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1. Large-scale map of RNA-binding protein interactomes across the mRNA life cycle

Author

Street, Lena A, Rothamel, Katherine L, Brannan, Kristopher W, Jin, Wenhao, Bokor, Benjamin J, Dong, Kevin, Rhine, Kevin, Madrigal, Assael, Al-Azzam, Norah, Kim, Jenny Kim, Ma, Yanzhe, Gorhe, Darvesh, Abdou, Ahmed, Wolin, Erica, Mizrahi, Orel, Ahdout, Joshua, Mujumdar, Mayuresh, Doron-Mandel, Ella, Jovanovic, Marko, and Yeo, Gene W

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, 1.1 Normal biological development and functioning, Neurological, Generic health relevance, Humans, RNA, Messenger, RNA-Binding Proteins, Protein Interaction Maps, Protein Binding, HeLa Cells, Protein Interaction Mapping, Ribonucleoproteins, Small Nuclear, HEK293 Cells, Mass Spectrometry, RNA Splicing, Hela Cells, ERH, IP-MS, RBP, RNA-binding proteins, RNA-dependent protein interactions, SEC-MS, SNRNP200, interactome, mRNA life-cycle, protein-protein interactions, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

mRNAs interact with RNA-binding proteins (RBPs) throughout their processing and maturation. While efforts have assigned RBPs to RNA substrates, less exploration has leveraged protein-protein interactions (PPIs) to study proteins in mRNA life-cycle stages. We generated an RNA-aware, RBP-centric PPI map across the mRNA life cycle in human cells by immunopurification-mass spectrometry (IP-MS) of ∼100 endogenous RBPs with and without RNase, augmented by size exclusion chromatography-mass spectrometry (SEC-MS). We identify 8,742 known and 20,802 unreported interactions between 1,125 proteins and determine that 73% of the IP-MS-identified interactions are RNA regulated. Our interactome links many proteins, some with unknown functions, to specific mRNA life-cycle stages, with nearly half associated with multiple stages. We demonstrate the value of this resource by characterizing the splicing and export functions of enhancer of rudimentary homolog (ERH), and by showing that small nuclear ribonucleoprotein U5 subunit 200 (SNRNP200) interacts with stress granule proteins and binds cytoplasmic RNA differently during stress.

Published
2024

2. Efficacy of Single-Dose Azithromycin for Ocular Chlamydial Infection: A Longitudinal Study.

Author

Pondicherry, Neha, Abdou, Amza, Kadri, Boubacar, Nassirou, Beido, Cotter, Sun, Varnado, Nicole, Porco, Travis, West, Sheila, Lietman, Thomas, and Keenan, Jeremy

Subjects
Azithromycin, Humans, Anti-Bacterial Agents, Child, Preschool, Infant, Female, Trachoma, Male, Longitudinal Studies, Chlamydia trachomatis, Treatment Outcome, Chlamydia Infections, Niger, Infant, Newborn
Abstract

Millions of doses of azithromycin are distributed each year for trachoma, yet the treatment efficacy of a single dose of azithromycin for ocular Chlamydia infection has not been well characterized. In this study, four villages in Niger received a mass azithromycin distribution for trachoma. All 426 children aged 0-5 years residing in the study villages were offered conjunctival swabbing every 6 months to test for ocular Chlamydia trachomatis. Among the children infected with ocular Chlamydia before treatment, 6% (95% CI: 2-15%) tested positive for ocular Chlamydia infection 6 months later, and 15% (95% CI: 7-28%) tested positive 12 months later. The most important predictor of post-treatment ocular Chlamydia infection was pretreatment ocular Chlamydia infection (relative risk: 3.5, 95% CI: 1.3-9.4). Although the 6-monthly monitoring schedule was suboptimal for testing the treatment efficacy of an antibiotic, these findings are nonetheless consistent with high treatment efficacy of a single dose of azithromycin and suggest that additional interventions might be most effective if targeted to those children infected prior to treatment.

Published
2024

3. Prolonged mass azithromycin distributions and macrolide resistance determinants among preschool children in Niger: A sub-study of a cluster-randomized trial (MORDOR).

Author

Arzika, Ahmed, Abdou, Amza, Maliki, Ramatou, Beido, Nassirou, Kadri, Boubacar, Harouna, Abdoul, Galo, Abdoul, Alio, Mankara, Lebas, Elodie, Oldenburg, Catherine, OBrien, Kieran, Chen, Cindi, Zhong, Lina, Zhou, Zhaoxia, Yan, Daisy, Hinterwirth, Armin, Doan, Thuy, Porco, Travis, Keenan, Jeremy, and Lietman, Thomas

Subjects
Humans, Azithromycin, Niger, Child, Preschool, Anti-Bacterial Agents, Infant, Female, Drug Resistance, Bacterial, Male, Macrolides, Mass Drug Administration, Child Mortality
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 Réduire les Décès avec un Oeil sur la Résistance (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.

Published
2024

4. District-Level Forecast of Achieving Trachoma Elimination as a Public Health Problem By 2030: An Ensemble Modelling Approach.

Author

Srivathsan, Ariktha, Abdou, Amza, Al-Khatib, Tawfik, Apadinuwe, Sue-Chen, Badiane, Mouctar, Bucumi, Victor, Chisenga, Tina, Kabona, George, Kabore, Martin, Kanyi, Sarjo, Bella, Lucienne, Mpo, Nekoua, Masika, Michael, Minnih, Abdellahi, Sitoe, Henis, Mishra, Sailesh, Olobio, Nicholas, Omar, Fatma, Phiri, Isaac, Sanha, Salimato, Seife, Fikre, Sharma, Shekhar, Tekeraoi, Rabebe, Traore, Lamine, Watitu, Titus, Bol, Yak, Borlase, Anna, Deiner, Michael, Renneker, Kristen, Hooper, P, Emerson, Paul, Vasconcelos, Andreia, Arnold, Benjamin, Porco, Travis, Hollingsworth, T, Lietman, Thomas, and Blumberg, Seth

Subjects
Trachoma, Humans, Child, Preschool, Infant, Child, Disease Eradication, Prevalence, Forecasting, Public Health, Models, Statistical, Mass Drug Administration, World Health Organization, Global Health, Male, Female
Abstract

Assessing the feasibility of 2030 as a target date for global elimination of trachoma, and identification of districts that may require enhanced treatment to meet World Health Organization (WHO) elimination criteria by this date are key challenges in operational planning for trachoma programmes. Here we address these challenges by prospectively evaluating forecasting models of trachomatous inflammation-follicular (TF) prevalence, leveraging ensemble-based approaches. Seven candidate probabilistic models were developed to forecast district-wise TF prevalence in 11 760 districts, trained using district-level data on the population prevalence of TF in children aged 1-9 years from 2004 to 2022. Geographical location, history of mass drug administration treatment, and previously measured prevalence data were included in these models as key predictors. The best-performing models were included in an ensemble, using weights derived from their relative likelihood scores. To incorporate the inherent stochasticity of disease transmission and challenges of population-level surveillance, we forecasted probability distributions for the TF prevalence in each geographic district, rather than predicting a single value. Based on our probabilistic forecasts, 1.46% (95% confidence interval [CI]: 1.43-1.48%) of all districts in trachoma-endemic countries, equivalent to 172 districts, will exceed the 5% TF control threshold in 2030 with the current interventions. Global elimination of trachoma as a public health problem by 2030 may require enhanced intervention and/or surveillance of high-risk districts.

Published
2024

5. Comparison of Population-Based Census versus Birth History for the Estimation of Under-5 Mortality in Niger.

Author

Peterson, Brittany, Arzika, Ahmed, Amza, Abdou, Karamba, Alio, Dodo, Nasser, Galo, Nasser, Beidi, Aboubacar, Moustapha, Abarchi, Lebas, Elodie, Cook, Catherine, Keenan, Jeremy, OBrien, Kieran, and Lietman, Thomas

Subjects
Child, Humans, Infant, Child, Preschool, Reproductive History, Niger, Censuses, Child Mortality, Mass Drug Administration, Mortality
Abstract

The WHO guidelines on mass distribution of azithromycin for child survival recommend monitoring of mortality to evaluate effectiveness. Trials that contributed evidence to these guidelines used a population-based census to monitor vital status, requiring census workers to visit each household biannually (twice yearly). Birth history is an alternative to the census approach that may be more feasible because it decreases the time and labor needed for mortality monitoring. This study aimed to compare the population-based census (reference standard) and birth history (index test) approaches to estimating mortality among children 1 to 59 months old using data from the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial. Sixteen communities that received 5 years of biannual census in the MORDOR trial were selected randomly also to receive birth history surveys. The census approach recorded more participants and households than birth history, with correlations more than 0.94 for each. The correlation between number of deaths in each community was 0.84 (95% CI, 0.59-0.94). A comparison of the mortality incidence rate estimated from the census against the under-5 mortality rate estimated from the birth history resulted in a correlation of 0.60 (95% CI, 0.15-0.84). Of the 47% of children who were linked individually to compare vital status from each method, the death status of children had a sensitivity of 80% (95% CI, 73-89) and a specificity of 98% (95% CI, 98-99), comparing birth history to census. Overall birth histories were found to be a reasonable alternative to biannual census for tracking vital status.

Published
2023

6. Comprehensive Profile of Pathogens and Antimicrobial Resistance in Conjunctivitis Cases from Niger.

Author

Amza, Abdou, Nassirou, Beido, Kadri, Boubacar, Ali, Saley, Mariama, Boubacar, Ibrahim, Cissé, Roufaye, Lamine, Lebas, Elodie, Colby, Emily, Zhong, Lina, Chen, Cindi, Ruder, Kevin, Yu, Danny, Liu, YuHeng, Abraham, Thomas, Chang, Aaron, Mai, Lina, Hinterwirth, Armin, Seitzman, Gerami, Lietman, Thomas, and Doan, Thuy

Subjects
Humans, Anti-Bacterial Agents, Respiratory Tract Infections, Niger, Coinfection, Epstein-Barr Virus Infections, Drug Resistance, Bacterial, Herpesvirus 4, Human, Conjunctivitis
Abstract

Infectious conjunctivitis outbreaks remain a public health burden. This study focuses on the pathogen and antimicrobial resistance (AMR) profiles identified in Niger. Sixty-two patients with acute infectious conjunctivitis who presented to health posts were enrolled from December 2021 to May 2022. Nasal and conjunctival swabs were obtained from each patient. Unbiased RNA deep sequencing (RNA-seq) was used to identify associated pathogens. A pathogen was identified in 39 patients (63%; 95% CI, 50-74). Of those, an RNA virus was detected in 23 patients (59%; 95% CI, 43-73). RNA viruses were diverse and included human coronaviruses (HCoVs): SARS-CoV-2, HCoV-229E, HCoV-HKU1, and HCoV-OC43. A DNA virus was identified in 11 patients (28%; 95% CI, 17-44). Of those, four patients had a coinfection with an RNA virus and two patients had a coinfection with both an RNA virus and a bacterium. DNA viruses were predominantly human herpesvirus (cytomegalovirus, Epstein-Barr virus, human herpesvirus 8) and human adenovirus species B, C, and F. Eighteen patients (46%; 95% CI, 32-61) had a bacteria-associated infection that included Haemophilus influenza, Haemophilus aegyptius, Staphylococcus aureus, Streptococcus pneumoniae, and Moraxella spp. Antimicrobial resistance determinants were detected in either the conjunctiva or nasal samples of 20 patients (32%; 95% CI, 22-45) and were found to be more diverse in the nose (Shannon alpha diversity, 1.12 [95% CI, 1.05-1.26] versus 1.02 [95% CI, 1.00-1.05], P = 0.01). These results suggest the potential utility of leveraging RNA-seq to surveil pathogens and AMR for ocular infections.

Published
2023

7. Temporal Trends in Phenotypic Macrolide and Nonmacrolide Resistance for Streptococcus pneumoniae Nasopharyngeal Samples Up to 36 Months after Mass Azithromycin Administration in a Cluster-Randomized Trial in Niger.

Author

Hazel, Ashley, Arzika, Ahmed, Abdou, Amza, Lebas, Elodie, Porco, Travis, Maliki, Ramatou, Doan, Thuy, Keenan, Jeremy, Blumberg, Seth, and Lietman, Thomas

Subjects
Child, Humans, Infant, Azithromycin, Anti-Bacterial Agents, Macrolides, Streptococcus pneumoniae, Mass Drug Administration, Niger, Drug Resistance, Bacterial
Abstract

Azithromycin mass drug administration decreases child mortality but also selects for antibiotic resistance. Herein, we evaluate macrolide resistance of nasopharyngeal Streptococcus pneumoniae after azithromycin MDA. In a cluster-randomized trial, children 1-59 months received azithromycin or placebo biannually. Fifteen villages from each arm were randomly selected for antimicrobial resistance testing, and 10-15 randomly selected swabs from enrolled children at each village were processed for S. pneumoniae isolation and resistance testing. The primary prespecified outcome was macrolide resistance fraction for azithromycin versus placebo villages at 36 months. Secondary non-prespecified outcomes were comparisons of azithromycin and placebo for: 1) macrolide resistance at 12, 24, and 36 months; 2) nonmacrolide resistance at 36 months; and 3) suspected-erm mutation. At 36 months, 423 swabs were obtained and 322 grew S. pneumoniae, (azithromycin: 146/202, placebo: 176/221). Mean resistance prevalence was non-significantly higher in treatment than placebo (mixed-effects model: 14.6% vs. 8.9%; OR = 2.0, 95% CI: 0.99-3.97). However, when all time points were evaluated, macrolide resistance prevalence was significantly higher in the azithromycin group (β = 0.102, 95% CI: 0.04-0.167). For all nonmacrolides, resistance prevalence at 36 months was not different between the two groups. Azithromycin and placebo were not different for suspected-erm mutation prevalence. Macrolide resistance was higher in the azithromycin group over all time points, but not at 36 months. Although this suggests resistance may not continue to increase after biannual MDA, more studies are needed to clarify when MDA can safely decrease mortality and morbidity in lower- and middle-income countries.

Published
2023

8. Wastewater-Based Surveillance of Antimicrobial Resistance in Niger: An Exploratory Study.

Author

Ousmane, Sani, Kollo, Issifi, Jambou, Ronan, Boubacar, Rakia, Arzika, Ahmed, Maliki, Ramatou, Amza, Abdou, Liu, Zijun, Lebas, Elodie, Colby, Emily, Zhong, Lina, Chen, Cindi, Hinterwirth, Armin, Doan, Thuy, OBrien, Kieran, and Lietman, Thomas

Subjects
Humans, Anti-Bacterial Agents, Drug Resistance, Bacterial, Wastewater-Based Epidemiological Monitoring, Wastewater, Niger
Abstract

Wastewater-based surveillance is increasingly recognized as an important approach to monitoring population-level antimicrobial resistance (AMR). In this exploratory study, we examined the use of metagenomics to evaluate AMR using untreated wastewater samples routinely collected by the Niger national polio surveillance program. Forty-eight stored samples from two seasons each year over 4 years (2016-2019) in three regions were selected for inclusion in this study and processed using unbiased DNA deep sequencing. Normalized number of reads of genetic determinants for different antibiotic classes were compared over time, by season, and by location. Correlations in resistance were examined among classes. Changes in reads per million per year were demonstrated for several classes, including decreases over time in resistance determinants for phenicols (-3.3, 95% CI: -8.7 to -0.1, P = 0.029) and increases over time for aminocoumarins (3.8, 95% CI: 0.0 to 11.4, P = 0.043), fluoroquinolones (6.8, 95% CI: 0.0 to 20.5, P = 0.048), and beta-lactams (0.85, 95% CI: 0.1 to 1.7, P = 0.006). Sulfonamide resistance was higher in the post-rainy season compared with the dry season (5.2-fold change, 95% CI: 3.4 to 7.9, P < 0.001). No differences were detected when comparing other classes by season or by site for any antibiotic class. Positive correlations were identified in genetic determinants of resistance among several antibiotic classes. These results demonstrate the potential utility of leveraging existing wastewater sample collection in this setting for AMR surveillance.

Published
2023

9. Monitoring transmission intensity of trachoma with serology.

Author

Tedijanto, Christine, Solomon, Anthony W, Martin, Diana L, Nash, Scott D, Keenan, Jeremy D, Lietman, Thomas M, Lammie, Patrick J, Aiemjoy, Kristen, Amza, Abdou, Aragie, Solomon, Arzika, Ahmed M, Callahan, E Kelly, Carolan, Sydney, Dawed, Adisu Abebe, Goodhew, E Brook, Gwyn, Sarah, Hammou, Jaouad, Kadri, Boubacar, Kalua, Khumbo, Maliki, Ramatou, Nassirou, Beido, Seife, Fikre, Tadesse, Zerihun, West, Sheila K, Wittberg, Dionna M, Zeru Tadege, Taye, and Arnold, Benjamin F

Subjects
Humans, Chlamydia trachomatis, Trachoma, Antibodies, Bacterial, Antigens, Bacterial, Prevalence, Seroepidemiologic Studies, Child, Child, Preschool, Infant, Pediatric Research Initiative, Eye Disease and Disorders of Vision, Infectious Diseases, Detection, screening and diagnosis, Aetiology, 2.2 Factors relating to the physical environment, 4.1 Discovery and preclinical testing of markers and technologies, Infection, Good Health and Well Being
Abstract

Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.87, 95% CI: 0.57, 0.97). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any PCR-identified infection at high sensitivity ( >90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination.

Published
2023

10. Deep sequencing analysis of clinical samples from patients with acute infectious conjunctivitis during the COVID-19 delta surge in Madurai, India

Author

Lalitha, Prajna, Prajna, N Venkatesh, Gunasekaran, Rameshkumar, Teja, Gonugunta Vishnu, Sharma, Sankalp S, Hinterwirth, Armin, Ruder, Kevin, Zhong, Lina, Chen, Cindi, Deiner, Michael, Huang, ChunHong, Pinsky, Benjamin A, Lietman, Thomas M, Doan, Thuy, Seitzman, Gerami D, Prajna, Lalitha, Venkatesh Prajna, N, Gunasekaran, Ramesh, Sharma, Sankalp Singh, Teja, Vishnu, Chaudhary, Meenu, Sitaula, Sanjeeta, Sié, Ali, Coulibaly, Boubacar, Bountogo, Mamadou, Somkijrungroj, Thanapong, Satitpitakul, Vannarut, Tran, Huy, Mai, Linh Hoàng, Xuân, Thảo Hạ, Tran, Yen, Urzua, Cristhian A, Vega, Fabian, Salgado, Felipe, Cuitino, Loreto, Lopez, Emiliano Sebastian, Gimeno, Federico Luengo, Jaeschke, Tomas, Pérez, Fernando Pérez, Martínez, Jaime Macías, Lansingh, Van Charles, Thanapaisal, Sukhumal, Laovirojjanakul, Wipada, McKie, George, Chavez, Kenia, Redd, Travis, Chamberlain, Winston, Cheng, Angel, Tham, Vivien, Sansanayudh, Wiwan, Yakoura, Abba Kaka Hajia, Amza, Abdou, Souley, Abdoul Salam Youssoufou, Diori, Adam Nouhou, Nassirou, Beido, Kadri, Boubacar, Mariama, Boubacar, Ibrahim, Cissé Mamadou, Roufaye, Lamyne Aboubacar, Boulhassane, Ramatou, Ali, Saley, Abdou, Zakou, Goren, Lee, Sella, Ruti, Kelliher, Clare, Green, Laura, Ong, Hon Shing, Mehta, Jod, Liu, Yu-Chi, Hwang, De-Kuang, Fan, Nai-Wen, Chiong, Hong Sheng, Lacorzana, Javier, Cabrera-Aguas, Maria, Watson, Stephanie, Tsui, Edmund, Ramirez, Joana, Cherian, Nina M, Feit-Leichman, Rachel, Hughes, Reginald E, Onclinx, Tania, Yu, Carol, McClean, Esmeralda, Molina, Iliana, Yu, Danny, Liu, David, Lebas, Elodie, Colby, Emily, Seitzman, Gerami, Abraham, Thomas, Lietman, Thomas, Porco, Travis, and McLeod, Stephen

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Clinical Trials and Supportive Activities, Emerging Infectious Diseases, Infectious Diseases, Vaccine Related, Eye Disease and Disorders of Vision, Infection, Good Health and Well Being, Humans, COVID-19, SARS-CoV-2, Prospective Studies, India, Conjunctivitis, Adenoviruses, Human, Acute Disease, High-Throughput Nucleotide Sequencing, SCORPIO (Seasonal Conjunctivitis Outbreak Reporting for Prevention and Improved Outcomes) Study Group, Microbiology, Medical Microbiology, Virology, Clinical sciences, Medical microbiology
Abstract

BackgroundSeasonal outbreaks of infectious conjunctivitis remain a public health issue. Determination of outbreak etiologies in the context of a worldwide pandemic may provide useful information to guide public health strategies. The aim of this study was to identify pathogens associated with outpatient infectious conjunctivitis during the COVID-19 Delta surge.MethodsThis prospective study was conducted from April 2021 to September 2021. All outpatients presenting to the Aravind Eye Center (Madurai, India) with signs and symptoms consistent with acute infectious conjunctivitis were eligible. Three swabs were obtained from each participant: one from each conjunctiva and one from the anterior nares. Samples were processed for metagenomic RNA deep sequencing (RNA-seq).ResultsSamples from 106 study participants were sequenced. The most common presenting symptoms were tearing (86%) and itching (71%). Preauricular lymphadenopathy was present in 38% of participants. 20% of participants had close contacts with similar symptoms. Systemic symptoms such as coughing, runny nose, vomiting or diarrhea were uncommonly reported. 60% of all participants used some medicated eye drops upon enrollment. 75% of study participants demonstrated infection with human adenovirus D (HAdV-D). 11% of conjunctivitis was associated with SARS-CoV-2. 15% had no definitive pathogen detected. 8% of all participants had codetection of more than one pathogen on RNA-seq.ConclusionsDuring the COVID-19 Delta surge in India, HAdV-D was the most common pathogen associated with infectious conjunctivitis. SARS-CoV-2 was the second most common associated pathogen. Seasonal surveillance may be necessary for the determination of emerging and reemerging pathogens responsible for infectious conjunctivitis.

Published
2022

11. Adipocytes Encapsulating Telratolimod Recruit and Polarize Tumor‐Associated Macrophages for Cancer Immunotherapy

Author

Wen, Di, Liang, Tingxizi, Chen, Guojun, Li, Hongjun, Wang, Zejun, Wang, Jinqiang, Fu, Ruxing, Han, Xiao, Ci, Tianyuan, Zhang, Yuqi, Abdou, Peter, Li, Ruoxin, Bu, Linlin, Dotti, Gianpietro, and Gu, Zhen

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Humans, Tumor-Associated Macrophages, Macrophages, Immunotherapy, Melanoma, Adipocytes, Tumor Microenvironment, adipocyte, cancer immunotherapy, drug delivery, macrophage
Abstract

Tumor-associated adipocytes (TAAs) recruit monocytes and promote their differentiation into tumor-associated macrophages (TAMs) that support tumor development. Here, TAAs are engineered to promote the polarization of TAMs to the tumor suppressive M1 phenotype. Telratolimod, a toll-like receptor 7/8 agonist, is loaded into the lipid droplets of adipocytes to be released at the tumor site upon tumor cell-triggered lipolysis. Locally administered drug-loaded adipocytes increased tumor suppressive M1 macrophages in both primary and distant tumors and suppressed tumor growth in a melanoma model. Furthermore, drug-loaded adipocytes improved CD8+ T cell-mediated immune responses within the tumor microenvironment and favored dendritic cell maturation in the tumor draining lymph nodes.

Published
2023

12. Simplified dosing of oral azithromycin for children 1–11 months old in child survival programmes: age-based and height-based dosing protocols

Author

Hu, Huiyu, Arzika, Ahmed Mamane, Sie, Ali, Abdou, Amza, Maliki, Ramatou, Mankara, Alio Karamba, Outtara, Mamadou, Bountogo, Mamadou, Boudo, Valentin, Yago-Wienne, Fanny, Bamba, Issouf, Knirsch, Charles, Emerson, Paul, Hooper, PJ, Lebas, Elodie, Brogdon, Jessica, Nyatigo, Fanice, Oldenburg, Catherine E, Lietman, Thomas M, and O'Brien, Kieran S

Subjects
Health Services and Systems, Public Health, Health Sciences, Pediatric, Clinical Research, Clinical Trials and Supportive Activities, Good Health and Well Being, Anti-Bacterial Agents, Azithromycin, Body Height, Child, Child Mortality, Humans, Infant, Trachoma, child health, public health, Health services and systems, Public health
Abstract

BackgroundTo facilitate mass distribution of azithromycin, trachoma control programmes use height instead of weight to determine dose for children 6 months to 15 years old. WHO has recommended azithromycin distribution to children 1-11 months old to reduce mortality in high mortality settings under carefully monitored conditions. Weight was used to determine dose in children 1-5 months old in studies of azithromycin distribution for child survival, but a simplified approach using age or height for all aged 1-11 months old could increase programme efficiency in real-world settings.MethodsThis secondary analysis used data from two cluster randomised trials of azithromycin distribution for child mortality in Niger and Burkina Faso. An exhaustive search algorithm was developed to determine the optimal dose for different age groups, using tolerance limits of 10-20 mg/kg for children 1-2 months old and 15-30 mg/kg for children 3-11 months old. Height-based dosing was evaluated against the existing trachoma dosing pole and with a similar exhaustive search.ResultsThe optimal two-tiered age-based approach suggested a dose of 80 mg (2 mL) for children 1-2 months old and 160 mg (4 mL) for children 3-11 months old. Under this schedule, 89%-93% of children would have received doses within tolerance limits in both study populations. Accuracy was 93%-94% with a three-tiered approach, which resulted in doses of 80 mg (2 mL), 120 mg (3 mL) and 160 mg (4 mL) for children 1-2, 3-4 and 5-11 months old, respectively. For children 1-5 months old, the existing height pole would result in 70% of doses within tolerance limits. The optimisation identified height-based dosing options with 95% accuracy, although this would require changes to the existing dosing pole as well as additional training to measure infants lying flat.ConclusionsOverall, an age-based approach with two age tiers resulted in high accuracy while considering both concerns about overdosing in this young population and simplicity of field operations.

Published
2022

13. Impact of biannual mass azithromycin treatment on enteropathogen carriage in children younger than 5 years in Niger

Author

Platts-Mills, James A, Ayoub, Elias, Zhang, Jixian, McQuade, Elizabeth T Rogawski, Arzika, Ahmed Mamane, Maliki, Ramatou, Abdou, Amza, Keenan, Jeremy D, Lietman, Thomas M, Liu, Jie, and Houpt, Eric R

Subjects
Emerging Infectious Diseases, Infectious Diseases, Clinical Trials and Supportive Activities, Biotechnology, Clinical Research, Good Health and Well Being, Anti-Bacterial Agents, Azithromycin, Child, Child, Preschool, Humans, Infant, Mass Drug Administration, Niger, Prevalence, enteropathogens, Shigella, Shigella, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

We analyzed samples obtained at baseline and 24 months in a mass azithromycin administration trial in Niger using quantitative polymerase chain reaction. In villages randomized to azithromycin, Shigella was the only pathogen reduced at 24 months (prevalence ratio, 0.36 [95% confidence interval: .17-.79]; difference in log quantity, -.42 [-.75 to -.10]).

Published
2022

14. Multi-ethnic genome-wide association analyses of white blood cell and platelet traits in the Population Architecture using Genomics and Epidemiology (PAGE) study

Author

Hu, Yao, Bien, Stephanie A, Nishimura, Katherine K, Haessler, Jeffrey, Hodonsky, Chani J, Baldassari, Antoine R, Highland, Heather M, Wang, Zhe, Preuss, Michael, Sitlani, Colleen M, Wojcik, Genevieve L, Tao, Ran, Graff, Mariaelisa, Huckins, Laura M, Sun, Quan, Chen, Ming-Huei, Mousas, Abdou, Auer, Paul L, Lettre, Guillaume, Tang, Weihong, Qi, Lihong, Thyagarajan, Bharat, Buyske, Steve, Fornage, Myriam, Hindorff, Lucia A, Li, Yun, Lin, Danyu, Reiner, Alexander P, North, Kari E, Loos, Ruth JF, Raffield, Laura M, Peters, Ulrike, Avery, Christy L, and Kooperberg, Charles

Subjects
Clinical Research, Hematology, Genetics, American Indian or Alaska Native, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Leukocytes, Phenotype, Polymorphism, Single Nucleotide, GWAS, White blood cells, Platelets, Multi-ethnic, Blood Cell Consortium, Biological Sciences, Information and Computing Sciences, Medical and Health Sciences, Bioinformatics
Abstract

BackgroundCirculating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented.ResultsWe performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations.ConclusionsOur results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.

Published
2021

15. Azithromycin Reduction to Reach Elimination of Trachoma (ARRET): study protocol for a cluster randomized trial of stopping mass azithromycin distribution for trachoma

Author

Amza, Abdou, Kadri, Boubacar, Nassirou, Beido, Arzika, Ahmed M, Austin, Ariana, Nyatigo, Fanice, Lebas, Elodie, Arnold, Benjamin F, Lietman, Thomas M, and Oldenburg, Catherine E

Subjects
Clinical Trials and Supportive Activities, Eye Disease and Disorders of Vision, Clinical Research, Good Health and Well Being, Anti-Bacterial Agents, Azithromycin, Chlamydia trachomatis, Humans, Infant, Prevalence, Randomized Controlled Trials as Topic, Trachoma, Pediatric Research Initiative, Infectious Diseases, Pediatric, Prevention, Aetiology, 2.4 Surveillance and distribution, Infection, Adolescent, Anti-Infective Agents, Antibodies, Bacterial, Child, Child, Preschool, Cross-Sectional Studies, Endemic Diseases, Eye Infections, Bacterial, Female, Follow-Up Studies, Forecasting, Male, Nepal, Population Surveillance, Retrospective Studies, Withholding Treatment, Mass drug administration, Neglected tropical diseases, Opthalmology and Optometry, Ophthalmology & Optometry
Abstract

BackgroundThe World Health Organization (WHO) recommends annual mass azithromycin distribution until districts drop below 5% prevalence of trachomatous inflammation-follicular (TF). Districts with very low TF prevalence may have little or no transmission of the ocular strains of Chlamydia trachomatis that cause trachoma, and additional rounds of mass azithromycin distribution may not be useful. Here, we describe the protocol for a randomized controlled trial designed to evaluate whether mass azithromycin distribution can be stopped prior to the current WHO guidelines.MethodsThe Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) study is a 1:1 community randomized non-inferiority trial designed to evaluate whether mass azithromycin distribution can be stopped in districts with baseline prevalence of TF under 20%. Communities in Maradi, Niger are randomized after baseline assessment either to continued annual mass azithromycin distribution or stopping annual azithromycin distribution over a 3-year period. We will compare the prevalence of ocular C. trachomatis (primary outcome), TF and other clinical signs of trachoma, and serologic markers of trachoma after 3 years. We hypothesize that stopping annual azithromycin distribution will be non-inferior to continued annual azithromycin distributions for all markers of trachoma prevalence and transmission.DiscussionThe results of this trial are anticipated to provide potentially guideline-changing evidence for when mass azithromycin distributions can be stopped in low TF prevalence areas. TRIAL REGISTRATION NUMBER: This study is registered at clinicaltrials.gov ( NCT04185402 ). Registered December 4, 2019; prospectively registered pre-results.

Published
2021

16. Gut resistome of preschool children after prolonged mass azithromycin distribution: a cluster-randomized trial

Author

Arzika, Ahmed M, Maliki, Ramatou, Abdou, Amza, Mankara, Alio K, Harouna, Abdoul N, Cook, Catherine, Hinterwirth, Armin, Worden, Lee, Zhong, Lina, Chen, Cindi, Ruder, Kevin, Zhou, Zhaoxia, Lebas, Elodie, O’Brien, Kieran S, Oldenburg, Catherine E, Le, Victoria, Arnold, Benjamin F, Porco, Travis, Keenan, Jeremy D, Lietman, Thomas M, and Doan, Thuy

Subjects
Clinical Trials and Supportive Activities, Pediatric, Antimicrobial Resistance, Clinical Research, Anti-Bacterial Agents, Azithromycin, Child, Preschool, Drug Resistance, Bacterial, Humans, Macrolides, Mass Drug Administration, azithromycin, antibiotic resistance, gut resistome, mass drug distribution, Niger, preschool children, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

We evaluated the gut resistome of children from communities treated with 10 twice-yearly azithromycin distributions. Although the macrolide resistance remained higher in the azithromycin arm, the selection of non-macrolide resistance observed at earlier time points did not persist. Longitudinal resistance monitoring should be a critical component of mass distribution programs.Clinical trials registrationNCT02047981.

Published
2021

17. Can we eradicate trachoma? A survey of stakeholders.

Author

Oldenburg, Catherine E, Aragie, Solomon, Amza, Abdou, Solomon, Anthony W, Brogdon, Jessica, Arnold, Benjamin F, Keenan, Jeremy D, and Lietman, Thomas M

Subjects
Humans, Trachoma, Azithromycin, Anti-Bacterial Agents, Health Care Surveys, Prevalence, Preventive Health Services, Health Plan Implementation, World Health Organization, Disease Eradication, Global Health, Cornea, Epidemiology, Infection, Public health, Eye Disease and Disorders of Vision, Clinical Research, Good Health and Well Being, Clinical Sciences, Opthalmology and Optometry, Public Health and Health Services, Ophthalmology & Optometry
Abstract

Background/aimsAlthough tremendous progress towards the 2020 goal of global elimination of trachoma as a public health problem has been made, it will not be achieved. Future targets are now being considered. One option is changing the goal to eradication. We surveyed trachoma experts to assess beliefs related to trachoma eradication and determine perceived obstacles to achieving it.MethodsWe conducted a survey at the beginning of a trachoma eradication session at the 2019 Coalition for Operational Research on Neglected Tropical Diseases meeting in National Harbor, Maryland, USA. We asked respondents what the most important goal of azithromycin mass drug administration was for trachoma (control, elimination of infection or eradication) and if and when they believed trachoma eradication would occur. We then asked what the biggest obstacles were to global eradication.ResultsFifty-six surveys were returned (95%). Most (91%) participants reported that the most important goal of azithromycin mass drug administration was control or elimination of infection, and 24% of participants reported that global eradication was not possible. Of the 76% who reported a year by which they believed trachoma could be eradicated, most fell between 2040 and 2050. Commonly cited barriers to global eradication included lack of surveillance tools to confirm eradication or monitor for infection recrudescence (32%) and lack of resources (23%).ConclusionsDevelopment of alternative indicators for trachoma surveillance and continued investment in trachoma programmes, particularly focused support in the most heavily affected populations, might increase enthusiasm for the feasibility of eradication.

Published
2021

18. Age-based targeting of biannual azithromycin distribution for child survival in Niger: an adaptive cluster-randomized trial protocol (AVENIR).

Author

O'Brien, Kieran S, Arzika, Ahmed M, Amza, Abdou, Maliki, Ramatou, Ousmane, Sani, Kadri, Boubacar, Nassirou, Beido, Mankara, Alio Karamba, Harouna, Abdoul Naser, Colby, Emily, Lebas, Elodie, Liu, Zijun, Le, Victoria, Nguyen, William, Keenan, Jeremy D, Oldenburg, Catherine E, Porco, Travis C, Doan, Thuy, Arnold, Benjamin F, Lietman, Thomas M, and AVENIR Study Group

Subjects
AVENIR Study Group, Humans, Macrolides, Azithromycin, Anti-Bacterial Agents, Drug Resistance, Bacterial, Child, Child, Preschool, Infant, Niger, Randomized Controlled Trials as Topic, Mass Drug Administration, Adaptive trial, Cluster-randomized trial, Mass drug administration, Mortality, Public Health, Public Health and Health Services
Abstract

BackgroundBiannual 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.MethodsAVENIR 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.DiscussionAs 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 registrationThis trial was registered on January 13, 2020 (clinicaltrials.gov: NCT04224987 ).

Published
2021

19. Small and sick newborn care during the COVID-19 pandemic: global survey and thematic analysis of healthcare providers’ voices and experiences

Author

Rao, Suman PN, Minckas, Nicole, Medvedev, Melissa M, Gathara, David, Prashantha, YN, Estifanos, Abiy Seifu, Silitonga, Alfrida Camelia, Jadaun, Arun Singh, Adejuyigbe, Ebunoluwa A, Brotherton, Helen, Arya, Sugandha, Gera, Rani, Ezeaka, Chinyere V, Gai, Abdou, Gobezayehu, Abebe Gebremariam, Dube, Kumar, Aarti, Naburi, Helga, Chiume, Msandeni, Tumukunde, Victor, Medhanyie, Araya Abrha, Plange-Rhule, Gyikua, Shabini, Josephine, Ohuma, Eric O, Tadele, Henok, W/Gebriel, Fitsum, Hadgu, Amanuel, Alamineh, Lamesgin, Mehta, Rajesh, Molyneux, Elizabeth, Lawn, Joy E, Agyeman, Irene, Newton, Sam, Wireko-Brobby, Naana, Chellani, Harish, Kawaza, Kondwani, Adejuyigbe, Ebunoluwa, Anyabolu, Henry, Ugowe, Osagie, Massawe, Augustine, Irimu, Grace, Ezeaka, Chinyere, Salim, Nahya, Cross, James, Ohuma, Eric, Mambule, Ivan, Medvedev, Melissa, Tann, Cally, Waiswa, Peter, Woldegebriel, Fitsum, Mazumder, Sarmila, Bhandari, Nita, Rao, PN Suman, Cunningham, Troy, Rai, Prathibha, Kumar, Rashmi, Prakash, Ved, Singh, Vinay Pratap, Kumar, Vishwajeet, Bahl, Rajiv, and Yoshida, Sachiyo

Subjects
Health Services, Pediatric, Prevention, Clinical Research, Generic health relevance, Reproductive health and childbirth, Good Health and Well Being, Breast Feeding, COVID-19, Cross-Sectional Studies, Female, Health Personnel, Humans, Infant Care, Infant, Newborn, Kangaroo-Mother Care Method, Pandemics, Pregnancy, SARS-CoV-2, Surveys and Questionnaires, COVID-19 Small and Sick Newborn Care Collaborative Group, SARS, cross-sectional survey, paediatrics, public health
Abstract

The COVID-19 pandemic is disrupting health systems globally. Maternity care disruptions have been surveyed, but not those related to vulnerable small newborns. We aimed to survey reported disruptions to small and sick newborn care worldwide and undertake thematic analysis of healthcare providers' experiences and proposed mitigation strategies. Using a widely disseminated online survey in three languages, we reached out to neonatal healthcare providers. We collected data on COVID-19 preparedness, effects on health personnel and on newborn care services, including kangaroo mother care (KMC), as well as disruptors and solutions. We analysed 1120 responses from 62 countries, mainly low and middle-income countries (LMICs). Preparedness for COVID-19 was suboptimal in terms of guidelines and availability of personal protective equipment. One-third reported routine testing of all pregnant women, but 13% had no testing capacity at all. More than 85% of health personnel feared for their own health and 89% had increased stress. Newborn care practices were disrupted both due to reduced care-seeking and a compromised workforce. More than half reported that evidence-based interventions such as KMC were discontinued or discouraged. Separation of the mother-baby dyad was reported for both COVID-positive mothers (50%) and those with unknown status (16%). Follow-up care was disrupted primarily due to families' fear of visiting hospitals (~73%). Newborn care providers are stressed and there is lack clarity and guidelines regarding care of small newborns during the pandemic. There is an urgent need to protect life-saving interventions, such as KMC, threatened by the pandemic, and to be ready to recover and build back better.

Published
2021

20. Stopping azithromycin mass drug administration for trachoma: A systematic review

Author

Mahmud, Hamidah, Landskroner, Emma, Amza, Abdou, Aragie, Solomon, Godwin, William W, de Hostos Barth, Anna, O’Brien, Kieran S, Lietman, Thomas M, and Oldenburg, Catherine E

Subjects
Sexually Transmitted Infections, Eye Disease and Disorders of Vision, Infectious Diseases, Infection, Good Health and Well Being, Anti-Bacterial Agents, Azithromycin, Child, Child, Preschool, Chlamydia trachomatis, Female, Humans, Infant, Male, Mass Drug Administration, Randomized Controlled Trials as Topic, Trachoma, Biological Sciences, Medical and Health Sciences, Tropical Medicine
Abstract

The World Health Organization (WHO) recommends continuing azithromycin mass drug administration (MDA) for trachoma until endemic regions drop below 5% prevalence of active trachoma in children aged 1-9 years. Azithromycin targets the ocular strains of Chlamydia trachomatis that cause trachoma. Regions with low prevalence of active trachoma may have little if any ocular chlamydia, and, thus, may not benefit from azithromycin treatment. Understanding what happens to active trachoma and ocular chlamydia prevalence after stopping azithromycin MDA may improve future treatment decisions. We systematically reviewed published evidence for community prevalence of both active trachoma and ocular chlamydia after cessation of azithromycin distribution. We searched electronic databases for all peer-reviewed studies published before May 2020 that included at least 2 post-MDA surveillance surveys of ocular chlamydia and/or the active trachoma marker, trachomatous inflammation-follicular (TF) prevalence. We assessed trends in the prevalence of both indicators over time after stopping azithromycin MDA. Of 140 identified studies, 21 met inclusion criteria and were used for qualitative synthesis. Post-MDA, we found a gradual increase in ocular chlamydia infection prevalence over time, while TF prevalence generally gradually declined. Ocular chlamydia infection may be a better measurement tool compared to TF for detecting trachoma recrudescence in communities after stopping azithromycin MDA. These findings may guide future trachoma treatment and surveillance efforts.

Published
2021

21. Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution

Author

Doan, Thuy, Worden, Lee, Hinterwirth, Armin, Arzika, Ahmed M, Maliki, Ramatou, Abdou, Amza, Zhong, Lina, Chen, Cindi, Cook, Catherine, Lebas, Elodie, O’Brien, Kieran S, Oldenburg, Catherine E, Chow, Eric D, Porco, Travis C, Lipsitch, Marc, Keenan, Jeremy D, and Lietman, Thomas M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, HIV/AIDS, Clinical Research, Pediatric, Antimicrobial Resistance, Infectious Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Infection, Good Health and Well Being, 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, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundMass 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.MethodsWe 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' 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.ResultsOver the entire 48-month period, the mean (±SD) coverage was 86.6±12% in the villages that received placebo and 83.2±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.ConclusionsAmong 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.).

Published
2020

22. Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Author

Chen, Ming-Huei, Raffield, Laura M, Mousas, Abdou, Sakaue, Saori, Huffman, Jennifer E, Moscati, Arden, Trivedi, Bhavi, Jiang, Tao, Akbari, Parsa, Vuckovic, Dragana, Bao, Erik L, Zhong, Xue, Manansala, Regina, Laplante, Véronique, Chen, Minhui, Lo, Ken Sin, Qian, Huijun, Lareau, Caleb A, Beaudoin, Mélissa, Hunt, Karen A, Akiyama, Masato, Bartz, Traci M, Ben-Shlomo, Yoav, Beswick, Andrew, Bork-Jensen, Jette, Bottinger, Erwin P, Brody, Jennifer A, van Rooij, Frank JA, Chitrala, Kumaraswamynaidu, Cho, Kelly, Choquet, Hélène, Correa, Adolfo, Danesh, John, Di Angelantonio, Emanuele, Dimou, Niki, Ding, Jingzhong, Elliott, Paul, Esko, Tõnu, Evans, Michele K, Floyd, James S, Broer, Linda, Grarup, Niels, Guo, Michael H, Greinacher, Andreas, Haessler, Jeff, Hansen, Torben, Howson, Joanna MM, Huang, Qin Qin, Huang, Wei, Jorgenson, Eric, Kacprowski, Tim, Kähönen, Mika, Kamatani, Yoichiro, Kanai, Masahiro, Karthikeyan, Savita, Koskeridis, Fotis, Lange, Leslie A, Lehtimäki, Terho, Lerch, Markus M, Linneberg, Allan, Liu, Yongmei, Lyytikäinen, Leo-Pekka, Manichaikul, Ani, Martin, Hilary C, Matsuda, Koichi, Mohlke, Karen L, Mononen, Nina, Murakami, Yoshinori, Nadkarni, Girish N, Nauck, Matthias, Nikus, Kjell, Ouwehand, Willem H, Pankratz, Nathan, Pedersen, Oluf, Preuss, Michael, Psaty, Bruce M, Raitakari, Olli T, Roberts, David J, Rich, Stephen S, Rodriguez, Benjamin AT, Rosen, Jonathan D, Rotter, Jerome I, Schubert, Petra, Spracklen, Cassandra N, Surendran, Praveen, Tang, Hua, Tardif, Jean-Claude, Trembath, Richard C, Ghanbari, Mohsen, Völker, Uwe, Völzke, Henry, Watkins, Nicholas A, Zonderman, Alan B, Program, VA Million Veteran, Wilson, Peter WF, Li, Yun, Butterworth, Adam S, Gauchat, Jean-François, Chiang, Charleston WK, and Li, Bingshan

Subjects
Genetics, Good Health and Well Being, Asian People, Genome-Wide Association Study, HEK293 Cells, Humans, Interleukin-7, Mutation, Missense, Phenotype, Polymorphism, Single Nucleotide, White People, VA Million Veteran Program, interleukin-7, genetic architecture, fine-mapping, selective sweeps, polygenic trait score, phenome-wide association study, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Published
2020

23. Development and validation of a simplified score to predict neonatal mortality risk among neonates weighing 2000 g or less (NMR-2000): an analysis using data from the UK and The Gambia

Author

Medvedev, Melissa M, Brotherton, Helen, Gai, Abdou, Tann, Cally, Gale, Christopher, Waiswa, Peter, Elbourne, Diana, Lawn, Joy E, and Allen, Elizabeth

Subjects
Paediatrics, Biomedical and Clinical Sciences, Lung, Pediatric, Preterm, Low Birth Weight and Health of the Newborn, Infant Mortality, Clinical Research, Perinatal Period - Conditions Originating in Perinatal Period, Generic health relevance, Good Health and Well Being, Child, Preschool, Female, Gambia, Hospital Mortality, Humans, Income, Infant, Infant, Low Birth Weight, Infant, Newborn, Infant, Newborn, Diseases, Kangaroo-Mother Care Method, Male, Oximetry, Predictive Value of Tests, Retrospective Studies, Risk Assessment, Severity of Illness Index, United Kingdom, Public health
Abstract

Background78% of neonatal deaths occur in sub-Saharan Africa and southern Asia, among which, more than 80% are in low birthweight babies. Existing neonatal mortality risk scores have primarily been developed for high-resource settings. The aim of this study was to develop and validate a score that is practicable for low-income and middle-income countries to predict in-hospital mortality among neonates born weighing 2000 g or less using datasets from the UK and The Gambia.MethodsThis analysis used retrospective data held in the UK National Neonatal Research Database from 187 neonatal units, and data from the Edward Francis Small Teaching Hospital (EFSTH), Banjul, The Gambia. In the UK dataset, neonates were excluded if birthweight was more than 2000 g; if the neonate was admitted aged more than 6 h or following discharge; if the neonate was stillborn; if the neonate died in delivery room; or if they were moribund on admission. The Gambian dataset included all neonates weighing less than 2000 g who were admitted between May 1, 2018, and Sept 30, 2019, who were screened for but not enrolled in the Early Kangaroo Mother Care Trial. 18 studies were reviewed to generate a list of 84 potential parameters. We derived a model to score in-hospital neonatal mortality risk using data from 55 029 admissions to a random sample of neonatal units in England and Wales from Jan 1, 2010, to Dec 31, 2016. All candidate variables were included in a complete multivariable model, which was progressively simplified using reverse stepwise selection. We validated the new score (NMR-2000) on 40 329 admissions to the remaining units between the same dates and 14 818 admissions to all units from Jan 1, to Dec 31, 2017. We also validated the score on 550 neonates admitted to the EFSTH in The Gambia.Findings18 candidate variables were selected for inclusion in the modelling process. The final model included three parameters: birthweight, admission oxygen saturation, and highest level of respiratory support within 24 h of birth. NMR-2000 had very good discrimination and goodness-of-fit across the UK samples, with a c-index of 0·8859-0·8930 and a Brier score of 0·0232-0·0271. Among Gambian neonates, the model had a c-index of 0·8170 and a Brier score of 0·1688. Predictive ability of the simplified integer score was similar to the model using regression coefficients, with c-indices of 0·8903 in the UK full validation sample and 0·8082 in the Gambian validation sample.InterpretationNMR-2000 is a validated mortality risk score for hospitalised neonates weighing 2000 g or less in settings where pulse oximetry is available. The score is accurate and simplified for bedside use. NMR-2000 requires further validation using a larger dataset from low-income and middle-income countries but has the potential to improve individual and population-level neonatal care resource allocation.FundingBill & Melinda Gates Foundation; Eunice Kennedy Shriver National Institute of Child Health & Human Development; Wellcome Trust; and Joint Global Health Trials scheme of Department of Health and Social Care, Department for International Development, Medical Research Council, and Wellcome Trust.

Published
2020

24. Comparison of anthropometric indicators to predict mortality in a population-based prospective study of children under 5 years in Niger

Author

O’Brien, Kieran S, Amza, Abdou, Kadri, Boubacar, Nassirou, Beido, Cotter, Sun Y, Stoller, Nicole E, West, Sheila K, Bailey, Robin L, Porco, Travis C, Keenan, Jeremy D, Lietman, Thomas M, and Oldenburg, Catherine E

Subjects
Biomedical and Clinical Sciences, Public Health, Health Sciences, Nutrition and Dietetics, Obesity, Pediatric, Clinical Trials and Supportive Activities, Clinical Research, Nutrition, Zero Hunger, Good Health and Well Being, Anthropometry, Arm, Body Height, Body Weight, Child, Child Mortality, Child, Preschool, Female, Humans, Infant, Longitudinal Studies, Male, Malnutrition, Niger, Prospective Studies, Mortality, Medical and Health Sciences, Nutrition & Dietetics, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveIn the present study, we aimed to compare anthropometric indicators as predictors of mortality in a community-based setting.DesignWe conducted a population-based longitudinal study nested in a cluster-randomized trial. We assessed weight, height and mid-upper arm circumference (MUAC) on children 12 months after the trial began and used the trial's annual census and monitoring visits to assess mortality over 2 years.SettingNiger.ParticipantsChildren aged 6-60 months during the study.ResultsOf 1023 children included in the study at baseline, height-for-age Z-score, weight-for-age Z-score, weight-for-height Z-score and MUAC classified 777 (76·0 %), 630 (61·6 %), 131 (12·9 %) and eighty (7·8 %) children as moderately to severely malnourished, respectively. Over the 2-year study period, fifty-eight children (5·7 %) died. MUAC had the greatest AUC (0·68, 95 % CI 0·61, 0·75) and had the strongest association with mortality in this sample (hazard ratio = 2·21, 95 % CI 1·26, 3·89, P = 0·006).ConclusionsMUAC appears to be a better predictor of mortality than other anthropometric indicators in this community-based, high-malnutrition setting in Niger.

Published
2020

25. Biannual versus annual mass azithromycin distribution and malaria seroepidemiology among preschool children in Niger: a sub-study of a cluster randomized trial.

Author

Oldenburg, Catherine E, Amza, Abdou, Cooley, Gretchen, Kadri, Boubacar, Nassirou, Beido, Arnold, Benjamin F, Rosenthal, Philip J, O'Brien, Kieran S, West, Sheila K, Bailey, Robin L, Porco, Travis C, Keenan, Jeremy D, Lietman, Thomas M, and Martin, Diana L

Subjects
Humans, Malaria, Azithromycin, Merozoite Surface Protein 1, Antimalarials, Prevalence, Seroepidemiologic Studies, Time Factors, Child, Preschool, Infant, Niger, Female, Male, Mass Drug Administration, Mass drug administration, Microbiology, Medical Microbiology, Public Health and Health Services, Tropical Medicine
Abstract

BackgroundBiannual mass azithromycin administration to preschool children reduces all-cause mortality, but the mechanism for the effect is not understood. Azithromycin has activity against malaria parasites, and malaria is a leading cause of child mortality in the Sahel. The effect of biannual versus annual azithromycin distribution for trachoma control on serological response to merozoite surface protein 1 (MSP-119), a surrogate for malaria incidence, was evaluated among children in Niger.MethodsMarkers of malaria exposure were measured in two arms of a factorial randomized controlled trial designed to evaluate targeted biannual azithromycin distribution to children under 12 years of age compared to annual azithromycin to the entire community for trachoma control (N = 12 communities per arm). Communities were treated for 36 months (6 versus 3 distributions). Dried blood spots were collected at 36 months among children ages 1-5 years, and MSP-119 antibody levels were assessed using a bead-based multiplex assay to measure malaria seroprevalence.ResultsAntibody results were available for 991 children. MSP-119 seropositivity was 62.7% in the biannual distribution arm compared to 68.7% in the annual arm (prevalence ratio 0.91, 95% CI 0.83 to 1.00). Mean semi-quantitative antibody levels were lower in the biannual distribution arm compared to the annual arm (mean difference - 0.39, 95% CI - 0.05 to - 0.72).ConclusionsTargeted biannual azithromycin distribution was associated with lower malaria seroprevalence compared to that in a population that received annual distribution. Trial Registration Clinicaltrials.gov NCT00792922.

Published
2019

26. Community-level Association between Clinical Trachoma and Ocular Chlamydia Infection after MASS Azithromycin Distribution in a Mesoendemic Region of Niger

Author

Amza, Abdou, Kadri, Boubacar, Nassirou, Beido, Cotter, Sun Y, Stoller, Nicole E, West, Sheila K, Bailey, Robin L, Porco, Travis C, Keenan, Jeremy D, Lietman, Thomas M, and Oldenburg, Catherine E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Eye Disease and Disorders of Vision, Clinical Research, Sexually Transmitted Infections, Infectious Diseases, Infection, Good Health and Well Being, Anti-Bacterial Agents, Azithromycin, Child, Preschool, Chlamydia Infections, Chlamydia trachomatis, Eye Infections, Parasitic, Female, Humans, Incidence, Infant, Infant, Newborn, Male, Mass Drug Administration, Niger, Prevalence, Trachoma, azithromycin, mass drug administration, Opthalmology and Optometry, Public Health and Health Services, Epidemiology, Ophthalmology and optometry, Public health
Abstract

Purpose: The clinical sign trachomatous inflammation - follicular (TF) is used to monitor indication for and response to mass azithromycin distribution in trachoma-endemic communities. Here, we assess the relationship between TF, trachomatous inflammation - intense (TI), and infection with ocular Chlamydia trachomatis over time during annual mass azithromycin distribution. Methods: We used data from a cluster-randomized trial of mass azithromycin distribution for trachoma control in a mesoendemic region of Niger. This study includes 24 communities that received 3 years of annual mass azithromycin distribution. TF, TI, and ocular chlamydia infection were monitored among children aged 0-5 years. We assessed the correlation between the prevalence of ocular chlamydia infection and 1) TF and 2) TI prevalence over time. Results: At baseline, ocular chlamydia prevalence was 21.2% (95% CI 14.3-28.1%), TF prevalence was 27.7% (95% CI 21.2-34.2%), and TI prevalence was 8.3% (95% CI 5.2-11.5%). The prevalence of all three measures decreased significantly over time (P < 0.001). At baseline, ocular chlamydia infection prevalence was strongly correlated with both TF (rho = 0.78, P < 0.0001) and TI (rho = 0.76, P < 0.0001). The correlation between ocular chlamydia infection and both TF and TI was weak at months 12 and 24. At 36 months, when TF prevalence had dropped below 10%, ocular chlamydia infection and TF were moderately correlated (rho = 0.70, P= 0.0002). Conclusions: Both TF and TI are good indicators of infection prevalence prior to mass azithromycin distribution. However, this relationship may be affected by repeated rounds of mass azithromycin distribution.

Published
2019

27. Increasing access to integrated ESKD care as part of universal health coverage

Author

Harris, David CH, Davies, Simon J, Finkelstein, Fredric O, Jha, Vivekanand, Donner, Jo-Ann, Abraham, Georgi, Bello, Aminu K, Caskey, Fergus J, Garcia, Guillermo Garcia, Harden, Paul, Hemmelgarn, Brenda, Johnson, David W, Levin, Nathan W, Luyckx, Valerie A, Martin, Dominique E, McCulloch, Mignon I, Moosa, Mohammed Rafique, O’Connell, Philip J, Okpechi, Ikechi G, Filho, Roberto Pecoits, Shah, Kamal D, Sola, Laura, Swanepoel, Charles, Tonelli, Marcello, Twahir, Ahmed, van Biesen, Wim, Varghese, Cherian, Yang, Chih-Wei, Zuniga, Carlos, Summit, Working Groups of the International Society of Nephrology’s 2nd Global Kidney Health, Abu Alfa, Ali K, Aljubori, Harith M, Alrukhaimi, Mona N, Andreoli, Sharon P, Ashuntantang, Gloria, Bellorin-Font, Ezequiel, Bernieh, Bassam, Ibhais, Fuad M, Blake, Peter G, Brown, Mark, Brown, Edwina, Bunnag, Sakarn, Chan, Tak Mao, Chen, Yuqing, Granado, Rolando Claure-Del, Claus, Stefaan, Collins, Allan, Couchoud, Cecile, Cueto-Manzano, Alfonso, Cullis, Brett, Douthat, Walter, Dreyer, Gavin, Eiam-Ong, Somchai, Eke, Felicia U, Feehally, John, Ghnaimat, Mohammad A, Goh, BakLeong, Hassan, Mohamed H, Hou, Fan Fan, Jager, Kitty, Kalantar-Zadeh, Kamyar, Kazancioglu, Rumeyza T, Levin, Adeera, Liew, Adrian, McKnight, Marla, Mengistu, Yewondwassesn Tadesse, Morton, Rachael L, Muller, Elmi, Murtagh, Fliss EM, Naicker, Saraladevi, Nangaku, Masaomi, Niang, Abdou, Obrador, Gregorio T, Ossareh, Shahrzad, Perl, Jeffrey, Rahman, Muhibur, Rashid, Harun Ur, Richards, Marie, Rondeau, Eric, Sahay, Manisha, Saleh, Abdulkarim, Schneditz, Daniel, Tchokhonelidze, Irma, Tesar, Vladimir, Trask, Michele, Tungsanga, Kriang, Vachharajani, Tushar, Walker, Rachael C, Walker, Robert, Were, Anthony JO, Yao, Qiang, Yeates, Karen, Yu, Xueqing, Zakharova, Elena, Zemchenkov, Alexander, and Zhao, Ming-Hui

Subjects
Clinical Research, Health Services, Behavioral and Social Science, Kidney Disease, Health and social care services research, 8.1 Organisation and delivery of services, 8.3 Policy, ethics, and research governance, Good Health and Well Being, Quality Education, Conservative Treatment, Developing Countries, Global Burden of Disease, Global Health, Health Occupations, Health Planning, Health Policy, Health Services Accessibility, Health Workforce, Humans, Kidney Failure, Chronic, Patient Advocacy, Renal Replacement Therapy, Universal Health Insurance, advocacy, conservative care, dialysis, end-stage kidney disease, ESKD, funding, training, transplantation, universal health coverage, Working Groups of the International Society of Nephrology’s 2nd Global Kidney Health Summit, Clinical Sciences, Urology & Nephrology
Abstract

The global nephrology community recognizes the need for a cohesive strategy to address the growing problem of end-stage kidney disease (ESKD). In March 2018, the International Society of Nephrology hosted a summit on integrated ESKD care, including 92 individuals from around the globe with diverse expertise and professional backgrounds. The attendees were from 41 countries, including 16 participants from 11 low- and lower-middle-income countries. The purpose was to develop a strategic plan to improve worldwide access to integrated ESKD care, by identifying and prioritizing key activities across 8 themes: (i) estimates of ESKD burden and treatment coverage, (ii) advocacy, (iii) education and training/workforce, (iv) financing/funding models, (v) ethics, (vi) dialysis, (vii) transplantation, and (viii) conservative care. Action plans with prioritized lists of goals, activities, and key deliverables, and an overarching performance framework were developed for each theme. Examples of these key deliverables include improved data availability, integration of core registry measures and analysis to inform development of health care policy; a framework for advocacy; improved and continued stakeholder engagement; improved workforce training; equitable, efficient, and cost-effective funding models; greater understanding and greater application of ethical principles in practice and policy; definition and application of standards for safe and sustainable dialysis treatment and a set of measurable quality parameters; and integration of dialysis, transplantation, and comprehensive conservative care as ESKD treatment options within the context of overall health priorities. Intended users of the action plans include clinicians, patients and their families, scientists, industry partners, government decision makers, and advocacy organizations. Implementation of this integrated and comprehensive plan is intended to improve quality and access to care and thereby reduce serious health-related suffering of adults and children affected by ESKD worldwide.

Published
2019

28. Mass Azithromycin Distribution to Prevent Childhood Mortality: A Pooled Analysis of Cluster-Randomized Trials.

Author

Oldenburg, Catherine E, Arzika, Ahmed M, Amza, Abdou, Gebre, Teshome, Kalua, Khumbo, Mrango, Zakayo, Cotter, Sun Y, West, Sheila K, Bailey, Robin L, Emerson, Paul M, O'Brien, Kieran S, Porco, Travis C, Keenan, Jeremy D, and Lietman, Thomas M

Subjects
Humans, Communicable Diseases, Azithromycin, Anti-Bacterial Agents, Administration, Oral, Child Mortality, Infant Mortality, Communicable Disease Control, Child, Preschool, Infant, Mass Drug Administration, Clinical Research, Pediatric, Clinical Trials and Supportive Activities, Prevention, Good Health and Well Being, Medical and Health Sciences, Tropical Medicine
Abstract

Mass drug administration (MDA) with azithromycin may reduce under-5 child mortality (U5M) in sub-Saharan Africa. Here, we conducted a pooled analysis of all published cluster-randomized trials evaluating the effect of azithromycin MDA on child mortality. We pooled data from cluster-randomized trials randomizing communities to azithromycin MDA versus control. We calculated mortality rates in the azithromycin and control arms in each study, and by country for multisite studies including multiple countries. We conducted a two-stage individual community data meta-analysis to estimate the effect of azithromycin for prevention of child mortality. Three randomized controlled trials in four countries (Ethiopia, Malawi, Niger, and Tanzania) were identified. The overall pooled mortality rate was 15.9 per 1,000 person-years (95% confidence interval [CI]: 15.5-16.3). The pooled mortality rate was lower in azithromycin-treated communities than in placebo-treated communities (14.7 deaths per 1,000 person-years, 95% CI: 14.2-15.3 versus 17.2 deaths per 1,000 person-years, 95% CI: 16.5-17.8). There was a 14.4% reduction in all-cause child mortality in communities receiving azithromycin MDA (95% CI: 6.3-21.7% reduction, P = 0.0007). All-cause U5M was lower in communities receiving azithromycin MDA than in control communities, suggesting that azithromycin MDA could be a new tool to reduce child mortality in sub-Saharan Africa. However, heterogeneity in effect estimates suggests that the magnitude of the effect may vary in time and space and is currently not predictable.

Published
2019

29. Clinical Practice Approach to Nonalcoholic Fatty Liver Disease by Pediatric Gastroenterologists in the United States

Author

Shapiro, Warren L, Yu, Elizabeth L, Arin, Jennifer C, Murray, Karen F, Ali, Sabina, Desai, Nirav K, Xanthakos, Stavra A, Lin, Henry C, Alkhouri, Naim, Abdou, Reham, Abrams, Stephanie H, Butler, Megan W, Faasse, Sarah A, Gillis, Lynette A, Hadley, Timothy A, Jain, Ajay K, Kavan, Marianne, Kordy, Kattayoun, Lee, Peter, Panganiban, Jennifer, Pohl, John F, Potter, Carol, Rudolph, Bryan, Sundaram, Shikha S, Joshi, Shivali, Proudfoot, James A, Goyal, Nidhi P, Harlow, Kathryn E, Newton, Kimberly P, and Schwimmer, Jeffrey B

Subjects
Digestive Diseases, Clinical Research, Nutrition, Prevention, Liver Disease, Pediatric, Pediatric Research Initiative, Clinical Trials and Supportive Activities, Chronic Liver Disease and Cirrhosis, Management of diseases and conditions, 7.1 Individual care needs, Metabolic and endocrine, Child, Female, Gastroenterologists, Gastroenterology, Humans, Male, Non-alcoholic Fatty Liver Disease, Pediatrics, Practice Patterns, Physicians', United States, clinical practice, nonalcoholic steatohepatitis, obesity, Medical and Health Sciences, Gastroenterology & Hepatology
Abstract

ObjectivesNonalcoholic fatty liver disease (NAFLD) is common; however, no information is available on how pediatric gastroenterologists in the United States manage NAFLD. Therefore, study objectives were to understand how pediatric gastroenterologists in the US approach the management of NAFLD, and to identify barriers to care for children with NAFLD.MethodsWe performed structured one-on-one interviews to ascertain each individual pediatric gastroenterologist's approach to the management of NAFLD in children. Responses were recorded from open-ended questions regarding screening for comorbidities, recommendations regarding nutrition, physical activity, medications, and perceived barriers to care.ResultsResponse rate was 72.0% (486/675). Mean number of patients examined per week was 3 (standard deviation [SD] 3.5). Dietary intervention was recommended by 98.4% of pediatric gastroenterologists. Notably, 18 different dietary recommendations were reported. A majority of physicians provided targets for exercise frequency (72.6%, mean 5.6 days/wk, SD 1.6) and duration (69.9%, mean 40.2 minutes/session, SD 16.4). Medications were prescribed by 50.6%. Almost one-half of physicians (47.5%) screened for type 2 diabetes, dyslipidemia, and hypertension. Providers who spent more than 25 minutes at the initial visit were more likely to screen for comorbidities (P = 0.003). Barriers to care were reported by 92.8% with 29.0% reporting ≥3 barriers.ConclusionsThe majority of US pediatric gastroenterologists regularly encounter children with NAFLD. Varied recommendations regarding diet and exercise highlight the need for prospective clinical trials. NAFLD requires a multidimensional approach with adequate resources in the home, community, and clinical setting.

Published
2019

30. Community-level chlamydial serology for assessing trachoma elimination in trachoma-endemic Niger.

Author

Kim, Jessica S, Oldenburg, Catherine E, Cooley, Gretchen, Amza, Abdou, Kadri, Boubacar, Nassirou, Baido, Cotter, Sun Yu, Stoller, Nicole E, West, Sheila K, Bailey, Robin L, Keenan, Jeremy D, Gaynor, Bruce D, Porco, Travis C, Lietman, Thomas M, and Martin, Diana L

Subjects
Humans, Chlamydia trachomatis, Trachoma, Azithromycin, Bacterial Proteins, DNA, Bacterial, Antibodies, Bacterial, Antigens, Bacterial, Anti-Bacterial Agents, Endemic Diseases, Child, Preschool, Infant, Infant, Newborn, Niger, Disease Eradication, Mass Drug Administration, DNA, Bacterial, Antibodies, Antigens, Child, Preschool, Newborn, Biological Sciences, Medical and Health Sciences, Tropical Medicine
Abstract

BACKGROUND:Program decision-making for trachoma elimination currently relies on conjunctival clinical signs. Antibody tests may provide additional information on the epidemiology of trachoma, particularly in regions where it is disappearing or elimination targets have been met. METHODS:A cluster-randomized trial of mass azithromycin distribution strategies for trachoma elimination was conducted over three years in a mesoendemic region of Niger. Dried blood spots were collected from a random sample of children aged 1-5 years in each of 24 study communities at 36 months after initiation of the intervention. A multiplex bead assay was used to test for antibodies to two Chlamydia trachomatis antigens, Pgp3 and CT694. We compared seropositivity to either antigen to clinical signs of active trachoma (trachomatous inflammation-follicular [TF] and trachomatous inflammation-intense [TI]) at the individual and cluster level, and to ocular chlamydia prevalence at the community level. RESULTS:Of 988 children with antibody data, TF prevalence was 7.8% (95% CI 6.1 to 9.5) and TI prevalence was 1.6% (95% CI 0.9 to 2.6). The overall prevalence of antibody positivity to Pgp3 was 27.2% (95% CI 24.5 to 30), and to CT694 was 23.7% (95% CI 21 to 26.2). Ocular chlamydia infection prevalence was 5.2% (95% CI 2.8 to 7.6). Seropositivity to Pgp3 and/or CT694 was significantly associated with TF at the individual and community level and with ocular chlamydia infection and TI at the community level. Older children were more likely to be seropositive than younger children. CONCLUSION:Seropositivity to Pgp3 and CT694 correlates with clinical signs and ocular chlamydia infection in a mesoendemic region of Niger. TRIAL REGISTRATION:ClinicalTrials.gov NCT00792922.

Published
2019

31. Sensitivity and specificity of computer vision classification of eyelid photographs for programmatic trachoma assessment

Author

Kim, Matthew C, Okada, Kazunori, Ryner, Alexander M, Amza, Abdou, Tadesse, Zerihun, Cotter, Sun Y, Gaynor, Bruce D, Keenan, Jeremy D, Lietman, Thomas M, and Porco, Travis C

Subjects
Information and Computing Sciences, Biomedical and Clinical Sciences, Ophthalmology and Optometry, Clinical Research, Eye Disease and Disorders of Vision, Good Health and Well Being, Algorithms, Artificial Intelligence, Conjunctiva, Ethiopia, Eyelids, Humans, Image Processing, Computer-Assisted, Neural Networks, Computer, Niger, Photography, Prevalence, Trachoma, General Science & Technology
Abstract

Background/aimsTrachoma programs base treatment decisions on the community prevalence of the clinical signs of trachoma, assessed by direct examination of the conjunctiva. Automated assessment could be more standardized and more cost-effective. We tested the hypothesis that an automated algorithm could classify eyelid photographs better than chance.MethodsA total of 1,656 field-collected conjunctival images were obtained from clinical trial participants in Niger and Ethiopia. Images were scored for trachomatous inflammation-follicular (TF) and trachomatous inflammation-intense (TI) according to the simplified World Health Organization grading system by expert raters. We developed an automated procedure for image enhancement followed by application of a convolutional neural net classifier for TF and separately for TI. One hundred images were selected for testing TF and TI, and these images were not used for training.ResultsThe agreement score for TF and TI tasks for the automated algorithm relative to expert graders was κ = 0.44 (95% CI: 0.26 to 0.62, P < 0.001) and κ = 0.69 (95% CI: 0.55 to 0.84, P < 0.001), respectively.DiscussionFor assessing the clinical signs of trachoma, a convolutional neural net performed well above chance when tested against expert consensus. Further improvements in specificity may render this method suitable for field use.

Published
2019

32. Childhood Mortality After Mass Distribution of Azithromycin: A Secondary Analysis of the PRET Cluster-randomized Trial in Niger.

Author

O'Brien, Kieran S, Cotter, Sun Y, Amza, Abdou, Kadri, Boubacar, Nassirou, Beido, Stoller, Nicole E, Zhou, Zhaoxia, West, Sheila K, Bailey, Robin L, Keenan, Jeremy D, Porco, Travis C, and Lietman, Thomas M

Subjects
Humans, Trachoma, Communicable Diseases, Azithromycin, Anti-Bacterial Agents, Administration, Oral, Prevalence, Child Mortality, Child, Child, Preschool, Infant, Niger, Female, Male, Mass Drug Administration, Clinical Trials and Supportive Activities, Infectious Diseases, Pediatric, Clinical Research, Comparative Effectiveness Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, azithromycin, mortality, mass drug administration, cluster-randomized trial, Paediatrics and Reproductive Medicine, Public Health and Health Services, Pediatrics
Abstract

BACKGROUND:Mass distributions of azithromycin for trachoma have been associated with secondary benefits, including reductions in child mortality. METHODS:In the Partnership for the Rapid Elimination of Trachoma cluster-randomized trial in Niger, 24 communities were randomized to annual treatment of everyone and 24 communities were randomized to biannual treatment of children under 12 for 3 years (clinicaltrials.gov, NCT00792922). Treatment was a single dose of directly observed oral azithromycin (20 mg/kg up to 1 g in adults). Vital status was assessed during annual census and monitoring visits. In this prespecified secondary analysis, we compared the mortality rate among children 6 months to less than 5 years of age by treatment arm using negative binomial regression. RESULTS:Among children 6 months to less than 5 years of age, 404 deaths occurred during the study period. The mortality rate was 35.6 deaths per 1000 person-years (231 deaths, 95% CI: 30.9-40.9) in the annual arm and 29.0 deaths per 1000 person-years (173 deaths, 95% CI: 24.8-33.8) in the biannual arm. The mortality rate ratio comparing children in the biannual arm to the annual arm was 0.81 (95% CI: 0.66-1.00, P = 0.07; primary outcome). The mortality rate ratio comparing children who died from infectious causes in the biannual arm to the annual arm was 0.73 (95% CI: 0.57-0.94; P = 0.02). No adverse events were reported. CONCLUSIONS:This secondary analysis of a cluster-randomized trial found a nonsignificant 19% decrease in mortality among children 6 months to less than 5 years of age who received biannual azithromycin compared with children who received annual azithromycin. This study was conducted in a high mortality, trachoma-endemic area; thus, results may be specific to this environment only. In addition, the trial was neither designed nor powered to detect a mortality effect, and we cannot rule out the possibility that mortality differences resulted from bias.

Published
2018

33. Anthropometry and Malaria among Children in Niger: A Cross-Sectional Study.

Author

O'Brien, Kieran S, Amza, Abdou, Kadri, Boubacar, Nassirou, Baido, Cotter, Sun Y, Stoller, Nicole E, West, Sheila K, Bailey, Robin L, Porco, Travis C, Gaynor, Bruce D, Lietman, Thomas M, and Oldenburg, Catherine E

Subjects
Humans, Parasitemia, Malaria, Body Weight, Anthropometry, Body Height, Odds Ratio, Risk Factors, Cross-Sectional Studies, Nutritional Status, Pregnancy, Child, Child, Preschool, Niger, Female, Male, Vector-Borne Diseases, Clinical Research, Rare Diseases, Infectious Diseases, Infection, Good Health and Well Being, Zero Hunger, Medical and Health Sciences, Tropical Medicine
Abstract

The complex relationship between malnutrition and malaria affects morbidity and mortality in children younger than 5 years, particularly in parts of sub-Saharan Africa where these conditions occur together seasonally. Previous research on this relationship has been inconclusive. Here, we examine the association between anthropometric indicators and malaria infection in a population-based sample of children younger than 5 years in Niger. This cross-sectional study is a secondary analysis of a cluster-randomized trial comparing treatment strategies for trachoma in Niger. We included children aged 6-60 months residing in the 48 communities enrolled in the trial who completed anthropometric and malaria infection assessments at the final study visit. We evaluated the association between anthropometric indicators, including height-for-age z-score (HAZ) and weight-for-age z-score (WAZ) and indicators of malaria infection, including malaria parasitemia and clinical malaria. In May 2013, we collected data from 1,649 children. Of these, 780 (47.3%) were positive for malaria parasitemia and 401 (24.3%) had clinical malaria. In models of malaria parasitemia, the adjusted odds ratio (aOR) was 1.05 (95% confidence interval [CI]: 1.00-1.10) for HAZ and 1.07 (95% CI: 0.99, 1.15) for WAZ. In models of clinical malaria, the aOR was 1.07 (95% CI: 1.02-1.11) for HAZ and 1.09 (95% CI: 1.01-1.19) for WAZ. Overall, we did not find evidence of an association between most anthropometric indicators and malaria infection. Greater height may be associated with an increased risk of clinical malaria.

Published
2018

34. Annual Versus Biannual Mass Azithromycin Distribution and Malaria Parasitemia During the Peak Transmission Season Among Children in Niger.

Author

Oldenburg, Catherine E, Amza, Abdou, Kadri, Boubacar, Nassirou, Beido, Cotter, Sun Y, Stoller, Nicole E, West, Sheila K, Bailey, Robin L, Porco, Travis C, Keenan, Jeremy D, Lietman, Thomas M, and Gaynor, Bruce D

Subjects
Humans, Trachoma, Parasitemia, Malaria, Azithromycin, Anti-Bacterial Agents, Prevalence, Cluster Analysis, Seasons, Child, Child, Preschool, Infant, Niger, Female, Male, Mass Drug Administration, Rare Diseases, Pediatric, HIV/AIDS, Clinical Trials and Supportive Activities, Clinical Research, Infectious Diseases, Vector-Borne Diseases, Infection, Good Health and Well Being, azithromycin, malaria, Paediatrics and Reproductive Medicine, Public Health and Health Services, Pediatrics
Abstract

BackgroundAzithromycin has modest efficacy against malaria, and previous cluster randomized trials have suggested that mass azithromycin distribution for trachoma control may play a role in malaria control. We evaluated the effect of annual versus biannual mass azithromycin distribution over a 3-year period on malaria prevalence during the peak transmission season in a region with seasonal malaria transmission in Niger.MethodsTwenty-four communities in Matameye, Niger, were randomized to annual mass azithromycin distribution (3 distributions to the entire community during the peak transmission season) or biannual-targeted azithromycin distribution (6 distributions to children

Published
2018

35. Effectiveness of expanding annual mass azithromycin distribution treatment coverage for trachoma in Niger: a cluster randomised trial.

Author

Amza, Abdou, Kadri, Boubacar, Nassirou, Beido, Cotter, Sun Y, Stoller, Nicole E, West, Sheila K, Bailey, Robin L, Porco, Travis C, Gaynor, Bruce D, Keenan, Jeremy D, Lietman, Thomas M, and Oldenburg, Catherine E

Subjects
Humans, Trachoma, Azithromycin, Anti-Bacterial Agents, Antibiotic Prophylaxis, Prevalence, Child, Preschool, Infant, Delivery of Health Care, Niger, Female, Male, Child Health, Clinical Trial, Conjunctiva, Infection, Public Health, Infectious Diseases, Cost Effectiveness Research, Eye Disease and Disorders of Vision, Clinical Trials and Supportive Activities, Clinical Research, Good Health and Well Being, Clinical Sciences, Opthalmology and Optometry, Public Health and Health Services, Ophthalmology & Optometry
Abstract

Background/aimsThe WHO recommends 3-5 years of annual mass azithromycin distribution with at least 80% treatment coverage to districts with active trachoma prevalence over 10% among children. Here, we assess the efficacy of expanding the coverage target to at least 90% for trachoma control in a mesoendemic region of Niger.MethodsTwenty-four communities were randomised to a single day of azithromycin distribution with a coverage target of 80% of the community or up to 4 days of treatment, aiming for greater than 90% coverage. Distributions were annual and individuals above 6 months of age were treated. Children under 5 years of age were monitored for ocular chlamydia infection and active trachoma.ResultsAt baseline, ocular chlamydia prevalence was 20.5% (95% CI 9.8% to 31.2%) in the standard coverage arm and 21.9% (95% CI 11.3% to 32.5%) in the enhanced coverage arm, which reduced to 4.6% (95% CI 0% to 9.5%, p=0.008) and 7.1% (95% CI 2.7% to 11.4%, p

Published
2018

36. Comparison of Mass Azithromycin Coverage Targets of Children in Niger: A Cluster-Randomized Trachoma Trial.

Author

Oldenburg, Catherine E, Amza, Abdou, Kadri, Boubacar, Nassirou, Beido, Cotter, Sun Y, Stoller, Nicole E, West, Sheila K, Bailey, Robin L, Porco, Travis C, Gaynor, Bruce D, Keenan, Jeremy D, and Lietman, Thomas M

Subjects
Eye, Humans, Chlamydia trachomatis, Trachoma, Azithromycin, Anti-Bacterial Agents, Treatment Outcome, Prevalence, Cluster Analysis, Polymerase Chain Reaction, Child, Preschool, Infant, Niger, Female, Male, Eye Disease and Disorders of Vision, Clinical Trials and Supportive Activities, Pediatric, Clinical Research, Infectious Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Medical and Health Sciences, Tropical Medicine
Abstract

Repeated oral azithromycin distribution targeted only to children has proven effective in reducing the ocular Chlamydia that causes trachoma. Here, we assess whether an enhanced coverage target of at least 90% of children is superior to the World Health Organization recommendation of at least 80%. Twenty-four trachoma-endemic communities in Matamèye, Niger, were randomized to a single day of azithromycin distribution aiming for at least 80% coverage or up to 4 days of treatment and > 90% coverage of children under age 12. All distributions were biannual. Children < 5 years of age and adults > 15 years were monitored for ocular Chlamydia infection by polymerase chain reaction every 6 months for 36 months in children and at baseline and 36 months in adults. Ocular Chlamydia prevalence in children decreased from 24.9% (95% confidence interval [CI] 15.9-33.8%) to 4.4% (95% CI 0.6-8.2%, P < 0.001) at 36 months in the standard coverage arm and from 15.6% (95% CI 10.0-21.2%) to 3.3% (95% CI 1.0-5.5%; P < 0.001) in the enhanced coverage arm. Enhanced coverage reduced ocular Chlamydia prevalence in children more quickly over time compared with standard (P = 0.04). There was no difference between arms at 36 months in children (2.4% lower with enhanced coverage, 95% CI 7.7-12.5%; P = 0.60). No infection was detected in adults at 36 months. Increasing antibiotic coverage among children from 80% to 90% may yield only short term improvements for trachoma control programs. Targeting treatment to children alone may be sufficient for trachoma control in this setting.

Published
2018

37. Mass Azithromycin and Malaria Parasitemia in Niger: Results from a Community-Randomized Trial

Author

O'Brien, Kieran S, Cotter, Sun Y, Amza, Abdou, Kadri, Boubacar, Nassirou, Baido, Stoller, Nicole E, Zhou, Zhaoxia, Cotter, Chris, West, Sheila K, Bailey, Robin L, Rosenthal, Philip J, Gaynor, Bruce D, Porco, Travis C, and Lietman, Thomas M

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Clinical Research, Rare Diseases, HIV/AIDS, Infectious Diseases, Malaria, Vector-Borne Diseases, Clinical Trials and Supportive Activities, Infection, Good Health and Well Being, Anti-Bacterial Agents, Azithromycin, Female, Humans, Infant, Male, Niger, Parasitemia, Trachoma, Medical and Health Sciences, Tropical Medicine, Biomedical and clinical sciences, Health sciences
Abstract

Studies designed to determine the effects of mass administration of azithromycin on trachoma have suggested that mass azithromycin distributions may also reduce the prevalence of malaria. These studies have typically examined the impact of a small number of treatments over short durations. In this prespecified substudy of a cluster-randomized trial for trachoma, we compared malaria parasitemia prevalence in 24 communities in Niger randomized to receive either annual or biannual mass azithromycin distributions over 3 years. The 12 communities randomized to annual azithromycin received three treatments during the high-transmission season, and the 12 communities randomized to biannual azithromycin received a total of six treatments: three during the high-transmission season and three during the low-transmission season. Blood samples were taken to assess malariometric indices among children in all study communities at a single time point during the high-transmission season after 3 years of the intervention. No significant differences were identified in malaria parasitemia, parasite density, or hemoglobin concentration between the annual and biannual treatment arms. When compared with annual mass azithromycin alone, additional mass azithromycin distributions given during the low-transmission season did not significantly reduce the subsequent prevalence of malaria parasitemia or parasite density after 3 years, as measured during the high-transmission season.

Published
2017

38. Effects of hospital facilities on patient outcomes after cancer surgery

Author

Knight, Sr, Chu, K, Lapitan, Mc, Dare, Aj, Pius, R, Shaw, Ca, Drake, Tm, Norman, L, Ademuyiwa, Ao, Adisa, Ao, Aguilera, Ml, Al-Saqqa, Sw, Al-Slaibi, I, Bhangu, A, Biccard, Bm, Brocklehurst, P, Costas-Chavarri, A, Elhadi, M, Fairfield, Cj, Fitzgerald, Je, Ghosh, D, Glasbey, J, Henegouwen, Miv, Ingabire, Jca, Kingham, Tp, Lawani, I, Lieske, B, Lilford, R, Martin, J, Mclean, Ka, Moore, R, Morton, D, Nepogodiev, D, Ntirenganya, F, Pata, F, Pinkney, T, Stephen, R Knight, Catherine, A Shaw, Riinu, Pius, Thomas, M Drake, Lisa, Norman, Adesoji, O Ademuyiwa, Adewale, O Adisa, Maria Lorena Aguilera, Sara, W Al-Saqqa, Ibrahim, Al-Slaibi, Aneel, Bhangu, Bruce, M Biccard, Peter, Brocklehurst, Ainhoa, Costas-Chavarri, Kathryn, Chu, Anna, Dare, Muhammed, Elhadi, Cameron, J Fairfield, J Edward Fitzgerald, Dhruv, Ghosh, James, Glasbey, Mark, I van Berge Henegouwen, C Allen Ingabire, J, T Peter Kingham, Marie Carmela Lapitan, Ismaïl, Lawani, Bettina, Lieske, Richard, Lilford, Janet, Martin, Kenneth, A McLean, Rachel, Moore, Dion, Morton, Dmitri, Nepogodiev, Faustin, Ntirenganya, Francesco, Pata, Thomas, Pinkney, Ahmad Uzair Qureshi, Antonio Ramos-De la Medina, Aya, Riad, Hosni Khairy Salem, Joana, Simões, Richard, Spence, Neil, Smart, Stephen, Tabiri, Hannah, Thomas, Thomas, G Weiser, Malcolm, West, John, Whitaker, Ewen, M Harrison, Arben, Gjata, Maria Marta Modolo, Sebastian, King, Erick, Chan, Sayeda Nazmun Nahar, Ade, Waterman, Dominique, Vervoort, Alemayehu Ginbo Bedada, Bernardo De Azevedo, Ana Gabriela Figueiredo, Manol, Sokolov, Venerand, Barendegere, Gerald, Ekwen, Arnav, Agarwal, Qinyang, Liu, Juan Camilo Correa, Kalisya Luc Malemo, Jacques, Bake, Jakov, Mihanovic, Kamila, Kunčarová, Julius, Orhalmi, Hosni, Salem, Jyri, Teras, Aristotelis, Kechagias, Alexis, P Arnaud, Judith, Lindert, Vasileios, Kalles, Maria-Lorena, Aguilera-Arevalo, Gustavo, Recinos, Zsolt, Baranyai, Basant, Kumar, Harish Neelamraju Lakshmi, Sanoop Koshy Zachariah, Philip, Alexander, Sunil Kumar Venkatappa, Pramesh, C, Radhian, Amandito, Christina, Fleming, Luca, Ansaloni, Gianluca, Pellino, Ahmed, M Altibi, Ibrahim, Nour, Intisar, Hamdun, Ali, M Ghellai, Donatas, Venskutonis, Tomas, Poskus, Justas, Zilinskas, Precious, Malemia, Yong Yong Tew, Elaine, Borg, Sarah, Ellul, Fatima Zahraa Wafqui, David, W Borowski, Anne Sophie van Dalen, Cameron, Wells, Harissou, Adamou, Adesoji, Ademuyiwa, Adewale, Adisa, Kjetil, Søreide, Sara Al Saqqa, Osaid, Alser, Haya, Tahboub, Helmut Alfredo Segovia Lohse, Sebastian Shu Yip, Piotr, Major, António Sampaio Soares, Matei Razvan Bratu, Andrey, Litvin, Armen, Vardanyan, Ahmad, Gudal, Naif, Albati, Jovan, Juloski, Miran, Rems, Sarah, Rayne, Stephanie Van Straten, Yoshan, Moodley, Irene Ortega Vázquez, Jaime, Ruiz-Tovar, Kithsiri Janakantha Senanayake, Sujeewa Priyantha Bandara Thalgaspitiya, Omer Abdelbagi Omer, Anmar, Homeida, Yucel, Cengiz, Daniel, Clerc, Muhammad, Alshaar, Hanen, Bouaziz, Yuksel, Altinel, Matthew, Doe, Maryna, Freigofer, Ella, Teasdale, Rakan, Kabariti, Joshua Michael Clements, Stephen Richard Knight, Ahsan, Ashfaq, Ijeoma, Azodo, Gabriela, Wagner, Ivan, Trostchansky, Mayaba, Maimbo, David, Linyama, Helidon, Nina, Amanda, Zeko, Claudio Gabriel Fermani, Santiago, Villalobos, Federico, Carballo, Pablo, Farina, Sebastian, Guckenheimer, Marilla, Dickfos, Ankit, Ajmera, Chester, Chong, Ralph, Gourlay, Sikandar, Hussaini, Yi Jia Lee, Adeeb, Majid, Peter, Martin, Rebecca, Miles, Owen James Morris, Jamie, Phua, William, Ridley, Tarunpreet, Saluja, Ryan Renxin Tan, Jen, Teh, Anna, Wells, Bharti, Arora, Qaasim, Dollie, Debbie, Ho, Yanru, Ma, Omattage Mahasha Perera, Anthony, Truong, Amanda Caroline Dawson, Bryan, Lim, Upuli, Pahalawatta, Jacqueline, Phan, Xiao-Ming Sarah Woon-Shoo-Tong, Andrea, Yeoh, Lillian, Charman, Andrew, Drane, Sharon, Laura, Charmaine Chu Wen Lo, Amy, Mozes, Rita, Poon, Hao Han Tan, Ellen, Wall, Prakshi, Chopra, Jasmine De Giovanni, Bal, Dhital, Brian, Draganic, Alexander, Duller, Jonathan, Gani, Yao Kuan Goh, Jun Young Jeong, Brendan, Mcmanus, Prakash, Nagappan, Peter, Pockney, Anya, Rugendyke, Mahsa, Sarrami, Stephen, Smith, Vanessa, Wills, Hsu Ven Wong, Geoffrey, Ye, Geoffrey, Zhang, Ethan, Brooker, Daniel, Feng, Bonnie, Lau, Carlin, Ngai, Sarah, Birks, David, Gyorki, Jaime Otero de Pablos, Ali, Abbosh, Chris, Gillespie, Ahmed, Mahmoud, Bianca, Kwan, Joshua, Lawson, Andrea, Warwick, Janne, Bingham, Andrew, J Cockbain, Nagendra Naidu Dudi-Venkata, Jordan, Ellaby-Hall, Ben, Finlay, Emily, Humphries, Jade, Pisaniello, Monique, Pisaniello, Salma, Salih, Tarik, Sammour, Haidar Hadri Abd Wahab, April De Silva, Nicola, Hayward, Kartik, Iyer, Guy, Maddern, Gian Andrea Prevost, Naga, Annapureddy, Krishna Pranathi Settipalli, Jeremy, Yeo, Lucy, Hempenstall, Lily, Pham, Shaun, Purcell, Cherry, Talavera, Ashish, I Vaska, Gurpreet, Chaggar, Phillip, Chrapko, Annelise, Cocco, Sarah Michelle Crystal Jade Coulter-Nile, Grahame, Ctercteko, James, French, Houchen, Gong, Martijn, Gosselink, Thuvarahan, Jegathees, Ivan, Jin, Michelle, Kalachov, Kathryn, Kiefhaber, Katherine, Lee, Jason, Luong, Steven, Phan, Henry, Pleass, Kelly, Veale, Zhi, Zeng, Angela, Au, Ashe, Debiasio, Idy, Deng, Jananee, Myooran, Amrita, Nair, Peter, Stewart, Anton, Stift, Lukas Walter Unger, Kerstin, Wimmer, Nabila, Ahmed, Syed, Hasan, Saber, Rahman, Margaret, O'Shea, Greg, Padmore, Adrian, Peters, Pietro, Perduca, Guenda, Pulcina, Nicolas, Tinton, Frederic, Buxant, Elsa, Dabin, Giulia, Garofalo, Francis, Dossou, Freddy Houehanou Rodrigue Gnangnon, Yacoubou Imorou Souaibou, Pako, Motlaleselelo, Omphile, Tlhomelang, Igor Lima Buarque, Gustavo Mendonça Ataíde Gomes, Aldo Vieira Barros, Ilia, Batashki, Nikolai, Damianov, Vladislav, Stoyanov, Dragomir, Dardanov, Svilen, Maslyankov, Plamen, Petkov, George, Todorov, Evgeni, Zhivkov, Aygulya, Akisheva, Miguel Angel Castilla Moreno, Geno, Genov, Ivelina, Ilieva, Tsvetomir, Ivanov, Martin, Karamanliev, Azhar, Khan, Emil, Mitkov, Tsanko, Yotsov, Boyko, Atanasov, Nikolay, Belev, Mihail, Slavchev, Carlos, Nsengiyumva, Elgan, Jones, Simon, Stock, Steve, Kyota, James, Brown, Tresor Mabanza, K, Lemery Nigo Samuel, Chidi, Otuneme, Ngwang, Prosper, Franklin, Umenze, Marylise, Boutros, Natasha, Caminsky, Sinziana, Dumitra, Richard, Garfinkle, Dominique, Morency, Ebram, Salama, Alexander, Banks, Lorenzo, Ferri, Haitian, He, Amit, Katz, Alexander Sender Liberman, Sarkis, Meterissian, Allison, Pang, Elena, Parvez, Usmaan, Hameed, Fahima, Osman, Sangita, Sequeira, Natalie, Coburn, Alisha, Jaffer, Paul, Karanicolas, Matthew, Mosseler, Reilly, Musselman, Xinyuan, Liu, Ching Wan Yip, Juan Sebastian Garces-Otero, Carolina, Guzman, Sebastian, Sierra, Andres Uribe Valencia, Paulo Andrés Cabrera Rivera, Saul, Camelo, Andrea, Gonzalez, Alejandro, González-Orozco, Manuel Santiago Mosquera Paz, Carlos J- Perez Rivera, Felipe, Gonzalez, Andres, Isaza-Restrepo, Laura, Nino-Torres, Natalia Arias Madrid, Maria Clara Mendoza Arango, Justin, Tsandiraki, Damir, Jemendžić, Branislav, Kocman, Oliver, Šuman, Renata, Canic, Darko, Jurišić, Ivana, Karakas, Ana Krizanovic Rupcic, Vlatka, Pitlovic, Josip, Samardžić, Mario, Kopljar, Ivan, Bacic, Edgar, Domini, Robert, Karlo, Danijela, Miljanić, Andrea, Simic, Mariam, Ahmed, Majdi Al Nassrallah, Rabiya, Altaf, Talal, Amjad, Ruba, Eltoum, Heba, Haidar, Alhassan, Hassan, Omar, Khalil, Marwan, Qasem, Rommel, Ramesh, Gautham, Sajith, Maham, Wisal, Jan, Žatecký, Michele, Bujda, Katerina, Jirankova, Ales, Paclik, Aya, Abdallah, Mariam Abdulgawad Almogy, Esraa Ayman El-Sawy, Ahmed Moustafa ElFayoumy, Nourhan, Elghareeb, Nourhan Ahmed Esmat, Ahmed, Fadel, Abdullah, Habater, Heba, Hamdy, Amr, Hefni, Marwa, Kamal, Norhan Mohamed Abobakr, Ahmed, Sayed, Nancy, Shaker, Ehab, Taha, Hoda, Tharwat, Omar, Zakaria, Ibrahem, Abdelmotaleb, Ali, Al-Dhufri, Hamza, S Al-Himyari, Enas El Sheikh, Asmaa, Eldmaty, Aya, Elkhalawy, Ahmed, M Elkhashen, Kithara, Magdy, Safa, Mostafa, Habib Doutoum Sadia, Mohamed Mahmoud Saleh, Dina, Samir, Mohamed Yahia Mohamed Ali, Mahmoud, A Nassar, Samar, Abdelhady, Aly, Abdelrazek, Israa, Abdelsalam, Aya, El-Sawy, Eman, Essam, Mohamed, Gadelkarim, Khaled, Ghaly, Mohamed, Hassabalnaby, Rana, Masarani, Nourhan Mohamed Shaaban, Ahmed, Sabry, Menatalla, Salem, Nourhan Akram Soliman, Diaaaldin, Zahran, Moustafa Ramadan Abou El Soud, Esraa Tarek Badr, Hala, Borham, Nehal, Elmeslemany, Mohammad, Elsayed, Fawzia, Elsherif, Sara, Eslam, Gehad, Gaber, Sondos, Ibrahim, Yara, Kamh, Abdelrahman, Mahmoud, Shimaa Gamal Mohamed, Eman, Morshedy, Cinderella, Omar, Fatima Salem Soliman, Shaza, Abdelkawy, Naglaa, Abdelmohsen, Mahmoud, Abdelshakour, Ahmed, Dahy, Norhan, Gamal, Mohammed, Gamal, Ahmad, Hasan, Helal, Hetta, Nehad, Mousa, Mohamed, Omar, Somia, Rabie, Mahmoud, Saad, Bakeer, Saleh, Marwa Sayed Mohamed, Muhammad, Shawqi, Heba Abdelhady Mousa, Mostafa, Alnoury, Mohamed, Elbealawy, Ahmed, Elshafey, Muhammad Essam Ibrahim El Desouki Muhammad Ahmed, Mennatullah, Ghonaim, Fawzy, Hgag, Mohamed, Ibrahim, Mahmoud, Morsy, Mohamed Reda Loaloa, Ahmed, Refaat, Hadeer, Samir, Fatma, Shahien, Mohamed, Sobhy, Fathy, Sroor, Esraa, Abdellatif, Marina, Adel, Amr Abdelghani Afifi, Eman, Afifi, Marco, Antaky, Amr, Dawoud, Naira El Zoghby, Amira, El-Remaily, Ali Abdelazez Elzanfaly, Ahmed, Gadallah, Fatma Alzahraa Gamal, Omar, Hashem, Shrouk Medhat Youssef, Aliaa Muhammad Attyah, Malak, Munir, Omar, Shazly, Esraa, Taha, Karim, Wilson, Sawsan, Adel, Asmaa, Ali, Esraa, Eid, Esraa, Elhelow, Marwa, Elmahdy, Bassant, Elshatby, Amany Hossam El-Din Zakaria, Ahmad, Hossny, Eman, Ibrahim, Ahmed, M Yonis, Maram, Metwalli, Basant, Yousry, Esraa, Zid, Mina, A Yacoub, Ahmed, Abdelhakim, Nervana, Abouelsoad, Mo'Min, Alkhatib, Ahmed, Ashraf, Alaa, Ashraf, Yasmin, Elazab, Mahmoud, Elfanty, Osama, Elkabir, Mai, Elsayed, Ahmed, Elshimy, Hager, Elsobky, John, Eskander, Ahmed, Gad, Ward, Hamsho, Noura Khaled Abdelwahed, Menna, Magdy, Dalia, Moharam, Abeer, Osama, Shereen, Ramadan, Radwa, Roum, Taqwa, Sayed, Tarneem, Shehada, Ahmed Mohy Zidan, Khalid, Abbas, Amr, Ali, Mohamed, Attia, Mohamed, Balata, Ayman El Nakeeb, Mohamed Ibrahim Elsayed Elewaily, Ahmed, Elfallal, Hossam, Elfeki, Ahmed, Elkhadragy, Sameh, Emile, Helmy, Ezzat, Hasnaa, Hosni, Islam, Mansour, Waleed, Omar, Gehad, Othman, Kareem, Sadek, Mostafa, Shalaby, Noura, Shehab-Eldeen, Rawda Anas Khalifa, Helmy, Badr, Mostafa, Eldeep, Ahmed, Eldeep, Amany Eldoseuky Mohammed, Salwa, Khallaf, Eman Magdy Hegazy, Rokia, Mahmoud, Pola, Mikhail, Mahmoud, Morsi, Sara, Mowafy, Dina, Raafat, Amina, Safy, Marwa, Sera, Ahmed Shible Sera, Mostafa Salim Mohamed AbdAllah, Muhammad, Abdelkader, Abdulrahman Osama Abdou, Ahmedgaber, Ahmed, Shireen, Gaafar, Fatma Ibrahim Negm, Mina, Lapic, Ahmed, Maher, Hagar, Mahmoud, Ahmed, Mostafa, Mohamed, Samir, Fatma, Samy, Nourhan, Semeda, Hind, I Shalaby, Alaa, El-Taweel, Ahmed Galal Elnagar, Ahmed Gamal Hemidan, Mohamed, Hussein, Ahmed, A Kandil, Moawad, Mf, Ayat Allah Nasser Hamamah, Mostafa, Soliman, Mohamed, Abdelkhalek, Noura Abdelmaksoud Tawakel, Ahmed Mohamed Abdelwahed, Alrawy, Abdou, Khalid, Atallah, Mohammed Yasser Elsherbeny, Eman, Emara, Mohamed, Hamdy, Omar, Hamdy, Amira, Haron, Salma, Ismail, Islam Hany Metwally, Nihal Mohamed Hamed Elgaml, Ahmed, Nassar, Basel, Refky, Mirna, Sadek, Mahmoud, Saleh, Asmaa, Yunes, Mai, Zakaria, Mohammed, Zuhdy, Notila, Fayed, Mohammed Mustafa Hassan Mohammed, Sander, Kütner, Priit, Melnik, Indrek, Seire, Toomas, Ümarik, Eppu, Ainoa, Verner, Eerola, Hanna, Koppatz, Laura, Koskenvuo, Ville, Sallinen, Sini, Takala, Jevgeni, Katunin, Arto, Turunen, Niki, Christou, Muriel, Mathonnet, Vincent, Lavoue, Krystel Nyangoh Timoh, Lucie, Soulabaille, Romain, Lesourd, Aude, Merdrignac, Laurent, Sulpice, Benoît, André, Elodie, Chantalat, Charlotte, Vaysse, Bertrand, Dousset, Sebastien, Gaujoux, Gregory, Martin, Octavian, Clonda, Domantas, Juodis, Klaus, Kienle, Andras, Mravik, Samuel, Palmer, Gabor, Szabadhegyi, Anita Eseenam Agbeko, Solomon, Gyabaah, Frank Enoch Gyamfi, Nuhu, Naabo, Atta Owusu Senior, Joseph, Yorke, Frank, Owusu, Francis, Abantanga, Theophilus Teddy Kojo Anyomih, Abdul-Jalilu Mohammed Muntaka, Emmanuel Owusu Abem, Mohammed, Sheriff, Paul, M Wondoh, Dimitrios, Balalis, Dimitrios, Korkolis, Georgios, Gkiokas, Eirini, Pantiora, Theodosios, Theodosopoulos, Argyrios, Ioannidis, Konstantinos, Konstantinidis, Sofia, Konstantinidou, Nikolaos, Machairas, Anna, Paspala, Anastasia, Prodromidou, Christos, Chouliaras, Konstantinos, Papadopoulos, Ioannis, Baloyiannis, Ioannis, Mamaloudis, George, Tzovaras, Ioanna, Akrida, Maria-Ioanna, Argentou, Stylianos, Germanos, Evangelos, Iliopoulos, Ioannis, Maroulis, George, Skroubis, George, Theofanis, Christos, Chatzakis, Orestis, Ioannidis, Lydia, Loutzidou, Panagiotis, Karathanasis, Nikolaos, Michalopoulos, Charalampos, Theodoropoulos, Dimitrios, Theodorou, Tania, Triantafyllou, Zoe, Garoufalia, Natasha, Hasemaki, Michalis, Kontos, Gregory, Kouraklis, Stylianos, Kykalos, Theodore, Liakakos, Eustratia, Mpaili, Alexandros, Papalampros, Dimitrios, Schizas, Athanasios, Syllaios, Ekaterini Christina Tampaki, Antonios, Tsimpoukelis, Maria Ioanna Antonopoulou, Eirini, Deskou, Dimitrios, K Manatakis, Dimitrios, Papageorgiou, Menelaos, Zoulamoglou, Christos, Anthoulakis, Michalis, Margaritis, Nikolaos, Nikoloudis, Veronica, Campo, André, Ceballos, Mario-Andrés, Flores, Waleska, Giron, Donghyun, Ko, Gabriel, Martinez, Verónica Rivera Lara, Nataly, Rueda, Andres, Sanchez, Jorge Carlos Guillermo Tejeda Garrido, Alvaro Eduardo Alvarez Rivera, Elvis Benjamin Bamaca Ixcajoc, Lilian Elizabeth Barreda Zelaya, Patricia, Chacòn-Herrera, Ligia Margarita Corea Ruiz, Guillermo, Echeverria-Davila, Mario, Garcia, Danilo, García, Edgar Fernando Gutiérrez Mayen, Noriega, José, Nery, Mazariegos, Diego, Méndez, Michael Paniagua Espinoza, David, Bardos, Marton, Benke, Kristof, Illes, Balint András Kokas, Réka, Szabó, Akhila, Appukuttan, Anjitha, Asok, D K, Vijaykumar, Kapil, Malik, Praveen, Ravishankaran, Ritesh, Tapkire, Guru, Moorthy, Joyner, Abraham, Ramesh, Muthuvel, John, Alapatt, Abhay, Kattepur, Nizamudheen, Pareekutty, Mebanshanbor, Garod, Caleb, Harris, Cliff, Wanniang, Ashish, Gupta, Deepak, Nehra, Sanjeev, Parshad, Rajgopal, Acharya, Rajendra, Badwe, Manish, Bhandare, Urvashi, Jain, Karishma, Kirti, Nita, Nair, Shailesh, Shrikhande, Purvi, Thakkar, Premkumar, Anandan, C S, Archana, Arun Holenarasipur Narasannaiah, Tejaswi, Jagarlamudi, M R, Rashmi, Mallikarjuna, Manangi, Abhishek, Raghavendra, K Seshagiri Rao, Vinay, S, Vinay, Sajjan, Aneesh, Shenoy, Santhosh Shivashankar Chikkanayakanahalli, Kavya, Tharanath, Sushmita, V, Peter, Adidharma, Raksheeth, Agarwal, Phebe Anggita Gultom, Ghafur Rasyid Arifin, Matthew, Billy, Zatira, Elfizri, Alessa, Fahira, Devi, Felicia, Triana Hardianti Gunardi, Nadya, Johanna, Nadia Rahmadiani Nugrahadi, Sonar Soni Panigoro, Siti, Rahmayanti, Retta Catherina Sihotang, Santi Yuanita Brata, Hadi, Winoto, Nastaran, Barati, Manoochehr, Karami, Hamidreza, Khorshidi, Homa, Naderifar, Mazin, A Abdulla, Maggie, Coleman, Ronan, J Doherty, Rob, Hannon, Brenda, Murphy, Aine, Stakelum, Des, Winter, Lylas, Aljohmani, Richard, Farnan, Yeshey, Seldon, Tanna, Tan, Shriya, Varghese, Mohammad, Alherz, Muaaz, Ather, Mohammad, Bajilan, Vivien, Graziadei, Isobel, Pilkington, Omar, Quidwai, Paul, Ridgway, Haaris, Shiwani, Abd Al-Rahman Tahir, Eimear, Blunnie, Daniel, Burke, Niall, Kennedy, Kate, Macdonagh, Maeve, O'Neill, Siobhan, Rooney, Giuseppe, Falco, Guglielmo, Ferrari, Simone, Mele, Gabriela Elisa Nita, Lara, Ugoletti, Maurizio, Zizzo, Gianmaria, Confalonieri, Giovanni, Pesenti, Fulvio, Tagliabue, Gianluca, Baronio, Deborah, Ongaro, Giacomo, Pata, Bruno, Compagnoni, Renato, Salvadori, Lucio, Taglietti, Nicola, D'Alessandro, Pierpaolo Di Lascio, Giovanni, Pascale, Luca, Bortolasi, Tommaso, Campagnaro, Massimo, Carlini, Giorgio, Lisi, Davide, Lombardi, Corrado, Pedrazzani, Domenico, Spoletini, Giulia, Turri, Paola, Violi, Donato Francesco Altomare, Fabrizio, Aquilino, Nicola, Musa, Vincenzo, Papagni, Arcangelo, Picciariello, Leonardo, Vincenti, Dario, Andreotti, Savino, Occhionorelli, Matteo, Tondo, Stefano Maria Massimiliano Basso, Paolo, Ubiali, Riccardo, Cirelli, Marco Enrico Mario Maino, Guglielmo Niccolò Piozzi, Emanuele, Picone, Rosa, Scaramuzzo, Giovanni, Sinibaldi, Alfonso, Amendola, Lorenzo, Anastasio, Luigi, Bucci, Emanuele, Caruso, Antonio, Castaldi, Sara Di Maso, Vincenza Paola Dinuzzi, Giovanni, Esposito, Maria, Gaudiello, Mariano Cesare Giglio, Paola Antonella Greco, Gaetano, Luglio, Andrea, Manfreda, Ester, Marra, Federica, Mastella, Gianluca, Pagano, Roberto, Peltrini, Vincenzo, Pepe, Michele, Sacco, Viviana, Sollazzo, Giovanni, Spiezio, Ettore, Cianchetti, Nunzia, Menduni, Michele Maria Carvello, Francesca Di Candido, Antonino, Spinelli, Fabio, Corsi, Luca, Sorrentino, Fabio, Marino, Emanuele Luigi Giuseppe Asti, Luigi, Bonavina, Emanuele, Rausa, Martina, Asta, Andrea, Belli, Francesco, Bianco, Carmela, Cervone, Paolo, Delrio, Armando, Falato, Andrea Fares Bucci, Rita, Guarino, Ugo, Pace, Daniela, Rega, Emilia De Luca, Gaetano, Gallo, Giuseppe, Sammarco, Giuseppe, Sena, Giuseppina, Vescio, Letizia, Santandrea, Giampaolo, Ugolini, Davide, Zattoni, Nicola, Chetta, Gaetano, Logrieco, Serafino, Vanella, Gianluca, Garulli, Nicola, Zanini, Andrea, Bondurri, Francesco, Cammarata, Francesco, Colombo, Diego, Foschi, Giulia Maria Beatrice Lamperti, Anna, Maffioli, Gianluca Matteo Sampietro, Al'Ona, Yakushkina, Gloria, Zaffaroni, Enrico, Cicuttin, Maria Grazia Sibilla, Harmony, Impellizzeri, Marco, Inama, Gianluigi, Moretto, Sylvie, Mochet, Elisa, Ponte, Antonella, Usai, Stefano, Mancini, Andrea, Sagnotta, Luigi, Solinas, Elisa, Bolzonaro, Nicolò, Tamini, Gianluca, Curletti, Raffaele, Galleano, Michele, Malerba, Sofia, Campanella, Gianfranco, Cocorullo, Francesco, Colli, Paolino De Marco, Nicolò, Falco, Tommaso, Fontana, Leonel Jospin Kamdem Mambou, Antonella La Brocca, Leo, Licari, Brenda, Randisi, Giovanna, Rizzo, Giulia, Rotolo, Giuseppe, Salamone, Roberta, Tutino, Paolina, Venturelli, Stefano, Malabarba, Alessandro, Sgrò, Ivan, Vella, Bruno, Cirillo, Daniele, Crocetti, Giorgio De Toma, Pierfrancesco, Lapolla, Andrea, Mingoli, Paolo, Sapienza, Angela, Belvedere, Stefania, Bianchini, Margherita, Binetti, Arianna, Birindelli, Valeria, Tonini, Mauro, Podda, Fabio, Pulighe, Michele De Rosa, Lorenzo, Bono, Felice, Borghi, Paolo, Geretto, Maria Carmela Giuffrida, Corrado, Lauro, Alessandra, Marano, Luca, Pellegrino, Paola, Salusso, Diego, Sasia, Michela, Campanelli, Alberto Realis Luc, Mario, Trompetto, Roberto, Cardia, Nicola, Cillara, Antonio Nicola Giordano, Antonio, Costanzo, Mario Alessandro Giovilli, Luca, Turati, Silvestro, Canonico, Sciaudone, Guido, Francesco, Selvaggi, Lucio, Selvaggi, Nader, Albsoul, Ahmad, Albsoul, Ala'a Aldeen Alkhatib, Osama, Alsallaq, Justin, Z Amarin, Rami, Ayoub, Isam, Bsisu, S El Muhtaseb, M, Mohammad, Jabaiti, Jamal, Melhem, Yasmeen, Z Qwaider, Mohammad Hasan Salameh, Ahmad, Suleihat, Haya, H Suradi, Mohammad, Alammarin, Almoutuz, Aljaafreh, Mohammad Bani Hani, Zeina Bani Hani, Farah Bani Hani, Toqa, Fahmawee, Shadi, Hamouri, Cyrine, Katanani, Ra'Fat, Tawalbeh, Tamara, Tawalbeh, Hassan, Zawahrah, Mohamad, K Abou Chaar, Lana, Abusalem, Mahmoud, Al-Masri, Hani, Al-Najjar, Lutfi, Barghuthi, Zahra, Ahmed, Adnan, Maulana, Omar, Ngotho, Charbel, Kamau, Aruyaru Stanley Mwenda, Fridah, Bosire, Elizabeth, Mwachiro, Robert, Parker, Ian, Simel, Kimutai, Sylvester, Abdulmunem Ahmed Mustafa Althini, Sofian, Elbarouni, Aya Elseed Elbeshina, Ahmed, Gwea, Ans, Malek, Wedad Albashir Masoud Farag, Abdulwahab, Abdalei, Abu Baker Abdel Malik, Areej, Abo-Khammash, Ma'Aly, Abuhlaiga, Nour, Adnan, Marwa, Albaggar, Asma, Alfitory, Asma, Aljanfi, Fakhruddin, Almuzghi, Zohoor, Altumei, Fatima, Alzabti, Hana, Ashoushan, Mohamed, Assalhi, Joma, Azzubia, Sondos, Bnhameida, Malik, Delhen, Houssein, Elshafei, 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Alcides Ylatoma Díaz, Mark Anthony Fontanilla, Joseph Roy Fuentes, Anna Leah Salazar, Genieve, Dominguez, Marc Paul Lopez, Shiela, Macalindong, Mark Augustine Onglao, Arjel, Ramirez, Marie Dione Sacdalan, Mayou Martin Tampo, Gemma Leonora Uy, Jeremiah, Mangahas, Kenneth, Yabut, Joannes Paul Cañete, Bernalynn Eris Cansana, Ernes John Castro, Maria Kaiserin Lipana, Manuel Francisco Roxas, Vlu Jean Zara, Maciej, Chroł, Paula, Franczak, Michał, Orłowski, Piotr, Budzyński, Andrzej, Budzyński, Pawel, Bury, Agata, Czerwińska, Jadwiga, Dworak, Jacek, Dziedzic, Michał, Kisielewski, Jan, Kulawik, Anna, Lasek, Piotr, Małczak, Marcin, Migaczewski, Michał, Pędziwiatr, Magdalena, Pisarska, Dorota, Radkowiak, Mateusz, Rubinkiewicz, Anna, Rzepa, Tomasz, Skoczylas, Maciej, Stanek, Katarzyna, Truszkiewicz, Mateusz, Wierdak, Marek, Winiarski, Piotr, Zarzycki, Anna, Zub-Pokrowiecka, Piotr, Kowalewski, Rafał, Roszkowski, Maciej, Walędziak, Miguel, Tomé, Sara, Patrocinio, Ines, Guerreiro, Filipe, Almeida, 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Macedo Alves, Rita, Peixoto, Catarina, Quintela, Maria João Jervis, Débora, Melo, André, Pacheco, Valter, Paixão, Vera, Pedro, Joana, Pimenta, João Pimenta de Castro, Ana, Rocha, Mircea, Beuran, Cezar, Ciubotaru, Bogdan, Diaconescu, Sorin, Hostiuc, Ionut, Negoi, Bogdan, Stoica, Evgeny, Anokhin, Georgy, Kuznetsov, Giorgi, Oganezov, Fedor, Paramzin, Ekaterina, Romanova, Valeryan, Rutkovskii, Vasilii, Rutkovskii, Mikhail, Shushval, Mikhail, Zabiyaka, Khasan, Dzhumabaev, Valerii, Ivanov, Zaman, Mamedli, Sergey, Achkasov, Artem, Balkarov, Elnur, Nabiev, Marat, Nagudov, Evgeny, Rybakov, Karina, Saifutdinova, Oleg, Sushkov, Lule, Joseph, Isaac, Ndayishimiye, Ntirenganya, Faustin, Alphonse Zeta Mutabazi, Jean Paul Mvukiyehe, Vizir J, P Nsengimana, Carine, Uwakunda, Mohammad Monir Abbas, Nouf, Akeel, Murad, Aljiffry, Kholoud, Awaji, Ali, Farsi, Ghader, Jamjoum, Ahmad, Khoja, Ashraf, Maghrabi, Nadim, Malibary, Mohammed, Nassif, Abdulaziz, Saleem, Abdullah, Sultan, Wail, Tashkandi, Hanaa, 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M., Martin-Borregon, P., Martinez Caballero, J., Nevado Garcia, C., Rodriguez Fraga, P., De Castro Parga, G., Fernandez Veiga, M. P., Garrido Lopez, L., Infante Pino, H., Lages Cal, I., Lopez Otero, M., Nogueira Sixto, M., Paniagua Garcia Senorans, M., Rodriguez Fernandez, L., Ruano Poblador, A., Rufo Crespo, E., Sanchez-Santos, R., Vigorita, V., Alonso Batanero, E., Asnel, D., Cifrian Canales, I., Contreras Saiz, E., De Santiago Alvarez, I., Diaz Vico, T., Fernandez Arias, S., Fernandez Martinez, D., Garcia Bernardo, C., Garcia Florez, L. J., Garcia Gutierrez, C., Garcia Munar, M., Marquez Zorrilla Molina, C. A., Merayo, M., Michi Campos, J. L., Moreno Gijon, M., Otero-Diez, J. L., Rodicio Miravalles, J. L., Solar-Garcia, L., Suarez Sanchez, A., Truan, N., Alejandre Villalobos, C., Caballero Diaz, Y., Jimenez, M., Montesdeoca, D., Navarro-Sanchez, A., Vega, V., Beltran de Heredia, J., Gomez, Z., Jezieniecki, C., Legido Moran, A. P., Montes-Manrique, M., Rodriguez-Lopez, M., Ruiz Soriano, M., Trujillo Diaz, J., Vazquez Fernandez, A., Argudo, N., Pera, M., Torrent Jansa, L., Garcia Dominguez, M., Goded, I., Roldon Golet, M., Talal El-Abur, I., Utrilla Fornals, A., Zambrana Campos, V., Aguilar Martinez, M. D. M., Bosch, M., Garcia-Catala, L., Sanchez-Guillen, L., Artigau, E., Gomez Romeu, N., Julia Bergkvist, D., Espina Perez, B., Morato, O., Olona, C., Dieguez, B., Forero-Torres, A., Losada, M., Gomez-Abril, S., Gonzalvez, P., Martinez, R., Navarro Martinez, S., Paya-Llorente, C., Perez Rubio, A., Santarrufina Martinez, S., Sebastian Tomas, J. C., Trullenque Juan, R., Gegundez Simon, A., Mate, P., Prieto-Nieto, M. I., Rubio-Perez, I., Urbieta, A., Vicario Bravo, M., Abello, D., Frasson, M., Garcia-Granero, A., Abad Gurumeta, A., Abad-Motos, A., Lucena-de Pablo, E., Nozal, B., Ripolles-Melchor, J., Salvachua, R., Ferrero, E., Garcia-Sancho Tellez, L., Picardo, A. L., Rojo Lopez, J. A., Zorrilla Matilla, L. P., Cagigas Fernandez, C., Castanedo Bezanilla, S., Estevez Tesouro, J., Fernandez-Diaz, M. J., Garcia Cardo, J., Gomez Ruiz, M., Gonzalez-Tolaretxipi, E., Jimeno Fraile, J., Poch, C., Rodriguez-Aguirre, M., Troche Pesqueira, N., Trugeda-Carrera, M. S., de la Torre, J., Blanco-Colino, R., Espin-Basany, E., Espinosa-Bravo, M., Morales Comas, C., Reyes Afonso, E., Rivero Deniz, J., Siso Raber, C., Verdaguer Tremolosa, M., Chandrasinghe, P., Kumarage, S., Wijekoon Arachchilage, N., Abdalla Ahmed Elkamel, A., A. Adam, M., Blomme, N., Thorell, A., Wogensen, F., Alga, A., Ansarei, D., Celebioglu, F., Heinius, G., Nigard, L., Pieniowski, E., Ahlqvist, S., Bjorklund, I., Franberg, A., Hakansson, M., Adamo, K., Franklin, O., Sund, M., Wiberg, R., Andersson, Y., Chabok, A., Nikberg, M., Kugelberg, A., Canonica, C., Christoforidis, D., Fasolini, F., Gaffuri, P., Giuliani, M., Meani, F., Popeskou, S. G., Pozza, S., Wandschneider, W., Peterer, L., Widmer, L. W., Zimmermann, B., Bakoleas, P., Chanousi, I., Charalampidou, L., Grochola, L. F., Heid, F., Ntaoulas, S., Outos, M., Peros, G., Podolska-Skoczek, H., Reinisch, K. B., Zielasek, C., Demartines, N., Gilgien, J., Kefleyesus, A., St-Amour, P., Toussaint, A., Alhimyar, M., Alsaid, B., Alyafi, A., Alkhaledi, A., Kouz, B., Omarain, A., Al-Sabbagh, Y., Alkhatib, H., Sara, S., Alhaj, A., Danial, A., Kadoura, L., Maa Albared, S., Monawar, Y., Nahas, L., Abd, B., Saad, A., Wakkaf, H., Bouzaiene, H., Ghalleb, M., Akaydin, E., Akbaba, A. C., Atakul, O., Baltaci, E., Besli, S., Burgu, G., Cenal, U., de Muijnck, C., Demirkaya, H. C., Dogruoz, A., Gezer, Z. I., Gundogdu, Y., Kara, M., Korkmaz, H. K., Kurtoglu, G. K., Ozben, V., Ozmen, B. B., Pektas, A. M., Sel, E. K., Yenidunya, N., Bengur, F. B., Oral, B. M., Yozgatli, T. K., Abdullayev, S., Gunes, M. E., Sahbaz, N. A., Banaz, T., Kargici, K., Kuyumcu, O. F., Yanikoglu, E., Yesilsancak, M., Yilmaz, D., Aktas, M. K., Rencuzogullari, A., Isik, A., Leventoglu, S., Yalcinkaya, A., Yuksel, O., Kalayci, M. U., Kara, Y., Sarici, I. S., Akin, A., Alemdag, G. N., Arslan, E., Baki, B. E., Bodur, M. S., Calik, A., Candas Altinbas, B., Cihanyurdu, I., Erkul, O., Gul, B., Guner, A., Kose, B., Semiz, A., Sevim, Tayar, S., Tomas, K., Tufek, O. Y., Turkyilmaz, S., Ulusahin, M., Usta, A., Yildirim, R., Guler, S. A., Tatar, O. C., Varol, E., Kirimtay, B., Uysal, M., Yildiz, A., Kose, E., Ciftci, A. B., Colak, E., Eraslan, H., Kucuk, G. O., Yemez, K., Lule, H., Bienfait, M., Bua, E., Okalany, N., Basarab, M., Bielosludtsev, O., Kolhanova, K., Perepelytsia, K., Romanukha, K., Savenkov, D., Siryi, S., Tereshchenko, M., Viacheslav, N., Volovetskyi, A., Kebkalo, A., Tryliskyy, Y., Tyselskiy, V., Bruce, E., Chow, B. L., Iddles, E., Mcguckin, S., Newall, N., Ramsay, G., Sharma, P., Stewart, C., Wong, J., Badran, A., Bath, M., Belais, F., Butt, E., Joshi, K., Kapur, M., Shaw, M., Townson, A., Williams, C. Y. K., Gray, T., Greig, R., Husain, M., Murray, E., Mustafa, A., Asif, A., Gokul, A., Shah, M., Akitikori, M. T., Charalabopoulos, A., Davidson, S., Mcnally, S., Rupani, S., Juma, F., Mills, S. C., Muirhead, L., Sellars, K., Walsh, U., Warren, O., Chambers, A., Hunt, R., Boyce, S., Cornwall, H., Tol, I., Argyriou, E. O., Eardley, N., Povey, M., Aithie, J. M. S., Irfan, A., Mcguigan, M. -C., Starr, R., Warren, C. R., Archibald, J., Kirby, G., Kisyov, I., Khoo, C. K., Lee, R., Photiou, D., Davis, R., Prasad, U., Yang, P. Z., Bird, J., Leung, E., Summerour, V., Currow, C., Kiam, J., Tan, G. J. S., Muthusami, A., Pegba-Otemolu, I., Urbonas, T., Nunoo-Mensah, J., Smolskas, E., Boddy, A., Gravante, G., Hunter, D., Andrew, D., Koh, A., Thompson, A., Adams, L., Clements, H. A., De Silva, K., Ekpete, O., Haque, S., Henderson, S., Ibrahim, B., Jayasinghe, T., Livie, J., Mailley, K., Nair, G., Tan, D., Baggaley, C., Dawidziuk, A., Szyszka, B., Barter, C., Gandhi, N., Hassell, K., Hitchin, S., Kelsall, J., Nagy, E., Nessa, A., Whisker, L., Yanni, F., Ali, M., Arora, D., Hediwattege, S., Kumarasinghe, N., Rathore, M., Tennakoon, A., Ali Ahmad, S. M., Bajomo, O., Nadira, F., Celentano, V., Griffiths, E., Karri, R. S., Mak, J. K. C., Pipe, M., Bhatti, M. I., Rabie, M., Boyle, C., Hamilton, D., Mihuna, A., Ng, J. C. K., Nicholson, G., Oliwa, A., Pearson, R., Rose, A., Yong, S. Q., Boereboom, C., Hanna, M., Walter, C., Greensmith, T. S., Mitchell, R., Monaghan, E., Crawford, J., Moug, S., Blackwell, J., Boyd-Carson, H., Herrod, P., Al-Allaf, O., Beattie, M., Bullock, C., Burman, S., Clark, G., Flamey, N., Flannery, O., Harding, A., Kodiatt, B., Lawday, S., Mahapatra, S., Mukundu Nagesh, N., Ng, M., Rye, D., Yoong, A., Clark, L., Deans, C., Edirisooriya, M., Carrington, E. V., Wong, T. L. E., Yusuf, B., Chamberlain, C., Duke, K., Kmiotek, E., Botes, A., Condie, N., Schrire, T., Shah, R., Thomas-Jones, I., Yates, C., Anthony, N., Matthews, E., Sahnan, K., Tankel, J., Tucker, S., Winter Beatty, J., Ziprin, P., Duggan, W., Kantartzi, A., Sridhar, S., Khaw, R. A., Srivastava, P., Underwood, C., Alves do Canto Brum, H., Chopra, S., Davis, L., Hughes, R., Tulley, J., Alberts, J., Athisayaraj, T., Olugbemi, M., Ahmad, K., Chan, C., Chapman, G., Fleming, H., Fox, B., Grewar, J., Hulse, K., Rutherford, D., Sinead, M., Speake, D., Vaughan-Shaw, P. G., Christodoulides, N., Kudhail, S., Welch, M., Husaini, S. M., Lambracos, S., Anyanwu, C., Suresh, R., Thomas, J. S., Gleeson, E., Platoff, R., Saif, A., Enumah, Z., Etchill, E., Gabre-Kidan, A., Bernstein, M., Carrano, F. M., Connors, J., Lynn, P., Melis, M., Newman, E., Foster, D. S., Perrone, K., Titan, A., Ahmad, S., Bafford, A. C. M. D., Dal Molin, M., Hanna, N., Zafar, S. N., Hemmila, M., Napolitano, L., Wong, J. J., Chandler, J., Wood, L., Wren, S., Ottesen, T., You, L., Yu, K., Arcienega Yanez, M. D. P., Ferreira Fernandes, M., Gonzalez, D., Cubas, S., Gonzalez, M. C., Zubiaurre, V., Demolin, R., Giroff, N., Sciuto, P., Campos, M., Rodriguez Cantera, G., Deepika, G., Simuchimba, E., Bulaya, A., Chibuye, C., Chirengendure, B., Kabale, M. -R., Kabongo, K., Munthali, J., Mweso, O., Pikiti, F., Otieno, J., Lai, L. T., Blackman, B., Subramaniam, S., Karim, R., Kok, N., Lee, Y. D., Ali, S., Sinha, A., Corrigan, R., Barnes, N., Wong, F., Dennis, G., Jedamzik, J., Phillips, E., Piette, W., Van hentenryck, M., Koco, H., Lawani, S., Kassa, M. W., Santos Bezerra, T., Gribnev, P., Dimitrov, D., Krastev, P., Oum, S., Bonghaseh, D. T., Al Farsi, M., Alsharqawi, N., Acevedo, V., Castillo Barbosa, A. C., Giron, F., Leon Rodriguez, J. P., Kucan, D., Rosko, D., Barsic, N., Zupan, D., Hegazi, A., Truncikova, V., Fryba, V., Mohamed, M., Nagi, A., Rashad Temerik, A., Elshawy, M. E., Mahmoud, M. I., Anwar, M., Rageh, T., Elmokadem, A., Gaballa, K., Teppo, S., Pengerma, P., Ballouhey, Q., Bergeat, D., Weyl, A., Hain, E., Gyedu, A., Yenli, E., Osei-Poku, D., Rompou, V. -A., Zoikas, A., Gaitanidis, A., Koukis, G., Perivoliotis, K., Tavlas, P., Galanos-Demiris, K., Zografos, G., Karavokyros, I., Xanthopoulou, G., Iordanidou, E., Ayau, F., Garcia, A., Damjan, P., Wason, D., B L, A., Rangganata, E., Kamath, P., O'Connor, D. B., Pinto, M., Perrone, F., Tropeano, F. P., Troilo, F., Bossi, D., Scala, D., Pulitano, L., Carella, M., Pietrabissa, A., Gori, A., Giraudo, G., De Simone, V., Russo, A. A., Braccio, B., Al-Taher, R., Athamneh, S., Parker, A., Sawiee, A., Kattia, A., Tababa, O., Shaeeb, Z., Syminas, V., Jurgaitis, J., Damuleviciene, G., Svagzdys, S., Razafimanjato, N. N. M., Chieng Loo, L., Tiong, I. C., Wan Muhmad, W. F., Vijeyan, H., Li Ying, T., Grech, G., Arrangoiz, R., Jimenez Ley, V. B., Arizpe, D., Lagunes Lara, E., Castro Lopez, E. V., Eaazim, J., Gordinou de Gouberville, M., Bastiaenen, V., Rottier, S., Nahab, F., Ji, M. Y., Seyoji, M., Nwachukwu, C., Emeghara, O., Muhammed, S. E., Idowu, A., Sowemimo, O., Ogundoyin, O., Akande, O., Lott, A., Nadeem, M., Laghari, A. A., Loya, A., Mushtaq, H., Abdullah, M. T., Abuhilal, B., Atawneh, M., Hamdan, H., Alhabil, B., Srour, A., Mousa, I., Da Silva Medina, L., Bartosiak, K., Ferreira, P., Francisco, V., Lemos, R., Frutuoso, L., Fernandes, S., Fonseca, T., Pereira, J., Rachadell, J., Torre, A., Madeira Martins, F., Carvalho, A. C., Rodrigues Ferreira, J., Ribeiro da Silva, B., Devesa, H., Vieira, A., Monica, I., Amaro, M., Sousa, D., Reia, M., Louro, J., Martins, A., Dominguez, J., Santos, I., Freitas Oliveira, N. M., Pereira, J. C., Silva-Vaz, P., Freire, L., Escrevente, R., Negoita, V. M., Shakhmatov, D., Nezerwa, Y., Radulovic, R., Obery, G., Viljoen, F., Mendes, T., Suarez, A., Moncada, E., Fernandez-Hevia, M., Curtis Martinez, C., Gil Garcia, J. M., Gonzalez Zunzarren, M., Idris, T., Eklov, K., Grahn, O., Amin, L., Blomqvist, M., Ajani, C., Kraus, R., Seeger, N., Willemin, M., Rayya, F., Ayash, M., Msouti, R., Kannas, I., Abazid, E., Esper, A., Slim, S., Kavcar, A. S., Aytac, E., Dural, A. C., Ilker, A., Eray, I. C., Kurnaz, E., Altiner, S., Tepe, M. D., Sahin, C., Savli, E., Innocent, A., Babirye, L., Diachenko, A., Hordoskiy, V., Curry, H., Chau, C. Y. C., Robertson, H., Lennon, H., Loi, L., Kirkham, E., Mccann, C., Watts, D., Gurung, B., Wilson, M., Tribedi, T., Garofalo, E., Zahra, B., Macdonald, S., Daniels, I., Ng, N., Khosla, S., Olivier, J., Yue, S. Y. P., Suresh, G., Wellington, J., Lorejo, E., Mossaad, M., Crutcher, M., Alimi, M., Baiu, I., Abdou, H., Conway, A., Peck, C., Perdomo Perez, M. A., Zulu, S., Nakazwe, M., Burger, S., Davies, J., Donaldson, R., Ede, C., Garden, O. J., Lesetedi, C., Mabedi, C., Magill, L., Makinde Alakaloko, F., Makupe, A., Monahan, M., Mulira, S., Muller, E., Musowoyo, J., Olory-Togbe, J. L., Roberts, T., Smith, M., Tayler, V., Windsor, J., Yepez, R., Sundar, S., Runigamugabo, E., Verjee, A., Chen, J., Daya, L., El Aroussi, N., Farina, V., Gnintedeme Olivier, T., Gonzales Nacarino, M., Hammani, A., Honjo, S., Jacobs, R., Kimura, H., Nkoronko, M., Oscullo Yepez, J. J., Pin Hung, W., Raj, A., Romani Pozo, A., Rommaneh, M., Sassamela Fabiano, S. C., Shiroma Gago, C. M., Srinivas, A., Sung, C. -Y., Tai, A., Valle Aranda, Y. C., Venturini, S., Wilguens Lartigue, J., Public and occupational health, AMS - Sports, APH - Health Behaviors & Chronic Diseases, CCA - Cancer Treatment and quality of life, Amsterdam Gastroenterology Endocrinology Metabolism, Cancer Center Amsterdam, and Albarella, Sara

Subjects
global surgery, hospitals, humans, income, neoplasms, postoperative period, poverty, prospective studies, no keywords listed, General Medicine, Prospective Studie, Hospital, Settore MED/18 - Chirurgia Generale, outcome, Hospitals, Humans, Income, Neoplasms, surgery, Postoperative Period, Poverty, Prospective Studies, cancer surgery, Human, hospital facilities
Abstract

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p

Published
2022

39. Short-term forecasting of the prevalence of clinical trachoma: utility of including delayed recovery and tests for infection

Author

Liu, Fengchen, Porco, Travis C, Amza, Abdou, Kadri, Boubacar, Nassirou, Baido, West, Sheila K, Bailey, Robin L, Keenan, Jeremy D, and Lietman, Thomas M

Subjects
Paediatrics, Biomedical and Clinical Sciences, Prevention, Good Health and Well Being, Humans, Models, Theoretical, Niger, Prevalence, Trachoma, World Health Organization, Model, Mass drug administration, Forecast, Prediction, Medical Microbiology, Public Health and Health Services, Mycology & Parasitology, Tropical Medicine, Microbiology, Medical microbiology
Abstract

BackgroundThe World Health Organization aims to control blinding trachoma by 2020. Decisions on whether to start and stop mass treatments and when to declare that control has been achieved are currently based on clinical examination data generated in population-based surveys. Thresholds are based on the district-level prevalence of trachomatous inflammation-follicular (TF) in children aged 1-9 years. Forecasts of which districts may and may not meet TF control goals by the 2020 target date could affect resource allocation in the next few years.MethodsWe constructed a hidden Markov model fit to the prevalence of two clinical signs of trachoma and PCR data in 24 communities from the recent PRET-Niger trial. The prevalence of TF in children in each community at 36 months was forecast given data from earlier time points. Forecasts were scored by the likelihood of the observed results. We assessed whether use of TF with additional TI and PCR data rather than just the use of TF alone improves forecasts, and separately whether incorporating a delay in TF recovery is beneficial.ResultsIncluding TI and PCR data did not significantly improve forecasts of TF. Forecasts of TF prevalence at 36 months by the model with the delay in TF recovery were significantly better than forecasts by the model without the delay in TF recovery (p = 0.003). A zero-inflated truncated normal observation model was better than a truncated normal observation model, and better than a sensitivity-specificity observation model.ConclusionThe results in this study suggest that future studies could consider using just TF data for forecasting, and should include a delay in TF recovery.Trial registrationClinicaltrials.gov NCT00792922.

Published
2015

40. Short-term Forecasting of the Prevalence of Trachoma: Expert Opinion, Statistical Regression, versus Transmission Models.

Author

Liu, Fengchen, Porco, Travis C, Amza, Abdou, Kadri, Boubacar, Nassirou, Baido, West, Sheila K, Bailey, Robin L, Keenan, Jeremy D, Solomon, Anthony W, Emerson, Paul M, Gambhir, Manoj, and Lietman, Thomas M

Subjects
Humans, Trachoma, Anti-Bacterial Agents, Prevalence, Regression Analysis, Endemic Diseases, Models, Biological, Forecasting, Expert Testimony, Child, Child, Preschool, Infant, Niger, Randomized Controlled Trials as Topic, Models, Biological, Preschool, Tropical Medicine, Biological Sciences, Medical and Health Sciences
Abstract

BackgroundTrachoma programs rely on guidelines made in large part using expert opinion of what will happen with and without intervention. Large community-randomized trials offer an opportunity to actually compare forecasting methods in a masked fashion.MethodsThe Program for the Rapid Elimination of Trachoma trials estimated longitudinal prevalence of ocular chlamydial infection from 24 communities treated annually with mass azithromycin. Given antibiotic coverage and biannual assessments from baseline through 30 months, forecasts of the prevalence of infection in each of the 24 communities at 36 months were made by three methods: the sum of 15 experts' opinion, statistical regression of the square-root-transformed prevalence, and a stochastic hidden Markov model of infection transmission (Susceptible-Infectious-Susceptible, or SIS model). All forecasters were masked to the 36-month results and to the other forecasts. Forecasts of the 24 communities were scored by the likelihood of the observed results and compared using Wilcoxon's signed-rank statistic.FindingsRegression and SIS hidden Markov models had significantly better likelihood than community expert opinion (p = 0.004 and p = 0.01, respectively). All forecasts scored better when perturbed to decrease Fisher's information. Each individual expert's forecast was poorer than the sum of experts.InterpretationRegression and SIS models performed significantly better than expert opinion, although all forecasts were overly confident. Further model refinements may score better, although would need to be tested and compared in new masked studies. Construction of guidelines that rely on forecasting future prevalence could consider use of mathematical and statistical models.Trial registrationClinicaltrials.gov NCT00792922.

Published
2015

41. The distribution of the prevalence of ocular chlamydial infection in communities where trachoma is disappearing.

Author

Lietman, Thomas M, Gebre, Teshome, Abdou, Amza, Alemayehu, Wondu, Emerson, Paul, Blumberg, Seth, Keenan, Jeremy D, and Porco, Travis C

Subjects
Humans, Eye Infections, Bacterial, Trachoma, Chlamydia Infections, Azithromycin, Anti-Bacterial Agents, Prevalence, Longitudinal Studies, Cross-Sectional Studies, Models, Theoretical, Child, Child, Preschool, Infant, Infant, Newborn, Ethiopia, Female, Male, Eradication, Geometric distribution, Mass drug administration, Transmission model, Infectious Diseases, Pediatric, Infection, Good Health and Well Being, Clinical Sciences, Public Health and Health Services
Abstract

Mathematical models predict that the prevalence of infection in different communities where an infectious disease is disappearing should approach a geometric distribution. Trachoma programs offer an opportunity to test this hypothesis, as the World Health Organization (WHO) has targeted trachoma to be eliminated as a public health concern by the year 2020. We assess the distribution of the community prevalence of childhood ocular chlamydia infection from periodic, cross-sectional surveys in two areas of Ethiopia. These surveys were taken in a controlled setting, where infection was documented to be disappearing over time. For both sets of surveys, the geometric distribution had the most parsimonious fit of the distributions tested, and goodness-of-fit testing was consistent with the prevalence of each community being drawn from a geometric distribution. When infection is disappearing, the single sufficient parameter describing a geometric distribution captures much of the distributional information found from examining every community. The relatively heavy tail of the geometric suggests that the presence of an occasional high-prevalence community is to be expected, and does not necessarily reflect a transmission hot spot or program failure. A single cross-sectional survey can reveal which direction a program is heading. A geometric distribution of the prevalence of infection across communities may be an encouraging sign, consistent with a disease on its way to eradication.

Published
2015

42. Optimal Seasonal Timing of Oral Azithromycin for Malaria

Author

Gao, Daozhou, Amza, Abdou, Nassirou, Baidou, Kadri, Boubacar, Sippl-Swezey, Nicholas, Liu, Fengchen, Ackley, Sarah F, Lietman, Thomas M, and Porco, Travis C

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Vector-Borne Diseases, Malaria, Rare Diseases, Infection, Good Health and Well Being, Administration, Oral, Anti-Bacterial Agents, Azithromycin, Child, Humans, Incidence, Models, Theoretical, Niger, Prevalence, Public Health, Seasons, Trachoma, Treatment Outcome, Medical and Health Sciences, Tropical Medicine, Biomedical and clinical sciences, Health sciences
Abstract

Mass administration of azithromycin for trachoma has been shown to reduce malarial parasitemia. However, the optimal seasonal timing of such distributions for antimalarial benefit has not been established. We performed numerical analyses on a seasonally forced epidemic model (of Ross-Macdonald type) with periodic impulsive annual mass treatment to address this question. We conclude that when azithromycin-based trachoma elimination programs occur in regions of seasonal malaria transmission, such as Niger, the optimal seasonal timing of mass drug administration (MDA) may not occur during the season of maximum transmission.

Published
2014

43. Importance of Including Borderline Cases in Trachoma Grader Certification

Author

Gaynor, Bruce D, Amza, Abdou, Gebresailassie, Sintayehu, Kadri, Boubacar, Nassirou, Baido, Stoller, Nicole E, Yu, Sun N, Cuddapah, Puja A, Keenan, Jeremy D, and Lietman, Thomas M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Eye Disease and Disorders of Vision, Good Health and Well Being, Certification, Child, Preschool, Ethiopia, Humans, Infant, Observer Variation, Photography, Reproducibility of Results, Trachoma, Medical and Health Sciences, Tropical Medicine, Biomedical and clinical sciences, Health sciences
Abstract

We assessed trachoma grading agreement among field graders using photographs that included the complete spectrum of disease and compared it with cases where there was consensus among experienced graders. Trained photographers took photographs of children's conjunctiva during a clinical trial in Ethiopia. We calculated κ-agreement statistics using a complete set of 60 cases and then recalculated the κ using a consensus set where cases were limited to those cases with agreement among experienced graders. When the complete set of 60 cases was used, agreement was moderate (κ = 0.61, 95% confidence interval [95% CI] = 0.56-0.67). When the consensus set was used, agreement improved significantly (κ = 0.75, 95% CI = 0.68-0.80). The κ of the consensus set was higher than the complete set by 0.14 (95% CI = 0.12-0.16) (P < 0.001). If testing sets remove difficult-to-grade cases, agreement in trachoma grading may be higher than actually seen in population-based trachoma surveys.

Published
2014

44. Impact of Mass Azithromycin Distribution on Malaria Parasitemia during the Low-Transmission Season in Niger: A Cluster-Randomized Trial

Author

Gaynor, Bruce D, Amza, Abdou, Kadri, Boubacar, Nassirou, Baido, Lawan, Ousmane, Maman, Laouali, Stoller, Nicole E, Yu, Sun N, Chin, Stephanie A, West, Sheila K, Bailey, Robin L, Rosenthal, Philip J, Keenan, Jeremy D, Porco, Travis C, and Lietman, Thomas M

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Rare Diseases, Clinical Research, Vector-Borne Diseases, Malaria, Prevention, Infectious Diseases, 6.1 Pharmaceuticals, 2.2 Factors relating to the physical environment, Infection, Good Health and Well Being, Azithromycin, Child, Child, Preschool, Cluster Analysis, DNA, Protozoan, Female, Humans, Infant, Logistic Models, Male, Niger, Parasitemia, Prevalence, Seasons, Treatment Outcome, Medical and Health Sciences, Tropical Medicine, Biomedical and clinical sciences, Health sciences
Abstract

We assessed the effect of mass azithromycin treatment on malaria parasitemia in a trachoma trial in Niger. Twenty-four study communities received treatment during the wet, high-transmission season. Twelve of the 24 communities were randomized to receive an additional treatment during the dry, low-transmission season. Outcome measurements were conducted at the community-level in children < 1-72 months of age in May-June 2011. Parasitemia was higher in the 12 once-treated communities (29.8%, 95% confidence interval [CI] = 21.5-40.0%) than in the 12 twice-treated communities (19.5%, 95% CI = 13.0-26.5%, P = 0.03). Parasite density was higher in once-treated communities (354 parasites/μL, 95% CI = 117-528 parasites/μL) than in twice-treated communities (74 parasites/μL, 95% CI = 41-202 parasites/μL, P = 0.03). Mass distribution of azithromycin reduced malaria parasitemia 4-5 months after the intervention. The results suggest that drugs with antimalaria activity can have long-lasting impacts on malaria during periods of low transmission.

Published
2014

45. Reliability of trachoma clinical grading--assessing grading of marginal cases.

Author

Rahman, Salman A, Yu, Sun N, Amza, Abdou, Gebreselassie, Sintayehu, Kadri, Boubacar, Baido, Nassirou, Stoller, Nicole E, Sheehan, Joseph P, Porco, Travis C, Gaynor, Bruce D, Keenan, Jeremy D, and Lietman, Thomas M

Subjects
Conjunctiva, Humans, Trachoma, Observer Variation, Photography, Reproducibility of Results, Child, Child, Preschool, Infant, Infant, Newborn, Randomized Controlled Trials as Topic, Neglected Diseases, Preschool, Newborn, Tropical Medicine, Biological Sciences, Medical and Health Sciences
Abstract

BackgroundClinical examination of trachoma is used to justify intervention in trachoma-endemic regions. Currently, field graders are certified by determining their concordance with experienced graders using the kappa statistic. Unfortunately, trachoma grading can be highly variable and there are cases where even expert graders disagree (borderline/marginal cases). Prior work has shown that inclusion of borderline cases tends to reduce apparent agreement, as measured by kappa. Here, we confirm those results and assess performance of trainees on these borderline cases by calculating their reliability error, a measure derived from the decomposition of the Brier score.Methods and findingsWe trained 18 field graders using 200 conjunctival photographs from a community-randomized trial in Niger and assessed inter-grader agreement using kappa as well as reliability error. Three experienced graders scored each case for the presence or absence of trachomatous inflammation-follicular (TF) and trachomatous inflammation-intense (TI). A consensus grade for each case was defined as the one given by a majority of experienced graders. We classified cases into a unanimous subset if all 3 experienced graders gave the same grade. For both TF and TI grades, the mean kappa for trainees was higher on the unanimous subset; inclusion of borderline cases reduced apparent agreement by 15.7% for TF and 12.4% for TI. When we assessed the breakdown of the reliability error, we found that our trainees tended to over-call TF grades and under-call TI grades, especially in borderline cases.ConclusionsThe kappa statistic is widely used for certifying trachoma field graders. Exclusion of borderline cases, which even experienced graders disagree on, increases apparent agreement with the kappa statistic. Graders may agree less when exposed to the full spectrum of disease. Reliability error allows for the assessment of these borderline cases and can be used to refine an individual trainee's grading.

Published
2014

46. Community Risk Factors for Ocular Chlamydia Infection in Niger: Pre-Treatment Results from a Cluster-Randomized Trachoma Trial

Author

Amza, Abdou, Kadri, Boubacar, Nassirou, Baido, Stoller, Nicole E, Yu, Sun N, Zhou, Zhaoxia, Chin, Stephanie, West, Sheila K, Bailey, Robin L, Mabey, David CW, Keenan, Jeremy D, Porco, Travis C, Lietman, Thomas M, and Gaynor, Bruce D

Subjects
Clinical Research, Eye Disease and Disorders of Vision, Prevention, Clinical Trials and Supportive Activities, Sexually Transmitted Infections, Infection, Good Health and Well Being, Animals, Anti-Bacterial Agents, Azithromycin, Child, Preschool, Chlamydia trachomatis, Drug Therapy, Female, Humans, Infant, Infant, Newborn, Male, Niger, Prevalence, Risk Factors, Trachoma, Treatment Outcome, PRET Partnership, Biological Sciences, Medical and Health Sciences, Tropical Medicine
Abstract

BackgroundTrachoma control programs utilize mass azithromycin distributions to treat ocular Chlamydia trachomatis as part of an effort to eliminate this disease world-wide. But it remains unclear what the community-level risk factors are for infection.MethodsThis cluster-randomized, controlled trial entered 48 randomly selected communities in a 2×2 factorial design evaluating the effect of different treatment frequencies and treatment coverage levels. A pretreatment census and examination established the prevalence of risk factors for clinical trachoma and ocular chlamydia infection including years of education of household head, distance to primary water source, presence of household latrine, and facial cleanliness (ocular discharge, nasal discharge, and presence of facial flies). Univariate and multivariate associations were tested using linear regression and Bayes model averaging.FindingsThere were a total of 24,536 participants (4,484 children aged 0-5 years) in 6,235 households in the study. Before treatment in May to July 2010, the community-level prevalence of active trachoma (TF or TI utilizing the World Health Organization [WHO] grading system) was 26.0% (95% CI: 21.9% to 30.0%) and the mean community-level prevalence of chlamydia infection by Amplicor PCR was 20.7% (95% CI: 16.5% to 24.9%) in children aged 0-5 years. Univariate analysis showed that nasal discharge (0.29, 95% CI: 0.04 to 0.54; P = 0.03), presence of flies on the face (0.40, 95% CI: 0.17 to 0.64; P = 0.001), and years of formal education completed by the head of household (0.07, 95% CI: 0.07 to 0.13; P = 0.03) were independent risk factors for chlamydia infection. In multivariate analysis, facial flies (0.26, 95% CI: 0.02 to 0.49; P = 0.03) and years of formal education completed by the head of household (0.06, 95% CI: 0.008 to 0.11; P = 0.02) were associated risk factors for ocular chlamydial infection.InterpretationWe have found that the presence of facial flies and years of education of the head of the household are risk factors for chlamydia infection when the analysis is done at the community level.Trial registrationClinicalTrials.gov NCT00792922.

Published
2012

47. Communalism Predicts Prenatal Affect, Stress, and Physiology Better Than Ethnicity and Socioeconomic Status

Author

Abdou, Cleopatra M, Schetter, Christine Dunkel, Campos, Belinda, Hilmert, Clayton J, Dominguez, Tyan Parker, Hobel, Calvin J, Glynn, Laura M, and Sandman, Curt

Subjects
Mental Health, Behavioral and Social Science, Pediatric, Basic Behavioral and Social Science, 2.3 Psychological, social and economic factors, Aetiology, Reproductive health and childbirth, Reduced Inequalities, Good Health and Well Being, Adult, Affect, Black or African American, Depression, Ethnicity, Female, Health Status Disparities, Humans, Pregnancy, Prenatal Care, Prospective Studies, Risk Factors, Self Concept, Social Support, Socioeconomic Factors, Stress, Psychological, United States, White People, communalism, culture, pregnancy, stress, health disparities, Psychology, Cultural Studies, General Psychology & Cognitive Sciences
Abstract

The authors examined the relevance of communalism, operationalized as a cultural orientation emphasizing interdependence, to maternal prenatal emotional health and physiology and distinguished its effects from those of ethnicity and childhood and adult socioeconomic status (SES). African American and European American women (N = 297) were recruited early in pregnancy and followed through 32 weeks gestation using interviews and medical chart review. Overall, African American women and women of lower socioeconomic backgrounds had higher levels of negative affect, stress, and blood pressure, but these ethnic and socioeconomic disparities were not observed among women higher in communalism. Hierarchical multivariate regression analyses showed that communalism was a more robust predictor of prenatal emotional health than ethnicity, childhood SES, and adult SES. Communalism also interacted with ethnicity and SES, resulting in lower blood pressure during pregnancy for African American women and women who experienced socioeconomic disadvantage over the life course. The effects of communalism on prenatal affect, stress, and physiology were not explained by depressive symptoms at study entry, perceived availability of social support, self-esteem, optimism, mastery, nor pregnancy-specific factors, including whether the pregnancy was planned, whether the pregnancy was desired after conception, or how frequently the woman felt happy to be pregnant. This suggests that a communal cultural orientation benefits maternal prenatal emotional health and physiology over and above its links to better understood personal and social resources in addition to economic resources. Implications of culture as a determinant of maternal prenatal health and well-being and an important lens for examining ethnic and socioeconomic inequalities in health are discussed.

Published
2010

48. Familialism, Social Support, and Stress: Positive Implications for Pregnant Latinas

Author

Campos, Belinda, Schetter, Christine Dunkel, Abdou, Cleopatra M, Hobel, Calvin J, Glynn, Laura M, and Sandman, Curt A

Subjects
Pediatric, Infant Mortality, Behavioral and Social Science, Mental Health, Reproductive health and childbirth, Acculturation, Adult, Anxiety, Cross-Cultural Comparison, Emigrants and Immigrants, Family, Female, Hispanic or Latino, Humans, Infant, Newborn, Mexican Americans, Personality Inventory, Pregnancy, Prospective Studies, Social Support, Social Values, Stress, Psychological, Whites, familialism, Latinas, social support, stress, pregnancy, White People, Psychology, Cultural Studies, General Psychology & Cognitive Sciences
Abstract

This study examined the association of familialism, a cultural value that emphasizes close family relationships, with social support, stress, pregnancy anxiety, and infant birth weight. Foreign-born Latina (n = 31), U.S.-born Latina (n = 68), and European American (n = 166) women living in the United States participated in a prospective study of pregnancy in which they completed measures of familialism, social support, stress, and pregnancy anxiety during their second trimester. As expected, Latinas scored higher on familialism than European Americans. Familialism was positively correlated with social support and negatively correlated with stress and pregnancy anxiety in the overall sample. As predicted, however, the associations of familialism with social support and stress were significantly stronger among Latinas than European Americans. Moreover, higher social support was associated with higher infant birth weight among foreign-born Latinas only. Implications of cultural values for relationships and health are discussed.

Published
2008

49. Stress and Blood Pressure During Pregnancy: Racial Differences and Associations With Birthweight

Author

Hilmert, Clayton J, Schetter, Christine Dunkel, Dominguez, Tyan Parker, Abdou, Cleopatra, Hobel, Calvin J, Glynn, Laura, and Sandman, Curt

Subjects
Hypertension, Preterm, Low Birth Weight and Health of the Newborn, Cardiovascular, Perinatal Period - Conditions Originating in Perinatal Period, Clinical Research, Pediatric, Infant Mortality, Reproductive health and childbirth, Adult, African Americans, Birth Weight, Blood Pressure, Female, Health Status Disparities, Humans, Pregnancy, Pregnancy Complications, Cardiovascular, Prospective Studies, Risk Factors, Stress, Psychological, pregnancy, birthweight, African American, blood pressure, stress, Black or African American, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveTo extend findings that African American women report greater stress during pregnancy, have higher blood pressure (BP), and are twice as likely to have low birthweight infants relative to white women. This study examines a) racial differences in associations between stress and BP during pregnancy, and b) the combined effects of stress and BP on infant birthweight in a sample of 170 African American and white women.MethodsA prospective, longitudinal study of pregnant women was conducted in which measures of BP, stress, and other relevant variables were collected. Multiple measures of systolic and diastolic BP were taken at each of three points during pregnancy (18-20, 24-26, and 30-32 weeks gestation).ResultsBoth systolic blood pressure (SBP) and diastolic blood pressure (DBP) were positively associated with stress in pregnant African American women and not in pregnant white women. In analyses of birthweight, there were no main effects of BP or stress. However, a significant interaction demonstrated that, when stress was high, DBP was negatively associated with birthweight and a combination of high stress and high DBP predicted the lowest birthweight in the sample. Furthermore, African American women were twice as likely as white women to have a combination of high stress and high DBP.ConclusionsRacial differences in relationships between stress and BP, and the interactive effect of stress and DBP on birthweight together suggest that a high stress-high BP profile may pose a risk for lower birthweight among African American women, in particular, and possibly for all pregnant women.

Published
2008

50. Creatine Deficiency Syndromes: Comparison of Screening Methods and Characterization of Four Novel Intronic Variants

Author

Naira M. Mustafa, Nevine E. Elabd, Laila A. Selim, Doaa M. Abdou, and Julian L. Griffin

Subjects
Tandem Mass Spectrometry, Biochemistry (medical), Clinical Biochemistry, Humans, Guanidinoacetate N-Methyltransferase, Syndrome, General Medicine, Arginine, Creatine, Biochemistry, Chromatography, High Pressure Liquid
Abstract

Cerebral creatine deficiency syndromes (CCDS) are disorders affecting creatine synthesis or transport. Several methods have been developed to measure creatine and guanidinoacetate (GAA) in different body fluids including methods based on gas chromatography-mass spectrometry (GC-MS) and High-pressure liquid chromatography mass spectrometry (HPLC-MS). The diagnosis of CCDS is then confirmed by sequencing of creatine biosynthesis genes guanidinoacetate methyltransferase (GAMT) and Arginine: glycine amidinotransferase (GATM) and creatine transporter gene solute carrier family 6 member 8 (SLC6A8) or by functional enzymatic assay. The aim of the current study was to find the most reliable and accurate screening method for CCDS by comparing methods using Nuclear Magnetic Resonance spectroscopy (NMR), GC-MS and HPLC-MS. Additionally, this study was performed to estimate the prevalence of CCDS in a cohort of Egyptian patients and potentially to discover novel variants.The study was conducted on 150 subjects with clinical signs and symptoms consistent with CCDS. Metabolic profiling of urine samples was performed using three techniques: 1) GC-MS 2) Ultra high-pressure (or performance) liquid chromatography - Tandem Mass Spectrometry (UHPLC- MS/MS) and 3) NMR.The linearity of peak areas for creatine and GAA by UHPLC-MS/MS and NMR covered and exceeded the ranges normally found in urine. The limit of quantification and the inter-day precision results for creatine and GAA were more robust by UHPLC-MS/MS than NMR. Ten cases were identified as being positive for CCDS by our analytical approaches and underwent next generation sequencing (NGS) for GAMT, GATM and SLC6A8 genes. NGS was performed and confirmed one patient with one likely Pathogenic variant in GAMT gene: (NC_000019.10:g.1401317C G, NP_000147.1:p.Ala54Pro). Additionally, we describe four novel intronic variants in the GATM gene: c.1043-357del and c.1043-357_1043-356insT, and were predicted to activate cryptic acceptor site with potential alteration of splicing, c.979-227G A was found to significantly alter the Exon Splice Enhancer (ESE) xon Splice Silencer (ESS) motifs ratio and c.1042 + 262del which was found to have no implications on splicing.Both UHPLC-MS/MS and NMR spectroscopy are comparable to GC-MS in screening for CCDS. Nonetheless, the UHPLC-MS/MS method had better performance than NMR spectroscopy. Additionally, Sequencing of the full length of GATM, GAMT, and SLC6A8 genes is needed to identify intronic variants that could cause CCDS via affecting splice sites.

Published
2022

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