amza, Abdou and Maliki, Ramatou and Aichatou, Bawa and Bello, Ismael Mamane and Beidi, Diallo and Galo, Nasser and Harouna, Nasser and Karamba, Alio M and Mahamadou, Sani and Abarchi, Moustapha and Ibrahim, Almou and Brandt, Carolyn and Lebas, Elodie and Peterson, Brittany and Liu, Zijun and Oldenburg, Catherine E and Doan, Thuy and Porco, Travis C and Arnold, Benjamin F and Lietman, Thomas M and O{\textquoteright}Brien, Kieran S} } @article {1381, title = {Prolonged mass azithromycin distributions and macrolide resistance determinants among preschool children in Niger: A sub-study of a cluster-randomized trial (MORDOR).}, journal = {PLoS Med}, volume = {21}, year = {2024}, month = {2024 May}, pages = {e1004386}, abstract = {

BACKGROUND: Randomized controlled trials found that twice-yearly mass azithromycin administration (MDA) reduces childhood mortality, presumably by reducing infection burden. World Health Organization (WHO) issued conditional guidelines for mass azithromycin administration in high-mortality settings in sub-Saharan Africa given concerns for antibiotic resistance. While prolonged twice-yearly MDA has been shown to increase antibiotic resistance in small randomized controlled trials, the objective of this study was to determine if macrolide and non-macrolide resistance in the gut increases with the duration of azithromycin MDA in a larger setting.

METHODS AND FINDINGS: The Macrolide Oraux pour R{\'e}duire les D{\'e}c{\`e}s avec un Oeil sur la R{\'e}sistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95\% CI 1.5 to 3.51, Punadj \< 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95\% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95\% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability.

CONCLUSIONS: In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored.

TRIAL REGISTRATION: NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Resistance, Bacterial, Female, Humans, Infant, Macrolides, Male, Mass Drug Administration, Niger}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1004386}, author = {Arzika, Ahmed M and Abdou, Amza and Maliki, Ramatou and Beido, Nassirou and Kadri, Boubacar and Harouna, Abdoul N and Galo, Abdoul N and Alio, Mankara K and Lebas, Elodie and Oldenburg, Catherine E and O{\textquoteright}Brien, Kieran S and Chen, Cindi and Zhong, Lina and Zhou, Zhaoxia and Yan, Daisy and Hinterwirth, Armin and Keenan, Jeremy D and Porco, Travis C and Lietman, Thomas M and Doan, Thuy} } @article {1031, title = {Gut Resistome after Antibiotics among Children with Uncomplicated Severe Acute Malnutrition: A Randomized Controlled Trial.}, journal = {Am J Trop Med Hyg}, volume = {107}, year = {2022}, month = {2022 Jul 13}, pages = {59-64}, abstract = {

A broad-spectrum antibiotic, typically amoxicillin, is included in many country guidelines as part of the management of uncomplicated severe acute malnutrition (SAM) in children without overt clinical symptoms of infection. Alternative antibiotics may be beneficial for children with SAM without increasing selection for beta-lactam resistance. We conducted a 1:1 randomized controlled trial of single dose azithromycin versus a 7-day course of amoxicillin for SAM. Children 6-59 months of age with uncomplicated SAM (mid-upper arm circumference \< 11.5 cm and/or weight-for-height Z-score \< -3) were enrolled in Boromo District, Burkina Faso, from June through October 2020. Rectal swabs were collected at baseline and 8 weeks after treatment and processed using DNA-Seq. We compared the resistome at the class level in children randomized to azithromycin compared with amoxicillin. We found no evidence of a difference in the distribution of genetic antibiotic resistance determinants to any antibiotic class 8 weeks after treatment. There was no difference in genetic macrolide resistance determinants (65\% azithromycin, 65\% placebo, odds ratio, OR, 1.00, 95\% confidence interval, CI, 0.43-2.34) or beta-lactam resistance determinants (82\% azithromycin, 83\% amoxicillin, OR 0.94, 95\% CI, 0.33-2.68) at 8 weeks. Although presence of genetic antibiotic resistance determinants to macrolides and beta-lactams was common, we found no evidence of a difference in the gut resistome 8 weeks after treatment. If there are earlier effects of antibiotics on selection for genetic antibiotic resistance determinants, the resistome may normalize by 8 weeks.

}, keywords = {Amoxicillin, Anti-Bacterial Agents, Azithromycin, Child, Drug Resistance, Bacterial, Humans, Macrolides, Severe Acute Malnutrition}, issn = {1476-1645}, doi = {10.4269/ajtmh.22-0007}, author = {Oldenburg, Catherine E and Hinterwirth, Armin and Ourohir{\'e}, Millogo and Dah, Clarisse and Ou{\'e}draogo, Moussa and Sie, Ali and Boudo, Valentin and Chen, Cindi and Ruder, Kevin and Zhong, Lina and Lebas, Elodie and Nyatigo, Fanice and Arnold, Benjamin F and O{\textquoteright}Brien, Kieran S and Doan, Thuy} } @article {1161, title = {Ocular Rosacea microBiome Study (ORBS)-sub-microbial versus antibiotic dosing of doxycycline versus placebo in treatment of symptomatic ocular rosacea: study protocol for a parallel-arm randomized clinical trial.}, journal = {Trials}, volume = {23}, year = {2022}, month = {2022 Dec 20}, pages = {1033}, abstract = {

BACKGROUND: Ocular rosacea is common and is often managed with long-term antibiotic treatment. Doxycycline is the most commonly selected antibiotic for the treatment of rosacea. As there is no established standard of care treatment dose for rosacea, prescribed doses of doxycycline vary widely. The FDA classifies 40\ mg daily dose of doxycycline for ocular rosacea as sub-microbial in comparison to an antibiotic dose of 200\ mg daily. However, this "sub-microbial" dose has never been evaluated in patients with ocular rosacea, and even the sub-microbial dose has potential to alter systemic mucosa flora. Here, we present a randomized controlled trial using RNA sequencing to fully characterize the impact of sub-microbial antibiotic dosing of doxycycline on antimicrobial resistance and bacterial composition of the ocular and gut flora.

METHODS: In a triple-masked parallel randomized control trial, patients with ocular rosacea will be randomized to three arms: a 40-mg dose of doxycycline, a 200-mg antibiotic dose of doxycycline, or placebo. Collected rectal and lower eyelid samples will be compared for frequency of antimicrobial resistance genetic determinants and microbiome diversity. A subjective ocular surface disease index survey and objective tear breakup time measurement will be determined.

DISCUSSION: These results will enhance our understanding of the overall systemic impact of long-term systemic sub-microbial antibiotic dosing for the treatment of chronic recurrent ocular inflammatory diseases.

TRIAL REGISTRATION: This trial was registered on ClinicalTrials.org (NCT05296837) on March 22, 2022.

}, keywords = {Anti-Bacterial Agents, Anti-Infective Agents, Doxycycline, Gastrointestinal Microbiome, Humans, Randomized Controlled Trials as Topic, Rosacea}, issn = {1745-6215}, doi = {10.1186/s13063-022-06948-9}, author = {Mahmud, Hamidah and Keenan, Jeremy D and Gonzales, John and Schallhorn, Julie and Chan, Matilda and Arnold, Benjamin and Cavallino, Victoria and Lietman, Thomas M and Doan, Thuy and Seitzman, Gerami D} } @article {911, title = {Age-based targeting of biannual azithromycin distribution for child survival in Niger: an adaptive cluster-randomized trial protocol (AVENIR).}, journal = {BMC Public Health}, volume = {21}, year = {2021}, month = {2021 04 29}, pages = {822}, abstract = {

BACKGROUND: Biannual distribution of azithromycin to children 1-59 months old reduced mortality by 14\% in a cluster-randomized trial. The World Health Organization has proposed targeting this intervention to the subgroup of children 1-11 months old to reduce selection for antimicrobial resistance. Here, we describe a trial designed to determine the impact of age-based targeting of biannual azithromycin on mortality and antimicrobial resistance.

METHODS: AVENIR is a cluster-randomized, placebo-controlled, double-masked, response-adaptive large simple trial in Niger. During the 2.5-year study period, 3350 communities are targeted for enrollment. In the first year, communities in the Dosso region will be randomized 1:1:1 to 1) azithromycin 1-11: biannual azithromycin to children 1-11 months old with placebo to children 12-59 months old, 2) azithromycin 1-59: biannual azithromycin to children 1-59 months old, or 3) placebo: biannual placebo to children 1-59 months old. Regions enrolled after the first year will be randomized with an updated allocation based on the probability of mortality in children 1-59 months in each arm during the preceding study period. A biannual door-to-door census will be conducted to enumerate the population, distribute azithromycin and placebo, and monitor vital status. Primary mortality outcomes are defined as all-cause mortality rate (deaths per 1000 person-years) after 2.5 years from the first enrollment in 1) children 1-59 months old comparing the azithromycin 1-59 and placebo arms, 2) children 1-11 months old comparing the azithromycin 1-11 and placebo arm, and 3) children 12-59 months in the azithromycin 1-11 and azithromycin 1-59 arms. In the Dosso region, 50 communities from each arm will be followed to monitor antimicrobial resistance. Primary resistance outcomes will be assessed after 2 years of distributions and include 1) prevalence of genetic determinants of macrolide resistance in nasopharyngeal samples from children 1-59 months old, and 2) load of genetic determinants of macrolide resistance in rectal samples from children 1-59 months old.

DISCUSSION: As high-mortality settings consider this intervention, the results of this trial will provide evidence to support programmatic and policy decision-making on age-based strategies for azithromycin distribution to promote child survival.

TRIAL REGISTRATION: This trial was registered on January 13, 2020 (clinicaltrials.gov: NCT04224987 ).

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child, Child, Preschool, Drug Resistance, Bacterial, Humans, Infant, Macrolides, Mass Drug Administration, Niger, Randomized Controlled Trials as Topic}, issn = {1471-2458}, doi = {10.1186/s12889-021-10824-7}, author = {O{\textquoteright}Brien, Kieran S and Arzika, Ahmed M and Amza, Abdou and Maliki, Ramatou and Ousmane, Sani and Kadri, Boubacar and Nassirou, Beido and Mankara, Alio Karamba and Harouna, Abdoul Naser and Colby, Emily and Lebas, Elodie and Liu, Zijun and Le, Victoria and Nguyen, William and Keenan, Jeremy D and Oldenburg, Catherine E and Porco, Travis C and Doan, Thuy and Arnold, Benjamin F and Lietman, Thomas M} } @article {161, title = {Gut Bacterial Diversity and Growth among Preschool Children in Burkina Faso.}, journal = {Am J Trop Med Hyg}, volume = {103}, year = {2020}, month = {2020 12}, pages = {2568-2573}, abstract = {

There is a lack of empirical, prospective human data on the gut microbiome and its relationship with growth, especially in low- and middle-income countries. We prospectively assessed the association between gut microbial diversity and short-term growth in a cohort of preschool children in Burkina Faso to better characterize whether there is any evidence that changes in gut microbial diversity may affect growth. Data were obtained from a randomized controlled trial evaluating the effect of antibiotic administration on gut microbial diversity in preschool children. We followed up the enrolled children for 35 days, with anthropometric measurements at baseline and day 35 and microbial diversity measured at baseline and day 9 (analytic sample, = 155). We estimated linear mixed-effects regression models with household random intercepts to assess the association of Simpson{\textquoteright}s and Shannon{\textquoteright}s alpha diversity with measures of change in anthropometry (e.g., ponderal growth since baseline) and absolute anthropometric measurements (e.g., day 35 weight). We did not find evidence that alpha gut microbial diversity was associated with growth or absolute anthropometric measurements after adjusting for confounding variables. Effect estimates were close to the null ( >= 0.15 for all fully adjusted comparisons), with the association between Simpson{\textquoteright}s alpha diversity and day 35 height (cm) farthest from the null (coefficient = -0.03, 95\% CI: -0.07, 0.01). The change in gut microbial diversity also was not associated with the change in anthropometry in crude or adjusted models. Future research is needed to explore whether gut diversity has an impact on growth over a longer time period, in both healthy and malnourished children.

}, keywords = {Anti-Bacterial Agents, Bacteria, Burkina Faso, Child Development, Child, Preschool, Female, Gastrointestinal Microbiome, Humans, Infant, Male, Nutritional Status, Prospective Studies}, issn = {1476-1645}, doi = {10.4269/ajtmh.20-0059}, author = {Digitale, Jean and Sie, Ali and Coulibaly, Boubacar and Ouermi, Lucienne and Dah, Clarisse and Tapsoba, Charlemagne and B{\"a}rnighausen, Till and Lebas, Elodie and Arzika, Ahmed M and Glymour, Medellena Maria and Keenan, Jeremy D and Doan, Thuy and Oldenburg, Catherine E} } @article {171, title = {Gut Resistome After Oral Antibiotics in Preschool Children in Burkina Faso: A Randomized, Controlled Trial.}, journal = {Clin Infect Dis}, volume = {70}, year = {2020}, month = {2020 01 16}, pages = {525-527}, abstract = {

We evaluated the effect of systemic antibiotics (azithromycin, amoxicillin, cotrimoxazole, or placebo) on the gut resistome in children aged 6 to 59 months. Azithromycin and cotrimoxazole led to an increase in macrolide and sulfonamide resistance determinants. Resistome expansion can be induced with a single course of antibiotics.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Burkina Faso, Child, Preschool, Gastrointestinal Microbiome, Humans, Infant, Macrolides}, issn = {1537-6591}, doi = {10.1093/cid/ciz455}, author = {Oldenburg, Catherine E and Hinterwirth, Armin and Sie, Ali and Coulibaly, Boubacar and Ouermi, Lucienne and Dah, Clarisse and Tapsoba, Charlemagne and Cummings, Susie L and Zhong, Lina and Chen, Cindi and Sarkar, Samarpita and B{\"a}rnighausen, Till and Lietman, Thomas M and Keenan, Jeremy D and Doan, Thuy} } @article {71, title = {Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution.}, journal = {N Engl J Med}, volume = {383}, year = {2020}, month = {2020 11 12}, pages = {1941-1950}, abstract = {

BACKGROUND: Mass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear.

METHODS: We investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants{\textquoteright} gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months.

RESULTS: Over the entire 48-month period, the mean ({\textpm}SD) coverage was 86.6{\textpm}12\% in the villages that received placebo and 83.2{\textpm}16.4\% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95\% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95\% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of nonmacrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa.

CONCLUSIONS: Among villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02047981.).

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Resistance, Bacterial, Female, Gastrointestinal Microbiome, Humans, Infant, Macrolides, Male, Mass Drug Administration, Metagenome, Niger, Sequence Analysis, DNA}, issn = {1533-4406}, doi = {10.1056/NEJMoa2002606}, author = {Doan, Thuy and Worden, Lee and Hinterwirth, Armin and Arzika, Ahmed M and Maliki, Ramatou and Abdou, Amza and Zhong, Lina and Chen, Cindi and Cook, Catherine and Lebas, Elodie and O{\textquoteright}Brien, Kieran S and Oldenburg, Catherine E and Chow, Eric D and Porco, Travis C and Lipsitch, Marc and Keenan, Jeremy D and Lietman, Thomas M} } @article {86, title = {Post-antibiotic Ocular Surface Microbiome in Children: A Cluster-Randomized Trial.}, journal = {Ophthalmology}, volume = {127}, year = {2020}, month = {2020 08}, pages = {1127-1130}, keywords = {Anti-Bacterial Agents, Child, Cornea, Humans, Microbiota, Randomized Controlled Trials as Topic}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2020.02.014}, author = {Doan, Thuy and Hinterwirth, Armin and Worden, Lee and Arzika, Ahmed M and Maliki, Ramatou and Chen, Cindi and Zhong, Lina and Zhou, Zhaoxia and Acharya, Nisha R and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M} } @article {206, title = {Rapid Reduction of Species in the Gut Microbiome of Preschool Children after Oral Azithromycin: A Randomized Controlled Trial.}, journal = {Am J Trop Med Hyg}, volume = {103}, year = {2020}, month = {2020 09}, pages = {1266-1269}, abstract = {

has emerged as a potential important cause of childhood morbidity in sub-Saharan Africa. Biannual mass azithromycin distribution has previously been shown to reduce all-cause child mortality in sub-Saharan Africa. We conducted a randomized controlled trial in Burkina Faso in which children were randomized in a 1:1 fashion to a 5-day course of azithromycin or placebo to investigate the effect of oral antibiotics on the gut microbiome. We evaluated the changes in the gut microbiome of preschool children treated with azithromycin using metagenomic DNA sequencing. We found that three species were reduced with azithromycin treatment compared with placebo. These results were consistent with other studies that have shown decreases in species after azithromycin treatment, generating the hypothesis that a decrease in may contribute to observations of reduction in mortality following azithromycin distribution.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Burkina Faso, Campylobacter, Campylobacter Infections, Child Mortality, Child, Preschool, Gastrointestinal Microbiome, Humans, Infant, Metagenomics, Sequence Analysis, DNA}, issn = {1476-1645}, doi = {10.4269/ajtmh.19-0940}, author = {Hinterwirth, Armin and Sie, Ali and Coulibaly, Boubacar and Ouermi, Lucienne and Dah, Clarisse and Tapsoba, Charlemagne and Zhong, Lina and Chen, Cindi and Lietman, Thomas M and Keenan, Jeremy D and Doan, Thuy and Oldenburg, Catherine E} } @article {231, title = {A double-masked placebo-controlled trial of azithromycin to prevent child mortality in Burkina Faso, West Africa: Community Health with Azithromycin Trial (CHAT) study protocol.}, journal = {Trials}, volume = {20}, year = {2019}, month = {2019 Dec 04}, pages = {675}, abstract = {

BACKGROUND: Biannual, mass azithromycin distribution has previously been shown to reduce all-cause child mortality in sub-Saharan Africa. Subgroup analysis suggested that the strongest effects were in the youngest children, leading to the hypothesis that targeting younger age groups might be an effective strategy to prevent mortality. We present the methods of two randomized controlled trials designed to evaluate mass and targeted azithromycin distribution for the prevention of child mortality in Burkina Faso, West Africa.

METHODS/DESIGN: The Child Health with Azithromycin Treatment (CHAT) study consists of two nested, randomized controlled trials. In the first, communities are randomized in a 1:1 fashion to biannual, mass azithromycin distribution or placebo. The primary outcome is under-5 all-cause mortality measured at the community level. In the second, children attending primary healthcare facilities during the first 5-12 weeks of life for a healthy child visit (e.g., for vaccination) are randomized in a 1:1 fashion to a single orally administered dose of azithromycin or placebo. The primary outcome is all-cause mortality measured at 6 months of age. The trial commenced enrollment in August 2019.

DISCUSSION: This study is expected to provide evidence on two health systems delivery approaches (mass and targeted treatment) for azithromycin to prevent all-cause child mortality. The results will inform global and national policies related to azithromycin for the prevention of child mortality.

TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03676764. Registered on 19 September 2018; prospectively registered pre results.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Double-Blind Method, Humans, Infant, Outcome Assessment, Health Care, Randomized Controlled Trials as Topic, Sample Size}, issn = {1745-6215}, doi = {10.1186/s13063-019-3855-9}, author = {Sie, Ali and Ouattara, Mamadou and Bountogo, Mamadou and Bagagnan, Cheik and Coulibaly, Boubacar and Boudo, Valentin and Lebas, Elodie and Brogdon, Jessica M and Lin, Ying and B{\"a}rnighausen, Till and Porco, Travis C and Doan, Thuy and Lietman, Thomas M and Oldenburg, Catherine E} } @article {151, title = {High-throughput sequencing of pooled samples to determine community-level microbiome diversity.}, journal = {Ann Epidemiol}, volume = {39}, year = {2019}, month = {2019 11}, pages = {63-68}, abstract = {

PURPOSE: Community-level interventions in cluster randomized controlled trials may alter the gut microbiome of individuals. The current method of estimating community diversities uses microbiome data obtained from multiple individual{\textquoteright}s specimens. Here we propose randomly pooling a number of microbiome samples from the same community into one sample before sequencing to estimate community-level microbiome diversity.

METHODS: We design and analyze an experiment to compare community microbiome diversity (gamma-diversity) estimates derived from 16S rRNA gene sequencing of 1) individually sequenced specimens vs. 2) pooled specimens collected from a community. Pool sizes of 10, 20, and 40 are considered. We then compare the gamma-estimates using Pearson{\textquoteright}s correlation as well as using Bland and Altman agreement analysis for three established diversity indices including richness, Simpson{\textquoteright}s and Shannon{\textquoteright}s.

RESULTS: The gamma-diversity estimates are highly correlated, with most being statistically significant. All correlations between all three diversity estimates are significant in the 10-pooled data. Pools comprising 40 specimens are closest to the line of agreement, but all pooled samples and individual samples fall within the 95\% limits of agreement.

CONCLUSIONS: Pooling microbiome samples before DNA amplification and metagenomics sequencing to estimate community-level diversity is a viable measure to consider in population-level association research studies.

}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Bacteria, Biodiversity, Child, Preschool, Female, Gastrointestinal Microbiome, Gastrointestinal Tract, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Metagenomics, Microbiota, Niger, Placebos, RNA, Ribosomal, 16S, Sequence Analysis, DNA}, issn = {1873-2585}, doi = {10.1016/j.annepidem.2019.09.002}, author = {Ray, Kathryn J and Cotter, Sun Y and Arzika, Ahmed M and Kim, Jessica and Boubacar, Nameywa and Zhou, Zhaoxia and Zhong, Lina and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M and Doan, Thuy} } @article {61, title = {Infectious corneal ulceration: a proposal for neglected tropical disease status.}, journal = {Bull World Health Organ}, volume = {97}, year = {2019}, month = {2019 Dec 01}, pages = {854-856}, keywords = {Anti-Bacterial Agents, Bacterial Infections, Corneal Ulcer, Developing Countries, Global Health, Health Promotion, Humans, Leprosy, Neglected Diseases, Onchocerciasis, Ocular, Trachoma}, issn = {1564-0604}, doi = {10.2471/BLT.19.232660}, author = {Ung, Lawson and Acharya, Nisha R and Agarwal, Tushar and Alfonso, Eduardo C and Bagga, Bhupesh and Bispo, Paulo Jm and Burton, Matthew J and Dart, John Kg and Doan, Thuy and Fleiszig, Suzanne Mj and Garg, Prashant and Gilmore, Michael S and Gritz, David C and Hazlett, Linda D and Iovieno, Alfonso and Jhanji, Vishal and Kempen, John H and Lee, Cecilia S and Lietman, Thomas M and Margolis, Todd P and McLeod, Stephen D and Mehta, Jod S and Miller, Darlene and Pearlman, Eric and Prajna, Lalitha and Prajna, N Venkatesh and Seitzman, Gerami D and Shanbhag, Swapna S and Sharma, Namrata and Sharma, Savitri and Srinivasan, Muthiah and Stapleton, Fiona and Tan, Donald Th and Tandon, Radhika and Taylor, Hugh R and Tu, Elmer Y and Tuli, Sonal S and Vajpayee, Rasik B and Van Gelder, Russell N and Watson, Stephanie L and Zegans, Michael E and Chodosh, James} } @article {121, title = {Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa.}, journal = {N Engl J Med}, volume = {380}, year = {2019}, month = {2019 Jun 06}, pages = {2207-2214}, abstract = {

BACKGROUND: The MORDOR I trial (Macrolides Oraux pour R{\'e}duire les D{\'e}c{\`e}s avec un Oeil sur la R{\'e}sistance) showed that in Niger, mass administration of azithromycin twice a year for 2 years resulted in 18\% lower postneonatal childhood mortality than administration of placebo. Whether this benefit could increase with each administration or wane owing to antibiotic resistance was unknown.

METHODS: In the Niger component of the MORDOR I trial, we randomly assigned 594 communities to four twice-yearly distributions of either azithromycin or placebo to children 1 to 59 months of age. In MORDOR II, all these communities received two additional open-label azithromycin distributions. All-cause mortality was assessed twice yearly by census workers who were unaware of participants{\textquoteright} original assignments.

RESULTS: In the MORDOR II trial, the mean ({\textpm}SD) azithromycin coverage was 91.3{\textpm}7.2\% in the communities that received twice-yearly azithromycin for the first time (i.e., had received placebo for 2 years in MORDOR I) and 92.0{\textpm}6.6\% in communities that received azithromycin for the third year (i.e., had received azithromycin for 2 years in MORDOR I). In MORDOR II, mortality was 24.0 per 1000 person-years (95\% confidence interval [CI], 22.1 to 26.3) in communities that had originally received placebo in the first year and 23.3 per 1000 person-years (95\% CI, 21.4 to 25.5) in those that had originally received azithromycin in the first year, with no significant difference between groups (P = 0.55). In communities that had originally received placebo, mortality decreased by 13.3\% (95\% CI, 5.8 to 20.2) when the communities received azithromycin (P = 0.007). In communities that had originally received azithromycin and continued receiving it for an additional year, the difference in mortality between the third year and the first 2 years was not significant (-3.6\%; 95\% CI, -12.3 to 4.5; P = 0.50).

CONCLUSIONS: We found no evidence that the effect of mass administration of azithromycin on childhood mortality in Niger waned in the third year of treatment. Childhood mortality decreased when communities that had originally received placebo received azithromycin. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT02047981.).

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Administration Schedule, Female, Humans, Infant, Infant Mortality, Male, Mass Drug Administration, Niger}, issn = {1533-4406}, doi = {10.1056/NEJMoa1817213}, author = {Keenan, Jeremy D and Arzika, Ahmed M and Maliki, Ramatou and Boubacar, Nameywa and Elh Adamou, Sanoussi and Moussa Ali, Maria and Cook, Catherine and Lebas, Elodie and Lin, Ying and Ray, Kathryn J and O{\textquoteright}Brien, Kieran S and Doan, Thuy and Oldenburg, Catherine E and Callahan, E Kelly and Emerson, Paul M and Porco, Travis C and Lietman, Thomas M} } @article {141, title = {Macrolide Resistance and Longer-Term Assessment of Azithromycin in MORDOR I. Reply.}, journal = {N Engl J Med}, volume = {381}, year = {2019}, month = {2019 11 28}, pages = {2184-2185}, keywords = {Africa, Anti-Bacterial Agents, Azithromycin, Child Mortality, Drug Resistance, Bacterial, Macrolides}, issn = {1533-4406}, doi = {10.1056/NEJMc1910014}, author = {Lietman, Thomas M and Doan, Thuy and Keenan, Jeremy D} } @article {136, title = {Macrolide Resistance in MORDOR I - A Cluster-Randomized Trial in Niger.}, journal = {N Engl J Med}, volume = {380}, year = {2019}, month = {2019 Jun 06}, pages = {2271-2273}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Child, Preschool, Drug Resistance, Bacterial, Humans, Infant, Macrolides, Niger, Pneumococcal Infections, Streptococcus pneumoniae}, issn = {1533-4406}, doi = {10.1056/NEJMc1901535}, author = {Doan, Thuy and Arzika, Ahmed M and Hinterwirth, Armin and Maliki, Ramatou and Zhong, Lina and Cummings, Susie and Sarkar, Samarpita and Chen, Cindi and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M} } @article {131, title = {Neonatal azithromycin administration to prevent infant mortality: study protocol for a randomised controlled trial.}, journal = {BMJ Open}, volume = {9}, year = {2019}, month = {2019 09 04}, pages = {e031162}, abstract = {

INTRODUCTION: Biannual mass azithromycin distribution to children aged 1-59 months has been shown to reduce all-cause mortality. Children under 28 days of age were not treated in studies evaluating mass azithromycin distribution for child mortality due to concerns related to infantile hypertrophic pyloric stenosis (IHPS). Here, we report the design of a randomised controlled trial to evaluate the efficacy and safety of administration of a single dose of oral azithromycin during the neonatal period.

METHODS AND ANALYSIS: The (NAITRE) study is a double-masked randomised placebo-controlled trial designed to evaluate the efficacy of a single dose of azithromycin (20 mg/kg) for the prevention of child mortality. Newborns (n=21 712) aged 8-27 days weighing at least 2500 g are 1:1 randomised to a single, directly observed, oral dose of azithromycin or matching placebo. Participants are followed weekly for 3 weeks after treatment to screen for adverse events, including IHPS. The primary outcome is all-cause mortality at the 6-month study visit.

ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Boards at the University of California, San Francisco in San Francisco, USA (Protocol $\#$18-25027) and the Comit{\'e} National d{\textquoteright}Ethique pour la Recherche in Ouagadougou, Burkina Faso (Protocol $\#$2018-10-123). The findings of this trial will be presented at local, regional and international meetings and published in open access peer-reviewed journals.

TRIAL REGISTRATION NUMBER: NCT03682653; Pre-results.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Body Size, Body Weight, Child Development, Double-Blind Method, Humans, Infant, Infant Mortality, Infant, Newborn, Randomized Controlled Trials as Topic}, issn = {2044-6055}, doi = {10.1136/bmjopen-2019-031162}, author = {Sie, Ali and Bountogo, Mamadou and Nebie, Eric and Ouattara, Mamadou and Coulibaly, Boubacar and Bagagnan, Cheik and Zabre, Pascal and Lebas, Elodie and Brogdon, Jessica and Godwin, William W and Lin, Ying and Porco, Travis and Doan, Thuy and Lietman, Thomas M and Oldenburg, Catherine E} } @article {56, title = {Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa.}, journal = {N Engl J Med}, volume = {378}, year = {2018}, month = {2018 Apr 26}, pages = {1583-1592}, abstract = {

BACKGROUND: We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations.

METHODS: In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses.

RESULTS: A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean ({\textpm}SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4{\textpm}10.4\%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5\% lower overall (95\% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P\<0.001); the rate was 5.7\% lower in Malawi (95\% CI, -9.7 to 18.9), 18.1\% lower in Niger (95\% CI, 10.0 to 25.5), and 3.4\% lower in Tanzania (95\% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9\% lower mortality than that with placebo; 95\% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing.

CONCLUSIONS: Among postneonatal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR ClinicalTrials.gov number, NCT02047981 .).

}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Communicable Disease Control, Communicable Diseases, Drug Resistance, Bacterial, Female, Humans, Infant, Infant Mortality, Malawi, Male, Mass Drug Administration, Niger, Public Health, Tanzania}, issn = {1533-4406}, doi = {10.1056/NEJMoa1715474}, author = {Keenan, Jeremy D and Bailey, Robin L and West, Sheila K and Arzika, Ahmed M and Hart, John and Weaver, Jerusha and Kalua, Khumbo and Mrango, Zakayo and Ray, Kathryn J and Cook, Catherine and Lebas, Elodie and O{\textquoteright}Brien, Kieran S and Emerson, Paul M and Porco, Travis C and Lietman, Thomas M} } @article {226, title = {Diversity of Chlamydia trachomatis in Trachoma-Hyperendemic Communities Treated With Azithromycin.}, journal = {Am J Epidemiol}, volume = {187}, year = {2018}, month = {2018 09 01}, pages = {1840-1845}, abstract = {

Prior studies have theorized that low chlamydial genetic diversity following mass azithromycin treatments for trachoma may create a population bottleneck that prevents the return of infection, but little empirical evidence exists to support this hypothesis. In this study, a single mass azithromycin distribution was administered to 21 communities in the Gurage Zone of Ethiopia in 2003. All children aged 1-5 years had conjunctival swabs performed before treatment and 2 and 6 months after treatment. All swabs positive for Chlamydia trachomatis at 2 months underwent typing of the gene encoding the major outer membrane protein (ompA) of C. trachomatis, as did the same number of swabs per community from the pretreatment and 6-month visits. Diversity of ompA types, expressed as the reciprocal of Simpson{\textquoteright}s index, was calculated for each community. In total, 15 ompA types belonging to the A and B genovars were identified. The mean diversity was 2.11 (95\% confidence interval: 1.79, 2.43) before treatment and 2.16 (95\% confidence interval: 1.76, 2.55) 2 months after treatment (P = 0.78, paired t test). Diversity of ompA was not associated with the prevalence of ocular chlamydia (P = 0.76) and did not predict subsequent changes in the prevalence of ocular chlamydia (P = 0.32). This study found no evidence to support the theory that ompA diversity is associated with transmission of ocular chlamydia.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Bacterial Outer Membrane Proteins, Chlamydia trachomatis, Genetic Variation, Humans, Trachoma}, issn = {1476-6256}, doi = {10.1093/aje/kwy071}, author = {Chin, Stephanie A and Morberg, Daniel P and Alemayehu, Wondu and Melese, Muluken and Lakew, Takele and Chen, Michael C and Zhou, Zhaoxia and Doan, Thuy and Cevallos, Vicky and Lietman, Thomas M and Keenan, Jeremy D} } @article {276, title = {Gut Microbial Diversity in Antibiotic-Naive Children After Systemic Antibiotic Exposure: A Randomized Controlled Trial.}, journal = {Clin Infect Dis}, volume = {64}, year = {2017}, month = {2017 05 01}, pages = {1147-1153}, abstract = {

Background: Antibiotic exposure can alter the gut microbiome. We evaluate the effects of azithromycin on the gut microbiome diversity of children from an antibiotic-naive community in Niger.

Methods: A population-based sample of 80 children aged 1-60 months in the Dosso region of Niger was randomized to receive a single dose of either oral azithromycin or placebo. Fecal samples were collected immediately before treatment and 5 days after treatment for 16S rRNA gene sequencing. The prespecified outcome was α-diversity (inverse Simpson{\textquoteright}s α-diversity index), with secondary outcomes of β and γ Simpson{\textquoteright}s and Shannon{\textquoteright}s diversities.

Results: At 5 days after treatment, 40 children aged 1-60 months were analyzed in the azithromycin-treated group and 40 children in the placebo-treated group. Diversity of the gut microbiome was significantly lower in the treated group (inverse Simpson{\textquoteright}s α-diversity, 5.03; 95\% confidence interval [CI], 4.08-6.14) than in the placebo group (6.91; 95\% CI, 5.82-8.21; P = .03). Similarly, the Shannon{\textquoteright}s α-diversity was lower in the treated group (10.60; 95\% CI, 8.82-12.36) than the placebo group (15.42; 95\% CI, 13.24-17.80; P = .004). Simpson{\textquoteright}s community-level (γ) diversity decreased with azithromycin exposure from 17.72 (95\% CI, 13.80-20.21) to 10.10 (95\% CI, 7.80-11.40; P = .00008), although β-diversity was not significantly reduced (2.56, 95\% CI, 1.88-3.12; to 2.01, 95\% CI, 1.46-2.51; P = .26).

Conclusions: Oral administration of azithromycin definitively decreases the diversity of the gut microbiome of children in an antibiotic-naive community.

Clinical Trials Registration: NCT02048007.

}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Bacteria, Biodiversity, Child, Preschool, Cluster Analysis, DNA, Ribosomal, Female, Gastrointestinal Microbiome, Gastrointestinal Tract, Humans, Infant, Male, Niger, Phylogeny, Placebos, RNA, Ribosomal, 16S, Sequence Analysis, DNA}, issn = {1537-6591}, doi = {10.1093/cid/cix141}, author = {Doan, Thuy and Arzika, Ahmed M and Ray, Kathryn J and Cotter, Sun Y and Kim, Jessica and Maliki, Ramatou and Zhong, Lina and Zhou, Zhaoxia and Porco, Travis C and Vanderschelden, Benjamin and Keenan, Jeremy D and Lietman, Thomas M} }