@article {1586, title = {Association Between Baseline Macular Morphologic Features on Optical Coherence Tomography and Visual Outcomes in Patients with Vogt-Koyanagi-Harada Disease.}, journal = {Ocul Immunol Inflamm}, volume = {33}, year = {2025}, month = {2025 Feb}, pages = {263-270}, abstract = {

PURPOSE: The choroidal thickening and serous retinal detachments that characterize Vogt-Koyanagi-Harada (VKH) disease can be imaged in detail using spectral domain optical coherence tomography (SD-OCT). Whether specific qualitative and quantitative SD-OCT features at presentation were associated with visual outcomes in a randomized controlled trial comparing methotrexate to mycophenolate for steroid-sparing control of uveitis were evaluated.

METHODS: An exploratory subanalysis of data from the FAST trial in which SD-OCT images from VKH participants were analyzed for presence/absence of bacillary detachments, retinal pigment epithelium (RPE) folds, and internal limiting membrane (ILM) fluctuations was performed. A modified RPE undulation index was calculated to provide a quantifiable surrogate marker for choroidal folds.

RESULTS: SD-OCT images were available from 158 eyes with VKH. At baseline, bacillary detachments were present in 23.5\% of eyes, RPE folds in 22.8\% of eyes, and ILM fluctuations in 35.2\% of eyes. For each 0.1 unit increase in modified RPE undulation index, there was an associated 0.13 increase in mean logMAR BSCVA at baseline. None of the SD-OCT features were associated with BSCVA at the 6-month primary endpoint. Indeed, mean final BSCVA was similar in those with and without the SD-OCT features of interest at baseline, and was between 0.1 and 0.2 logMAR (Snellen visual acuity 20/25 to 20/30).

CONCLUSIONS: While eyes with VKH may present with a variety of SD-OCT imaging pathology prior to starting immunosuppression with methotrexate or mycophenolate mofetil, final visual outcome in our study was excellent. With appropriate immunosuppression, good visual outcomes are possible in VKH.ClinicalTrials.gov Identifier NCT01829295Date of Registration: April 11, 2013.

}, keywords = {Adult, Female, Fluorescein Angiography, Humans, Immunosuppressive Agents, Macula Lutea, Male, Methotrexate, Middle Aged, Mycophenolic Acid, Retinal Detachment, Retinal Pigment Epithelium, Tomography, Optical Coherence, Uveomeningoencephalitic Syndrome, Visual Acuity}, issn = {1744-5078}, doi = {10.1080/09273948.2024.2391420}, author = {Sundararajan, Miel and Rathinam, Sivakumar R and Thundikandy, Radhika and Kanakath, Anuradha and Balamurugan, S and Vedhanayaki, R and Miller, D Claire and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Arellanes-Garcia, Lourdes and Reddy, Amit K and Feng, Shu and Doan, Thuy and Porco, Travis C and Shantha, Jessica G and Acharya, Nisha R and Gonzales, John A} } @article {1581, title = {Multiple Anterior Chamber Paracenteses May Be Needed to Identify Cytomegalovirus Anterior Uveitis.}, journal = {Am J Ophthalmol}, volume = {269}, year = {2025}, month = {2025 Jan}, pages = {189-194}, abstract = {

PURPOSE: To demonstrate cases of anterior uveitis requiring more than one anterior chamber paracenesis to elucidate CMV as the causative etiology.

DESIGN: Retrospective chart review.

METHODS: Patients were seen at the Francis I. Proctor Foundation at the University of California, San Francisco between 2013 and 2024. Patients who required more than one anterior chamber paracentesis to detect CMV as the etiologic agent of their anterior uveitis were included. Number of anterior chamber paracenteses required to detect CMV, demographic and clinical features, viral load at time of positive anterior chamber paracentesis and association between topical corticosteroid use and viral load at time of positive anterior chamber paracentesis.

RESULTS: Fourteen patients required a median of 2 (range 2-4) anterior chamber paracenteses to detect CMV. Mean age was 48.2 years, and 57.1\% were male. Most patients (64.3\%) were born in East and Southeast Asia. All affected eyes featured ocular hypertension. Five patients (35.7\%) were initially treated with systemic immunosuppression before CMV was detected. Increasing frequency of topical corticosteroid use was significantly associated with higher CMV viral loads (P \< .001). Five patients (35.7\%) required glaucoma surgery. In 13 patients with available data, uveitis was present for an average of 2776 days (range 23-7889 days) prior to CMV detection. Once diagnosed, most patients were treated with oral valganciclovir, with one patient transitioning to letermovir due to side effects.

CONCLUSIONS: CMV anterior uveitis may be more prevalent than previously recognized and often requires multiple anterior chamber paracenteses for diagnosis. Reliance on a signle negative test may lead to misdiagnosis and inappropriate treatment. Clinicians should maintain a high index of suspicion for CMV in cases of recurrent anterior uveitis, particularly in patients of East and Southeast Asian descent. This study highlights the importance of repeated testing and appropriate antiviral treatment to prevent complications such as glaucoma.

}, keywords = {Adult, Aged, Anterior Chamber, Antiviral Agents, Cytomegalovirus, Cytomegalovirus Infections, DNA, Viral, Eye Infections, Viral, Female, Glucocorticoids, Humans, Male, Middle Aged, Retrospective Studies, Uveitis, Anterior, Viral Load, Young Adult}, issn = {1879-1891}, doi = {10.1016/j.ajo.2024.08.025}, author = {Benador-Shen, Christine and Shantha, Jessica and Lee, Jennifer and Qian, Ying and Doan, Thuy and Gonzales, John A} } @article {1566, title = {Ongoing transmission of trachoma in low prevalence districts in Mozambique: results from four cross-sectional enhanced impact surveys, 2022.}, journal = {Sci Rep}, volume = {14}, year = {2024}, month = {2024 Oct 15}, pages = {22842}, abstract = {

Mozambique is making progress towards elimination of trachoma as a public health problem, but in some districts trachomatous inflammation-follicular (TF) prevalence remains above the 5\% elimination threshold despite years of various interventions, including antibiotic mass drug administration. To characterize transmission in four districts, we incorporated testing of ocular infection and serology into routine trachoma impact surveys (TIS) in August 2022. We examined residents aged >= 1 year for trachoma and collected information on household water, sanitation, and hygiene. Among children aged 1-9 years, we tested conjunctival swabs for Chlamydia trachomatis nucleic acid and dried blood spots for C. trachomatis antibodies. We modeled age-dependent seroprevalence to estimate seroconversion rate (SCR). We examined 4841 children aged 1-9 years. TF prevalence ranged between 1.1 and 6.0\% with three districts below the 5\% threshold. PCR-confirmed infection prevalence ranged between 1.1 and 4.8\%, and Pgp3 seroprevalence ranged between 8.8 and 24.3\%. Pgp3 SCR was 1.9 per 100 children per year in the district with the lowest TF prevalence. Two other districts with TF < 5\% had SCR of 5.0 and 4.7. The district with TF >= 5\% had a SCR of 6.0. This enhanced TIS furthered understanding of transmission in these districts and provides information on additional indicators for monitoring trachoma programs.

}, keywords = {Antibodies, Bacterial, Child, Child, Preschool, Chlamydia trachomatis, Cross-Sectional Studies, Female, Humans, Infant, Male, Mozambique, Prevalence, Seroepidemiologic Studies, Trachoma}, issn = {2045-2322}, doi = {10.1038/s41598-024-71201-z}, author = {Sitoe, Henis Mior and Oswald, William E and Zita, Felizmina and Fall, Mawo and Momade, Tamimo and Adams, Molly W and Flueckiger, Rebecca M and McPherson, Scott and Eyob, Sabrina and Doan, Thuy and Lietman, Thomas M and Arnold, Benjamin F and Wickens, Karana and Gwyn, Sarah and Martin, Diana L and Kasubi, Mabula and Boyd, Sarah and Bakhtiari, Ana and Jimenez, Cristina and Solomon, Anthony W and Harding-Esch, Emma M and Mwingira, Upendo J and Ngondi, Jeremiah M} } @article {1381, title = {Prolonged mass azithromycin distributions and macrolide resistance determinants among preschool children in Niger: A sub-study of a cluster-randomized trial (MORDOR).}, journal = {PLoS Med}, volume = {21}, year = {2024}, month = {2024 May}, pages = {e1004386}, abstract = {

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

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

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

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

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Resistance, Bacterial, Female, Humans, Infant, Macrolides, Male, Mass Drug Administration, Niger}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1004386}, author = {Arzika, Ahmed M and Abdou, Amza and Maliki, Ramatou and Beido, Nassirou and Kadri, Boubacar and Harouna, Abdoul N and Galo, Abdoul N and Alio, Mankara K and Lebas, Elodie and Oldenburg, Catherine E and O{\textquoteright}Brien, Kieran S and Chen, Cindi and Zhong, Lina and Zhou, Zhaoxia and Yan, Daisy and Hinterwirth, Armin and Keenan, Jeremy D and Porco, Travis C and Lietman, Thomas M and Doan, Thuy} } @article {1266, title = {Aqueous Fluid Transcriptome Profiling Differentiates Between Non-Neovascular and Neovascular AMD.}, journal = {Invest Ophthalmol Vis Sci}, volume = {64}, year = {2023}, month = {2023 Jul 03}, pages = {26}, abstract = {

PURPOSE: Early and intermediate non-neovascular AMD (NN-AMD) has the potential to progress to either advanced NN-AMD with geographic atrophy, or to neovascular AMD (N-AMD) with CNV. This exploratory study performed an unbiased analysis of aqueous humor transcriptome in patients with early or intermediate NN-AMD vs. treatment-na{\"\i}ve N-AMD to determine the feasibility of using this method in future studies investigating pathways and triggers for conversion from one form to another.

METHODS: Aqueous humor samples were obtained from 20 patients with early or intermediate NN-AMD and 20 patients with untreated N-AMD, graded on clinical examination and optical coherence tomography. Transcriptome profiles were generated using next-generation sequencing methods optimized for ocular samples. Top-ranked transcripts were compared between groups, and pathway enrichment analysis was performed.

RESULTS: Seventy-eight differentially expressed transcripts were identified. Unsupervised clustering of differentially expressed transcripts was able to successfully differentiate between the two groups based on aqueous transcriptome alone. Pathway analysis highlighted changes in expression of genes associated with mitochondrial respiration, oxidative stress, ubiquitination, and neurogenesis between the two groups.

CONCLUSIONS: This pilot study compared the aqueous fluid transcriptome of patients with early or intermediate NN-AMD and untreated N-AMD. Differences in transcripts and transcriptome pathways identified in the aqueous of patients with early or intermediate NN-AMD compared with patients with N-AMD are consistent with those previously implicated in the pathogenesis of these distinct AMD subtypes. The findings from this exploratory study warrant further investigation using a larger, prospective study design, with the inclusion of a control group of eyes without AMD.

}, keywords = {Choroidal Neovascularization, Gene Expression Profiling, Geographic Atrophy, Humans, Pilot Projects, Prospective Studies, Tomography, Optical Coherence, Wet Macular Degeneration}, issn = {1552-5783}, doi = {10.1167/iovs.64.10.26}, author = {Kaidonis, Georgia and Lamy, Ricardo and Wu, Joshua and Yang, Daphne and Psaras, Catherine and Doan, Thuy and Stewart, Jay M} } @article {1221, title = {Isolated Ocular Mpox without Skin Lesions, United States.}, journal = {Emerg Infect Dis}, volume = {29}, year = {2023}, month = {2023 Jun}, pages = {1285-1288}, abstract = {

We report a case of a 53-year-old HIV-negative patient in San Francisco, California, USA, with no classic mpox prodromal symptoms or skin lesions who experienced fulminant, vision-threatening scleritis, keratitis, and uveitis. Deep sequence analysis identified monkeypox virus RNA in the aqueous humor. We confirmed the virus on the cornea and sclera by PCR.

}, keywords = {Face, Humans, Middle Aged, Monkeypox, Polymerase Chain Reaction, Prodromal Symptoms, RNA, Viral, United States}, issn = {1080-6059}, doi = {10.3201/eid2906.230032}, author = {Nguyen, Minh T and Mentreddy, Akshay and Schallhorn, Julie and Chan, Matilda and Aung, Su and Doernberg, Sarah B and Babik, Jennifer and Miles, Kevin and Yang, Katherine and Lydon, Emily and Minter, Daniel J and Gonzales, John and Shantha, Jessica and Doan, Thuy and Seitzman, Gerami D} } @article {1031, title = {Gut Resistome after Antibiotics among Children with Uncomplicated Severe Acute Malnutrition: A Randomized Controlled Trial.}, journal = {Am J Trop Med Hyg}, volume = {107}, year = {2022}, month = {2022 Jul 13}, pages = {59-64}, abstract = {

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

}, keywords = {Amoxicillin, Anti-Bacterial Agents, Azithromycin, Child, Drug Resistance, Bacterial, Humans, Macrolides, Severe Acute Malnutrition}, issn = {1476-1645}, doi = {10.4269/ajtmh.22-0007}, author = {Oldenburg, Catherine E and Hinterwirth, Armin and Ourohir{\'e}, Millogo and Dah, Clarisse and Ou{\'e}draogo, Moussa and Sie, Ali and Boudo, Valentin and Chen, Cindi and Ruder, Kevin and Zhong, Lina and Lebas, Elodie and Nyatigo, Fanice and Arnold, Benjamin F and O{\textquoteright}Brien, Kieran S and Doan, Thuy} } @article {901, title = {Impact of Sample Collection Order on the Diagnostic Performance of Metagenomic Deep Sequencing for Infectious Keratitis.}, journal = {Cornea}, volume = {41}, year = {2022}, month = {2022 Jan 01}, pages = {39-44}, abstract = {

PURPOSE: The purpose of this article was to evaluate the impact of sample collection order on the diagnostic yield of metagenomic deep sequencing (MDS) for determining the causative pathogen in infectious keratitis.

METHODS: We performed a cross-sectional diagnostic test evaluation among subjects with infectious keratitis at Aravind Eye Hospital in Madurai, India. All subjects underwent corneal scrapings of the affected eye to obtain potassium hydroxide smear, Gram stain, bacterial culture, and fungal culture, in this order. The order of MDS specimen collection relative to smear and culture samples was randomized and served as the primary predictor. Outcomes included the normalized copy number of pathogenic RNA detected by MDS, the proportion of MDS samples that were diagnostic, and the agreement of MDS results with cultures.

RESULTS: MDS samples from 46 subjects with corneal ulcers were evaluated. MDS was positive in 33 subjects (76\%) and had 74\% overall agreement with culture results. There was no association between order of MDS sample collection and normalized copy number of genetic material detected (P = 0.62) or the likelihood of MDS positivity (P = 0.46). However, the likelihood of agreement between MDS and cultures decreased when MDS corneal swabs were collected after other diagnostic corneal scrapings (P = 0.05).

CONCLUSIONS: The overall yield of MDS for detecting the cause of infectious keratitis was not affected by sample collection order. However, diagnostic agreement between MDS and cultures decreased when MDS samples were collected after other specimens. Additional investigation is warranted to determine whether this represents increased sensitivity of MDS compared with cultures or higher susceptibility to contaminants.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Bacteria, Cornea, Cross-Sectional Studies, DNA, Bacterial, DNA, Fungal, Eye Infections, Bacterial, Eye Infections, Fungal, Female, Fungi, High-Throughput Nucleotide Sequencing, Humans, Keratitis, Male, Metagenome, Middle Aged, Specimen Handling, Young Adult}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000002766}, author = {Redd, Travis K and Lalitha, Prajna and Prajna, N Venkatesh and Sikha, Misra and Gunasekaran, Rameshkumar and Hinterwirth, Armin and Chen, Cindi and Zhong, Lina and Liu, Zijun and Lietman, Thomas M and Keenan, Jeremy D and Doan, Thuy and Seitzman, Gerami D} } @article {1161, title = {Ocular Rosacea microBiome Study (ORBS)-sub-microbial versus antibiotic dosing of doxycycline versus placebo in treatment of symptomatic ocular rosacea: study protocol for a parallel-arm randomized clinical trial.}, journal = {Trials}, volume = {23}, year = {2022}, month = {2022 Dec 20}, pages = {1033}, abstract = {

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

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

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

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

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

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

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

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

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

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child, Child, Preschool, Drug Resistance, Bacterial, Humans, Infant, Macrolides, Mass Drug Administration, Niger, Randomized Controlled Trials as Topic}, issn = {1471-2458}, doi = {10.1186/s12889-021-10824-7}, author = {O{\textquoteright}Brien, Kieran S and Arzika, Ahmed M and Amza, Abdou and Maliki, Ramatou and Ousmane, Sani and Kadri, Boubacar and Nassirou, Beido and Mankara, Alio Karamba and Harouna, Abdoul Naser and Colby, Emily and Lebas, Elodie and Liu, Zijun and Le, Victoria and Nguyen, William and Keenan, Jeremy D and Oldenburg, Catherine E and Porco, Travis C and Doan, Thuy and Arnold, Benjamin F and Lietman, Thomas M} } @article {46, title = {Azithromycin for severe COVID-19.}, journal = {Lancet}, volume = {396}, year = {2020}, month = {2020 10 03}, pages = {936-937}, keywords = {Azithromycin, Betacoronavirus, Brazil, Coronavirus Infections, COVID-19, Humans, Pandemics, Pneumonia, Viral, SARS-CoV-2, Standard of Care}, issn = {1474-547X}, doi = {10.1016/S0140-6736(20)31863-8}, author = {Oldenburg, Catherine E and Doan, Thuy} } @article {161, title = {Gut Bacterial Diversity and Growth among Preschool Children in Burkina Faso.}, journal = {Am J Trop Med Hyg}, volume = {103}, year = {2020}, month = {2020 12}, pages = {2568-2573}, abstract = {

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

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

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

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

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

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

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

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

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Resistance, Bacterial, Female, Gastrointestinal Microbiome, Humans, Infant, Macrolides, Male, Mass Drug Administration, Metagenome, Niger, Sequence Analysis, DNA}, issn = {1533-4406}, doi = {10.1056/NEJMoa2002606}, author = {Doan, Thuy and Worden, Lee and Hinterwirth, Armin and Arzika, Ahmed M and Maliki, Ramatou and Abdou, Amza and Zhong, Lina and Chen, Cindi and Cook, Catherine and Lebas, Elodie and O{\textquoteright}Brien, Kieran S and Oldenburg, Catherine E and Chow, Eric D and Porco, Travis C and Lipsitch, Marc and Keenan, Jeremy D and Lietman, Thomas M} } @article {66, title = {No Time for Tears.}, journal = {Ophthalmology}, volume = {127}, year = {2020}, month = {2020 07}, pages = {980-981}, keywords = {Betacoronavirus, Coronavirus, Coronavirus Infections, COVID-19, Humans, Pandemics, Pneumonia, Viral, SARS-CoV-2, Tears, Virus Shedding}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2020.03.030}, author = {Seitzman, Gerami D and Doan, Thuy} } @article {86, title = {Post-antibiotic Ocular Surface Microbiome in Children: A Cluster-Randomized Trial.}, journal = {Ophthalmology}, volume = {127}, year = {2020}, month = {2020 08}, pages = {1127-1130}, keywords = {Anti-Bacterial Agents, Child, Cornea, Humans, Microbiota, Randomized Controlled Trials as Topic}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2020.02.014}, author = {Doan, Thuy and Hinterwirth, Armin and Worden, Lee and Arzika, Ahmed M and Maliki, Ramatou and Chen, Cindi and Zhong, Lina and Zhou, Zhaoxia and Acharya, Nisha R and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M} } @article {206, title = {Rapid Reduction of Species in the Gut Microbiome of Preschool Children after Oral Azithromycin: A Randomized Controlled Trial.}, journal = {Am J Trop Med Hyg}, volume = {103}, year = {2020}, month = {2020 09}, pages = {1266-1269}, abstract = {

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

}, keywords = {Anti-Bacterial Agents, Azithromycin, Burkina Faso, Campylobacter, Campylobacter Infections, Child Mortality, Child, Preschool, Gastrointestinal Microbiome, Humans, Infant, Metagenomics, Sequence Analysis, DNA}, issn = {1476-1645}, doi = {10.4269/ajtmh.19-0940}, author = {Hinterwirth, Armin and Sie, Ali and Coulibaly, Boubacar and Ouermi, Lucienne and Dah, Clarisse and Tapsoba, Charlemagne and Zhong, Lina and Chen, Cindi and Lietman, Thomas M and Keenan, Jeremy D and Doan, Thuy and Oldenburg, Catherine E} } @article {106, title = {Reduction of Coronavirus Burden With Mass Azithromycin Distribution.}, journal = {Clin Infect Dis}, volume = {71}, year = {2020}, month = {2020 11 19}, pages = {2282-2284}, abstract = {

We evaluated the potential antiviral effects of azithromycin on the nasopharyngeal virome of Nigerien children who had received multiple rounds of mass drug administration. We found that the respiratory burden of non-severe acute respiratory syndrome coronaviruses was decreased with azithromycin distributions. Clinical Trials Registration. NCT02047981.

}, keywords = {Administration, Oral, Antiviral Agents, Azithromycin, Child, Preschool, Coronavirus, Coronavirus Infections, Humans, Infant, Infant, Newborn, Mass Drug Administration, Nasopharynx, Nigeria, Viral Load}, issn = {1537-6591}, doi = {10.1093/cid/ciaa606}, author = {Doan, Thuy and Hinterwirth, Armin and Arzika, Ahmed M and Worden, Lee and Chen, Cindi and Zhong, Lina and Oldenburg, Catherine E and Keenan, Jeremy D and Lietman, Thomas M} } @article {36, title = {Rigorous Randomized Controlled Trial Implementation in the Era of COVID-19.}, journal = {Am J Trop Med Hyg}, volume = {102}, year = {2020}, month = {2020 06}, pages = {1154-1155}, keywords = {Antiviral Agents, Azithromycin, Betacoronavirus, Clinical Laboratory Techniques, Coronavirus Infections, COVID-19, COVID-19 Testing, Drug Repositioning, Humans, Hydroxychloroquine, Lopinavir, Pandemics, Pneumonia, Viral, Practice Guidelines as Topic, Randomized Controlled Trials as Topic, Ritonavir, Sample Size, SARS-CoV-2, United States}, issn = {1476-1645}, doi = {10.4269/ajtmh.20-0262}, author = {Oldenburg, Catherine E and Doan, Thuy} } @article {101, title = {Association Between Noninfectious Uveitis and Psychological Stress.}, journal = {JAMA Ophthalmol}, volume = {137}, year = {2019}, month = {2019 02 01}, pages = {199-205}, abstract = {

Importance: Uveitis involves dysregulation of the ocular immune system. Stress has been shown to affect immune function, but it is unclear whether there is an association between stress and uveitis.

Objective: To determine whether having uveitis is associated with psychological stress.

Design, Setting, and Participants: A cross-sectional, case-control study including a self-administered survey, medical records review, and diurnal salivary cortisol test was conducted at a university-based uveitis clinic and comprehensive eye clinic. Participants included 146 consecutive adults with noninfectious uveitis and age-matched controls with no eye disease. The study was conducted from December 1, 2017, to March 14, 2018.

Main Outcomes and Measures: Participants completed the self-administered, Cohen 10-item Perceived Stress Scale (PSS-10), a demographics questionnaire. Responses to each question were categorized on a 5-point Likert scale, with total scores ranging from 0 (no stress) to 40 (high stress). In addition, participants submitted 3 salivary cortisol samples. Those with uveitis were classified as having recently active or controlled disease through medical records review. The prespecified primary analysis was a linear regression of PSS-10 score and uveitis correcting for age, sex, educational level, employment, and median income. Secondary analyses included comparing PSS-10 scores in patients with recently active and controlled uveitis, determining predictors of stress, and comparing diurnal salivary cortisol between uveitis and control groups.

Results: Of 146 eligible patients, 17 declined participation and 9 consented but were excluded because they did not complete both questionnaires, resulting in 120 patients (80 uveitis; 40 controls) in the final analysis. Eighty participants (66.7\%) were women, and 70 (58.3\%) were white. Median age was 40 years (interquartile range, 29-59 years). Having uveitis was associated with a 4.3-point increase in PSS-10 score (95\% CI, 1.8 to 6.9; P = .002). There was no significant difference in PSS-10 scores between patients with recently active and controlled uveitis (1.0 point greater for patients with active uveitis; 95\% CI, -2.0 to 3.9; P = .52). Factors associated with increased PSS-10 score in patients with uveitis included female sex (coefficient, 4.0; 95\% CI, 1.6 to 6.5; P = .002), current immunomodulatory therapy (coefficient, 2.5; 95\% CI, -0.3 to 5.2; P = .08), history of depression (coefficient, 3.8; 95\% CI, 0.8 to 6.8; P = .02), and having posterior or panuveitis (coefficient, 2.6; 95\% CI, 0.8 to 4.4; P = .006). Of the 70 participants (58.3\%) who had testable samples for cortisol analysis, diurnal salivary cortisol levels did not significantly differ between uveitis and nonuveitis groups.

Conclusions and Relevance: These findings suggest that patients with uveitis have higher levels of psychological stress compared with controls, yet no significant difference was identified in the stress of patients with active vs controlled uveitis. Consequently, comprehensive treatment for noninfectious uveitis may be able to address the psychological results of this disease.

}, keywords = {Adult, Case-Control Studies, Cross-Sectional Studies, Eye Infections, Female, Humans, Male, Middle Aged, Risk Factors, Stress, Psychological, Surveys and Questionnaires, Uveitis, Vision, Ocular, Visual Acuity}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2018.5893}, author = {Berlinberg, Elyse J and Gonzales, John A and Doan, Thuy and Acharya, Nisha R} } @article {96, title = {Association of Ocular Inflammation and Rubella Virus Persistence.}, journal = {JAMA Ophthalmol}, volume = {137}, year = {2019}, month = {2019 04 01}, pages = {435-438}, abstract = {

Importance: Metagenomic deep sequencing (MDS) demonstrates that persistent and active rubella virus (RV) infection is associated with Fuchs heterochromic iridocyclitis (FHI).

Objective: To assess the utility of MDS in identifying RV infection in patients with uveitis.

Design, Setting, and Participants: This case series assessed 6 patients diagnosed by MDS with RV-associated uveitis at a tertiary uveitis referral center in the United States.

Exposures: Prior RV infection.

Main Outcomes and Measures: Clinical examination findings, slitlamp photography, corneal confocal imaging, and infectious pathogen genome obtained from RNA sequencing.

Results: Six white men (age range, 36-61 years) were diagnosed with RV-associated uveitis by MDS. Three patients exhibited iris heterochromia associated with their uveitis in classic FHI fashion. The other 3 patients had less classic FHI features and exhibited anterior vitritis. Three patients had in vivo corneal confocal microscopy, with 2 demonstrating stellate keratic precipitates in addition to endothelial infiltration, spotlike holes, and enlarged intercellular boundaries. Of these 3 patients, 1 patient exhibited polymorphism and polymegathism of the endothelial cells.

Conclusions and Relevance: These findings suggest that persistent RV infection is associated with recurrent or chronic anterior or anterior-intermediate uveitis as well as corneal endothelial cell damage. Ophthalmologists should consider RV infection as a potential cause of hypertensive anterior and intermediate uveitis.

}, keywords = {Adult, Eye Infections, Viral, Humans, Male, Middle Aged, Rubella, Uveitis}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2018.6185}, author = {Gonzales, John A and Hinterwirth, Armin and Shantha, Jessica and Wang, Kaidi and Zhong, Lina and Cummings, Susie L and Qian, Ying and Wilson, Michael R and Acharya, Nisha R and Doan, Thuy} } @article {191, title = {Capnocytophaga Keratitis: Clinical Presentation and Use of Metagenomic Deep Sequencing for Diagnosis.}, journal = {Cornea}, volume = {38}, year = {2019}, month = {2019 Feb}, pages = {246-248}, abstract = {

PURPOSE: To report our experience with 2 cases of Capnocytophaga keratitis.

METHODS: This is a retrospective study of case reports. We present the clinical presentation, diagnosis, and treatment strategies of 2 patients who presented with Capnocytophaga keratitis.

RESULTS: Both patients had risk factors including systemic immune compromise and ocular trauma. Both patients had robust inflammatory keratitis with necrosis. Case 1 demonstrates identification of Capnocytophaga with traditional microbiologic techniques. Case 2 demonstrates the use of unbiased metagenomic deep sequencing for identification of this unusual corneal pathogen.

CONCLUSIONS: Capnocytophaga is a rare and aggressive infection. Even when traditional culture identifies the pathogen rapidly, keratitis can progress to perforation. In cases of severe keratitis in which traditional culture methods are unrevealing, metagenomic deep sequencing has potential to provide actionable diagnoses.

}, keywords = {Capnocytophaga, Eye Infections, Bacterial, Female, Gram-Negative Bacterial Infections, High-Throughput Nucleotide Sequencing, Humans, Keratitis, Male, Metagenome, Microbiological Techniques, Middle Aged, Retrospective Studies}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000001790}, author = {Seitzman, Gerami D and Thulasi, Praneetha and Hinterwirth, Armin and Chen, Cindi and Shantha, Jessica and Doan, Thuy} } @article {231, title = {A double-masked placebo-controlled trial of azithromycin to prevent child mortality in Burkina Faso, West Africa: Community Health with Azithromycin Trial (CHAT) study protocol.}, journal = {Trials}, volume = {20}, year = {2019}, month = {2019 Dec 04}, pages = {675}, abstract = {

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

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

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

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

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Double-Blind Method, Humans, Infant, Outcome Assessment, Health Care, Randomized Controlled Trials as Topic, Sample Size}, issn = {1745-6215}, doi = {10.1186/s13063-019-3855-9}, author = {Sie, Ali and Ouattara, Mamadou and Bountogo, Mamadou and Bagagnan, Cheik and Coulibaly, Boubacar and Boudo, Valentin and Lebas, Elodie and Brogdon, Jessica M and Lin, Ying and B{\"a}rnighausen, Till and Porco, Travis C and Doan, Thuy and Lietman, Thomas M and Oldenburg, Catherine E} } @article {166, title = {Dual-target, real-time PCR for the diagnosis of intraocular infections.}, journal = {Br J Ophthalmol}, volume = {103}, year = {2019}, month = {2019 04}, pages = {569-572}, abstract = {

BACKGROUND: is the most common infectious cause of posterior uveitis worldwide. Two multicopy targets (B1 and Rep529) are commonly used in PCR assays, but studies evaluating these targets in ocular fluid samples are limited. Herein, we determine the analytical characteristics of a single-reaction, internally controlled, dual-target, real-time PCR and evaluate the clinical performance of this assay in intraocular fluid samples obtained at a reference ophthalmologic centre in the USA.

METHODS: Lower limits of detection for the B1 and Rep529 components of the dual-target assay were determined using serial dilutions of cultured strain Z185. The dual-target assay was then used to test 148 archived intraocular samples (132 vitreous,16 aqueous humour) collected at the Francis I. Proctor Foundation between January 2010 and December 2015 for testing by a nested, conventional PCR targeting the B1 gene.

RESULTS: The 95\% lower limits of detection for the dual-target assay was determined to be 1.05 tachyzoites/mL for B1 and 0.83 tachyzoites/mL for Rep529. Using archived clinical intraocular specimens, the dual-target assay demonstrated 97.2\% positive per cent agreement (n=35/36; 95\% CI 83.7\% to 99.9\%) and 99.1\% negative per cent agreement (n=111/112; 95\% CI 94.4\% to 100\%) compared with the nested, conventional B1 PCR.

CONCLUSION: This single-reaction, internally controlled, dual-target (B1, Rep529) real-time PCR for the detection of DNA in intraocular specimens demonstrated excellent agreement with nested, conventional, B1 PCR. The dual-target design may ensure detection when variation is present in one of two target regions.

}, keywords = {Animals, Aqueous Humor, DNA, Protozoan, Eye Infections, Parasitic, Humans, Real-Time Polymerase Chain Reaction, Toxoplasma, Toxoplasmosis, Ocular, Uveitis, Posterior}, issn = {1468-2079}, doi = {10.1136/bjophthalmol-2018-313064}, author = {Gomez, Carlos A and Sahoo, Malaya K and Kahn, Ghazala Yasmeen and Zhong, Lina and Montoya, Jos{\'e} G and Pinsky, Benjamin A and Doan, Thuy} } @article {41, title = {Effect of Corticosteroid-Sparing Treatment With Mycophenolate Mofetil vs Methotrexate on Inflammation in Patients With Uveitis: A Randomized Clinical Trial.}, journal = {JAMA}, volume = {322}, year = {2019}, month = {2019 09 10}, pages = {936-945}, abstract = {

Importance: Methotrexate and mycophenolate mofetil are commonly used immunomodulatory therapies for achieving corticosteroid-sparing control of noninfectious uveitis, but there is uncertainty about which drug is more effective.

Objective: To compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis.

Design, Setting, and Participants: The First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial screened 265 adults with noninfectious uveitis requiring corticosteroid-sparing immunosuppressive therapy from 9 referral eye centers in India, the United States, Australia, Saudi Arabia, and Mexico between August 22, 2013, and August 16, 2017. Follow-up ended on August 20, 2018.

Interventions: Patients were randomized to receive oral methotrexate, 25 mg weekly (n = 107), or oral mycophenolate mofetil, 3 g daily (n = 109).

Main Outcomes and Measures: The primary outcome was treatment success at 6 months, which was defined as having control of inflammation in both eyes, no more than 7.5 mg prednisone daily and less than or equal to 2 drops of prednisolone acetate 1\%, and no treatment failure due to safety or intolerability. Patients underwent follow-up to 12 months while receiving the same treatment or switched to the other antimetabolite, depending on their 6-month outcome.

Results: Among 216 patients who were randomized (median age, 38 years; 135 (62.5\%) women), 194 (89.8\%) completed follow-up through 6 months. Treatment success occurred in 64 (66.7\%) patients in the methotrexate group vs 56 (57.1\%) in the mycophenolate group (difference, 9.5\% [95\% CI, -5.3\% to 21.8\%]; odds ratio [OR], 1.50 [95\% CI, 0.81 to 2.81]; P = .20). Among patients with posterior uveitis or panuveitis, treatment success was achieved in 58 (74.4\%) in the methotrexate group vs 42 (55.3\%) in the mycophenolate group (difference, 19.1\% [95\% CI, 3.6\% to 30.6\%]; OR, 2.35 [95\% CI, 1.16 to 4.90]; P = .02); whereas among patients with intermediate uveitis treatment success occurred in 6 (33.3\%) in the methotrexate group vs 14 (63.6\%) in the mycophenolate group (difference, -30.3\% [95\% CI, -51.6\% to 1.1\%]; OR, 0.29 [95\% CI, 0.08 to 1.05]; P = .07; P for interaction = .004). Elevated liver enzymes were the most common nonserious laboratory adverse event, occurring in 14 patients (13.0\%) in the methotrexate group and 8 patients (7.4\%) in the mycophenolate group.

Conclusions and Relevance: Among adults with noninfectious uveitis, the use of mycophenolate mofetil compared with methotrexate as first-line corticosteroid-sparing treatment did not result in superior control of inflammation. Further research is needed to determine if either drug is more effective based on the anatomical subtype of uveitis.

Trial Registration: ClinicalTrials.gov Identifier: NCT01829295.

}, keywords = {Adult, Anti-Inflammatory Agents, Drug Therapy, Combination, Enzyme Inhibitors, Female, Humans, Immunosuppressive Agents, Liver Function Tests, Male, Methotrexate, Middle Aged, Mycophenolic Acid, Prednisolone, Uveitis}, issn = {1538-3598}, doi = {10.1001/jama.2019.12618}, author = {Rathinam, S R and Gonzales, John A and Thundikandy, Radhika and Kanakath, Anuradha and Murugan, S Bala and Vedhanayaki, R and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Doan, Thuy and Keenan, Jeremy D and Rao, Maya M and Ebert, Caleb D and Nguyen, Hieu H and Kim, Eric and Porco, Travis C and Acharya, Nisha R} } @article {151, title = {High-throughput sequencing of pooled samples to determine community-level microbiome diversity.}, journal = {Ann Epidemiol}, volume = {39}, year = {2019}, month = {2019 11}, pages = {63-68}, abstract = {

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

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

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

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

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

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

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

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

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

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Administration Schedule, Female, Humans, Infant, Infant Mortality, Male, Mass Drug Administration, Niger}, issn = {1533-4406}, doi = {10.1056/NEJMoa1817213}, author = {Keenan, Jeremy D and Arzika, Ahmed M and Maliki, Ramatou and Boubacar, Nameywa and Elh Adamou, Sanoussi and Moussa Ali, Maria and Cook, Catherine and Lebas, Elodie and Lin, Ying and Ray, Kathryn J and O{\textquoteright}Brien, Kieran S and Doan, Thuy and Oldenburg, Catherine E and Callahan, E Kelly and Emerson, Paul M and Porco, Travis C and Lietman, Thomas M} } @article {136, title = {Macrolide Resistance in MORDOR I - A Cluster-Randomized Trial in Niger.}, journal = {N Engl J Med}, volume = {380}, year = {2019}, month = {2019 Jun 06}, pages = {2271-2273}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Child, Preschool, Drug Resistance, Bacterial, Humans, Infant, Macrolides, Niger, Pneumococcal Infections, Streptococcus pneumoniae}, issn = {1533-4406}, doi = {10.1056/NEJMc1901535}, author = {Doan, Thuy and Arzika, Ahmed M and Hinterwirth, Armin and Maliki, Ramatou and Zhong, Lina and Cummings, Susie and Sarkar, Samarpita and Chen, Cindi and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M} } @article {186, title = {Metagenomic Deep Sequencing for the Diagnosis of Corneal and External Disease Infections.}, journal = {Ophthalmology}, volume = {126}, year = {2019}, month = {2019 12}, pages = {1724-1726}, keywords = {Adult, Aged, Aged, 80 and over, Animals, Bacteria, Conjunctival Diseases, Corneal Diseases, Eye Infections, Female, Fungi, High-Throughput Nucleotide Sequencing, Humans, Male, Metagenome, Middle Aged, Parasites, Polymerase Chain Reaction, Retrospective Studies, Scleral Diseases}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2019.06.013}, author = {Seitzman, Gerami D and Hinterwirth, Armin and Zhong, Lina and Cummings, Susie and Chen, Cindi and Driver, Todd H and Lee, Michele D and Doan, Thuy} } @article {51, title = {Metagenomic Next-Generation Sequencing for Identification and Quantitation of Transplant-Related DNA Viruses.}, journal = {J Clin Microbiol}, volume = {57}, year = {2019}, month = {2019 12}, abstract = {

Infections with DNA viruses are frequent causes of morbidity and mortality in transplant recipients. This study describes the analytical and clinical performance characteristics of the Arc Bio Galileo Pathogen Solution, an all-inclusive metagenomic next-generation sequencing (mNGS) reagent and bioinformatics pipeline that allows the simultaneous quantitation of 10 transplant-related double-stranded DNA (dsDNA) viruses (adenovirus [ADV], BK virus [BKV], cytomegalovirus [CMV], Epstein-Barr virus [EBV], human herpesvirus 6A [HHV-6A], HHV-6B, herpes simplex virus 1 [HSV-1], HSV-2, JC virus [JCV], and varicella-zoster virus [VZV]). The mNGS 95\% limit of detection ranged from 14 copies/ml (HHV-6) to 191 copies/ml (BKV), and the lower limit of quantitation ranged from 442 international units (IU)/ml (EBV) to 661 copies/ml (VZV). An evaluation of 50 residual plasma samples with at least one DNA virus detected in prior clinical testing showed a total percent agreement of mNGS and quantitative PCR (qPCR) of 89.2\% (306/343), with a κ statistic of 0.725. The positive percent agreement was 84.9\% (73/86), and the negative percent agreement was 90.7\% (233/257). Furthermore, mNGS detected seven subsequently confirmed coinfections that were not initially requested by qPCR. Passing-Bablok regression revealed a regression line of = 0.953 + 0.075 (95\% confidence interval [CI] of the slope, 0.883 to 1.011; intercept, -0.100 to 0.299), and Bland-Altman analysis (mNGS - qPCR) showed a slight positive bias (0.28 log concentration; 95\% limits of agreement, -0.62 to 1.18). In conclusion, the mNGS-based Galileo pipeline demonstrates analytical and clinical performance comparable to that of qPCR for transplant-related DNA viruses.

}, keywords = {Computational Biology, DNA Virus Infections, DNA Viruses, High-Throughput Nucleotide Sequencing, Humans, Metagenomics, Molecular Diagnostic Techniques, Sensitivity and Specificity, Transplantation}, issn = {1098-660X}, doi = {10.1128/JCM.01113-19}, author = {Carpenter, Meredith L and Tan, Susanna K and Watson, Thomas and Bacher, Rowena and Nagesh, Vaishnavi and Watts, Alain and Bentley, Gordon and Weber, Jenna and Huang, ChunHong and Sahoo, Malaya K and Hinterwirth, Armin and Doan, Thuy and Carter, Theodore and Dong, Queeny and Gourguechon, St{\'e}phane and Harness, Eric and Kermes, Sean and Radhakrishnan, Srihari and Wang, Gongbo and Quiroz-Z{\'a}rate, Alejandro and Ching, Jesus and Pinsky, Benjamin A} } @article {131, title = {Neonatal azithromycin administration to prevent infant mortality: study protocol for a randomised controlled trial.}, journal = {BMJ Open}, volume = {9}, year = {2019}, month = {2019 09 04}, pages = {e031162}, abstract = {

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

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

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

TRIAL REGISTRATION NUMBER: NCT03682653; Pre-results.

}, keywords = {Anti-Bacterial Agents, Azithromycin, Body Size, Body Weight, Child Development, Double-Blind Method, Humans, Infant, Infant Mortality, Infant, Newborn, Randomized Controlled Trials as Topic}, issn = {2044-6055}, doi = {10.1136/bmjopen-2019-031162}, author = {Sie, Ali and Bountogo, Mamadou and Nebie, Eric and Ouattara, Mamadou and Coulibaly, Boubacar and Bagagnan, Cheik and Zabre, Pascal and Lebas, Elodie and Brogdon, Jessica and Godwin, William W and Lin, Ying and Porco, Travis and Doan, Thuy and Lietman, Thomas M and Oldenburg, Catherine E} } @article {116, title = {Time Trade-off Utility Values in Noninfectious~Uveitis.}, journal = {Am J Ophthalmol}, volume = {208}, year = {2019}, month = {2019 12}, pages = {47-55}, abstract = {

PURPOSE: To investigate time trade-off (TTO) utility values in patients with noninfectious uveitis and determine whether patient demographics and clinical characteristics are associated with utility scores.

DESIGN: Time trade-off utility analysis.

METHODS: Setting: A tertiary care uveitis center in San Francisco, California, USA.

PATIENT POPULATION: One hundred and four consecutive adults with noninfectious uveitis, enrolled between November 2016 and February 2017.

MAIN OUTCOME MEASURES: TTO utility values, as collected by an interviewer-guided survey. Information regarding general health, ocular symptoms, and religion was also collected and medical record review was conducted to record anatomic location of uveitis, disease activity, visual acuity, and treatments. Multivariable regression analysis with backward selection was used to identify variables associated with TTO values.

RESULTS: Median TTO score was 0.975 (interquartile range [IQR]: 0.8-1.0), corresponding to trading a median 1.28 years of remaining life for healthy eyes (IQR: 0-6.29). Regression analysis revealed that worse eye visual acuity, \>6\ months of oral corticosteroid use, and current antidepressant use were associated with lower TTO scores (P\ = .008, P\ = .006, P\ = .008, respectively), controlling for age and sex. In particular, patients who had been taking oral corticosteroids for more than 6\ months, regardless of dose, were 10.5 times more likely to trade 20\% or more years of remaining life (TTO <=0.8) than patients not taking oral corticosteroids (95\% confidence interval: 2.3, 48.1; P\ = .002).

CONCLUSIONS: Patients with noninfectious uveitis had measurable, though modest, reductions in quality of life, as assessed by TTO, and these decreases were significantly associated with visual acuity in the worse eye and long-term oral corticosteroid use.

}, keywords = {Administration, Oral, Adult, Antidepressive Agents, Cross-Sectional Studies, Female, Glucocorticoids, Health Status, Health Surveys, Humans, Male, Middle Aged, Quality of Life, Sickness Impact Profile, Surveys and Questionnaires, Tertiary Care Centers, Uveitis, Visual Acuity}, issn = {1879-1891}, doi = {10.1016/j.ajo.2019.06.005}, author = {Niemeyer, Katherine M and Gonzales, John A and Doan, Thuy and Browne, Erica N and Rao, Maya M and Acharya, Nisha R} } @article {126, title = {Unbiased Pathogen Detection and Host Gene Profiling for Conjunctivitis.}, journal = {Ophthalmology}, volume = {126}, year = {2019}, month = {2019 08}, pages = {1090-1094}, abstract = {

PURPOSE: The etiology of conjunctivitis is often misdiagnosed. An ideal diagnostic test would identify all possible infectious causes. In this study, we apply unbiased metagenomic RNA deep sequencing (MDS) to identify pathogens causing conjunctivitis.

DESIGN: Molecular study of prospectively collected conjunctival swabs from patients with presumed infectious conjunctivitis.

PARTICIPANTS: Patients with presumed acute infectious conjunctivitis.

METHODS: Conjunctival swabs were collected from patients presenting with acute conjunctivitis. Swabs were processed for MDS. Pathogens were identified using a rapid computational pipeline to analyze the nonhost sequences obtained from MDS. Differential gene expression analysis was performed to evaluate for host transcriptome signatures for infectious types. Clinical samples were deidentified, and laboratory personnel handling the samples and interpreting the data were masked.

MAIN OUTCOME MEASURES: Pathogens and differential transcripts identified by MDS.

RESULTS: Metagenomic RNA deep sequencing detected pathogens in 86\% (12/14) of the patients tested. Swabs from 10 of 14 patients were positive for human adenovirus (HAdV) while swabs from 2 of 14 patients were positive for Vittaforma corneae (a parasitic fungal species of the microsporidia group). Samples positive for HAdV by RNA-seq were independently verified in a CLIA-certified laboratory. Pathogen-directed polymerase chain reaction confirmed the presence of V.\ corneae genome in the samples positive by RNA-seq. Local host transcriptome analysis identified 12 differentially expressed genes that provided distinct expression signatures for patients infected with HAdV compared with V.\ corneae.

CONCLUSIONS: Metagenomic RNA deep sequencing can reliably detect and quantify common and rare pathogens causing conjunctivitis, and identify strains. The unbiased nature of metagenomic RNA deep sequencing allowed an expanded scope of pathogen detection, including fungal species not commonly associated with acute conjunctivitis. In addition, the identification of infection type-specific local host transcriptome signatures may allow for pathogen detection even when the pathogen load is too low for direct identification.

}, keywords = {Adult, Aged, Conjunctivitis, DNA, Bacterial, DNA, Fungal, DNA, Viral, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Metagenomics, Middle Aged, Young Adult}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2019.03.039}, author = {Lalitha, Prajna and Seitzman, Gerami D and Kotecha, Ritesh and Hinterwirth, Armin and Chen, Cindi and Zhong, Lina and Cummings, Susie and Lebas, Elodie and Sahoo, Malaya K and Pinsky, Benjamin A and Lietman, Thomas M and Doan, Thuy} } @article {271, title = {CYTOMEGALOVIRUS RETINITIS ASSOCIATED WITH OCCLUSIVE VASCULOPATHY IN AN ELDERLY, HUMAN IMMUNODEFICIENCY VIRUS-NEGATIVE MAN.}, journal = {Retin Cases Brief Rep}, volume = {12 Suppl 1}, year = {2018}, month = {2018 Fall}, pages = {S114-S117}, abstract = {

PURPOSE: To present a case of cytomegalovirus (CMV) retinitis associated with occlusive vasculopathy presenting as sudden unilateral loss of vision in a human immunodeficiency virus-negative elderly man.

METHODS: Clinical case report and literature review.

RESULTS: An 84-year-old Chinese man with diabetes mellitus and primary open-angle glaucoma was seen in consultation by our uveitis service for evaluation of sudden vision loss in the right eye. Examination revealed an occlusive retinal vasculopathy. An extensive diagnostic workup was performed, including fluorescein angiography, serologic testing for infectious etiologies including syphilis and tuberculosis and a temporal artery biopsy. The patient was treated with high-dose oral prednisone, after which the biopsy returned negative for giant-cell arteritis. Three weeks after initial presentation, the patient was noted to have a new area of retinitis in the temporal periphery. An anterior chamber paracentesis was performed, and the fluid was sent for directed polymerase chain reaction testing, which returned positive for CMV. Human immunodeficiency virus testing was negative. He was treated with oral valganciclovir and intravitreal foscarnet injections and the infection subsequently resolved.

CONCLUSION: Cytomegalovirus infection can be associated with occlusive vasculopathy in human immunodeficiency virus-negative individuals. The diagnosis of CMV retinitis should be considered in patients with human immunodeficiency virus-negative who have other conditions that may compromise immune function, particularly advanced age, diabetes mellitus, malignancy, or use of immunosuppressive agents.

}, keywords = {Aged, 80 and over, Cytomegalovirus Retinitis, HIV Seronegativity, Humans, Male, Retinal Vein Occlusion}, issn = {1937-1578}, doi = {10.1097/ICB.0000000000000639}, author = {Moussa, Kareem and Doan, Thuy and Stewart, Jay M and Shantha, Jessica and Gonzales, John and Acharya, Nisha and Cunningham, Emmett T} } @article {226, title = {Diversity of Chlamydia trachomatis in Trachoma-Hyperendemic Communities Treated With Azithromycin.}, journal = {Am J Epidemiol}, volume = {187}, year = {2018}, month = {2018 09 01}, pages = {1840-1845}, abstract = {

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

}, keywords = {Anti-Bacterial Agents, Azithromycin, Bacterial Outer Membrane Proteins, Chlamydia trachomatis, Genetic Variation, Humans, Trachoma}, issn = {1476-6256}, doi = {10.1093/aje/kwy071}, author = {Chin, Stephanie A and Morberg, Daniel P and Alemayehu, Wondu and Melese, Muluken and Lakew, Takele and Chen, Michael C and Zhou, Zhaoxia and Doan, Thuy and Cevallos, Vicky and Lietman, Thomas M and Keenan, Jeremy D} } @article {251, title = {Metagenomic deep sequencing of aqueous fluid detects intraocular lymphomas.}, journal = {Br J Ophthalmol}, volume = {102}, year = {2018}, month = {2018 01}, pages = {6-8}, abstract = {

INTRODUCTION: Currently, the detection of pathogens or mutations associated with intraocular lymphomas heavily relies on prespecified, directed PCRs. With metagenomic deep sequencing (MDS), an unbiased high-throughput sequencing approach, all pathogens as well as all mutations present in the host{\textquoteright}s genome can be detected in the same small amount of ocular fluid.

METHODS: In this cross-sectional case series, aqueous fluid samples from two patients were submitted to MDS to identify pathogens as well as common and rare cancer mutations.

RESULTS: MDS of aqueous fluid from the first patient with vitreal lymphoma revealed the presence of both Epstein-Barr virus (HHV-4/EBV) and human herpes virus 8 (HHV-8) RNA. Aqueous fluid from the second patient with intraocular B-cell lymphoma demonstrated a less common mutation in the gene associated with B-cell lymphoma.

CONCLUSION: MDS detects pathogens that, in some instances, may drive the development of intraocular lymphomas. Moreover, MDS is able to identify both common and rare mutations associated with lymphomas.

}, keywords = {Adult, Aqueous Humor, Biomarkers, Tumor, Cross-Sectional Studies, DNA Mutational Analysis, DNA, Neoplasm, Female, High-Throughput Nucleotide Sequencing, Humans, In Situ Hybridization, Intraocular Lymphoma, Lymphoma, B-Cell, Male, Middle Aged, Mutation, Myeloid Differentiation Factor 88}, issn = {1468-2079}, doi = {10.1136/bjophthalmol-2017-311151}, author = {Gonzales, John and Doan, Thuy and Shantha, Jessica G and Bloomer, Michele and Wilson, Michael R and DeRisi, Joseph L and Acharya, Nisha} } @article {276, title = {Gut Microbial Diversity in Antibiotic-Naive Children After Systemic Antibiotic Exposure: A Randomized Controlled Trial.}, journal = {Clin Infect Dis}, volume = {64}, year = {2017}, month = {2017 05 01}, pages = {1147-1153}, abstract = {

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

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

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

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

Clinical Trials Registration: NCT02048007.

}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Bacteria, Biodiversity, Child, Preschool, Cluster Analysis, DNA, Ribosomal, Female, Gastrointestinal Microbiome, Gastrointestinal Tract, Humans, Infant, Male, Niger, Phylogeny, Placebos, RNA, Ribosomal, 16S, Sequence Analysis, DNA}, issn = {1537-6591}, doi = {10.1093/cid/cix141}, author = {Doan, Thuy and Arzika, Ahmed M and Ray, Kathryn J and Cotter, Sun Y and Kim, Jessica and Maliki, Ramatou and Zhong, Lina and Zhou, Zhaoxia and Porco, Travis C and Vanderschelden, Benjamin and Keenan, Jeremy D and Lietman, Thomas M} } @article {241, title = {Metagenomic DNA Sequencing for the Diagnosis of Intraocular Infections.}, journal = {Ophthalmology}, volume = {124}, year = {2017}, month = {2017 08}, pages = {1247-1248}, keywords = {Cytomegalovirus, Cytomegalovirus Infections, DNA, Protozoan, DNA, Viral, Eye Infections, Parasitic, Eye Infections, Viral, Herpes Simplex, Herpes Zoster Ophthalmicus, Herpesvirus 3, Human, Humans, Metagenomics, Polymerase Chain Reaction, Sensitivity and Specificity, Sequence Analysis, DNA, Simplexvirus, Toxoplasma, Toxoplasmosis, Ocular, Uveitis, Vitreous Body}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2017.03.045}, author = {Doan, Thuy and Acharya, Nisha R and Pinsky, Benjamin A and Sahoo, Malaya K and Chow, Eric D and Banaei, Niaz and Budvytiene, Indre and Cevallos, Vicky and Zhong, Lina and Zhou, Zhaoxia and Lietman, Thomas M and DeRisi, Joseph L} } @article {211, title = {Current and future molecular diagnostics for ocular infectious diseases.}, journal = {Curr Opin Ophthalmol}, volume = {27}, year = {2016}, month = {2016 Nov}, pages = {561-567}, abstract = {

PURPOSE OF REVIEW: Confirmation of ocular infections can pose great challenges to the clinician. A fundamental limitation is the small amounts of specimen that can be obtained from the eye. Molecular diagnostics can circumvent this limitation and have been shown to be more sensitive than conventional culture. The purpose of this review is to describe new molecular methods and to discuss the applications of next-generation sequencing-based approaches in the diagnosis of ocular infections.

RECENT FINDINGS: Efforts have focused on improving the sensitivity of pathogen detection using molecular methods. This review describes a new molecular target for Toxoplasma gondii-directed polymerase chain reaction assays. Molecular diagnostics for Chlamydia trachomatis and Acanthamoeba species are also discussed. Finally, we describe a hypothesis-free approach, metagenomic deep sequencing, which can detect DNA and RNA pathogens from a single specimen in one test. In some cases, this method can provide the geographic location and timing of the infection.

SUMMARY: Pathogen-directed PCRs have been powerful tools in the diagnosis of ocular infections for over 20 years. The use of next-generation sequencing-based approaches, when available, will further improve sensitivity of detection with the potential to improve patient care.

}, keywords = {Acanthamoeba, Amebiasis, Chlamydia Infections, Chlamydia trachomatis, Eye Infections, High-Throughput Nucleotide Sequencing, Humans, Metagenome, Molecular Diagnostic Techniques, Polymerase Chain Reaction, Toxoplasma, Toxoplasmosis}, issn = {1531-7021}, doi = {10.1097/ICU.0000000000000311}, author = {Doan, Thuy and Pinsky, Benjamin A} } @article {266, title = {Illuminating uveitis: metagenomic deep sequencing identifies common and rare pathogens.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 08 25}, pages = {90}, abstract = {

BACKGROUND: Ocular infections remain a major cause of blindness and morbidity worldwide. While prognosis is dependent on the timing and accuracy of diagnosis, the etiology remains elusive in ~50\ \% of presumed infectious uveitis cases. The objective of this study is to determine if unbiased metagenomic deep sequencing (MDS) can accurately detect pathogens in intraocular fluid samples of patients with uveitis.

METHODS: This is a proof-of-concept study, in which intraocular fluid samples were obtained from five subjects with known diagnoses, and one subject with bilateral chronic uveitis without a known etiology. Samples were subjected to MDS, and results were compared with those from conventional diagnostic tests. Pathogens were identified using a rapid computational pipeline to analyze the non-host sequences obtained from MDS.

RESULTS: Unbiased MDS of intraocular fluid produced results concordant with known diagnoses in subjects with (n = 4) and without (n = 1) uveitis. Samples positive for Cryptococcus neoformans, Toxoplasma gondii, and herpes simplex virus 1 as tested by a Clinical Laboratory Improvement Amendments-certified laboratory were correctly identified with MDS. Rubella virus was identified in one case of chronic bilateral idiopathic uveitis. The subject{\textquoteright}s strain was most closely related to a German rubella virus strain isolated in 1992, one year before he developed a fever and rash while living in Germany. The pattern and the number of viral identified mutations present in the patient{\textquoteright}s strain were consistent with long-term viral replication in the eye.

CONCLUSIONS: MDS can identify fungi, parasites, and DNA and RNA viruses in minute volumes of intraocular fluid samples. The identification of chronic intraocular rubella virus infection highlights the eye{\textquoteright}s role as a long-term pathogen reservoir, which has implications for virus eradication and emerging global epidemics.

}, keywords = {Aqueous Humor, Cryptococcosis, Cryptococcus neoformans, Herpes Simplex, Herpesvirus 1, Human, High-Throughput Nucleotide Sequencing, Humans, Metagenomics, Phylogeny, Rubella, Rubella virus, Toxoplasma, Toxoplasmosis, Uvea, Uveitis, Virus Replication}, issn = {1756-994X}, doi = {10.1186/s13073-016-0344-6}, author = {Doan, Thuy and Wilson, Michael R and Crawford, Emily D and Chow, Eric D and Khan, Lillian M and Knopp, Kristeene A and O{\textquoteright}Donovan, Brian D and Xia, Dongxiang and Hacker, Jill K and Stewart, Jay M and Gonzales, John A and Acharya, Nisha R and DeRisi, Joseph L} } @article {256, title = {Paucibacterial Microbiome and Resident DNA Virome of the Healthy Conjunctiva.}, journal = {Invest Ophthalmol Vis Sci}, volume = {57}, year = {2016}, month = {2016 Oct 01}, pages = {5116-5126}, abstract = {

Purpose: To characterize the ocular surface microbiome of healthy volunteers using a combination of microbial culture and high-throughput DNA sequencing techniques.

Methods: Conjunctival swab samples from 107 healthy volunteers were analyzed by bacterial culture, 16S rDNA gene deep sequencing (n = 89), and biome representational in silico karyotyping (BRiSK; n = 80). Swab samples of the facial skin (n = 42), buccal mucosa (n = 50), and environmental controls (n = 27) were processed in parallel. 16S rDNA gene quantitative PCR was used to calculate the bacterial load in each site. Bacteria were characterized by site using principal coordinate analysis of metagenomics data. BRiSK data were analyzed for presence of fungi and viruses.

Results: Corynebacteria, Propionibacteria, and coagulase-negative Staphylococci were the predominant organisms identified by all three techniques. Quantitative 16S PCR demonstrated approximately 0.1 bacterial 16S rDNA/human actin copy on the ocular surface compared with greater than 10 16S rDNA/human actin copy for facial skin or the buccal mucosa. The conjunctival bacterial community structure is distinct compared with the facial skin (R = 0.474, analysis of similarities P = 0.0001), the buccal mucosa (R = 0.893, P = 0.0001), and environmental control samples (R = 0.536, P = 0.0001). 16S metagenomics revealed substantially more bacterial diversity on the ocular surface than other techniques, which appears to be artifactual. BRiSK revealed presence of torque teno virus (TTV) on the healthy ocular surface, which was confirmed by direct PCR to be present in 65\% of all conjunctiva samples tested.

Conclusions: Relative to adjacent skin or other mucosa, healthy ocular surface microbiome is paucibacterial. Its flora are distinct from adjacent skin. Torque teno virus is a frequent constituent of the ocular surface microbiome. (ClinicalTrials.gov number, NCT02298881.).

}, keywords = {Adult, Bacteria, Conjunctiva, DNA, Bacterial, Eye Infections, Bacterial, Female, Healthy Volunteers, High-Throughput Nucleotide Sequencing, Humans, Male, Microbiota, Middle Aged, Prospective Studies, Real-Time Polymerase Chain Reaction, Sequence Analysis, DNA}, issn = {1552-5783}, doi = {10.1167/iovs.16-19803}, author = {Doan, Thuy and Akileswaran, Lakshmi and Andersen, Dallin and Johnson, Benjamin and Ko, Narae and Shrestha, Angira and Shestopalov, Valery and Lee, Cecilia S and Lee, Aaron Y and Van Gelder, Russell N} } @article {756, title = {Retinal neovascularization and endogenous fungal endophthalmitis in intravenous drug users.}, journal = {Ophthalmology}, volume = {121}, year = {2014}, month = {2014 Sep}, pages = {1847-8.e2}, keywords = {Adult, Antifungal Agents, Endophthalmitis, Eye Infections, Fungal, Female, Humans, Male, Neovascularization, Pathologic, Retinal Diseases, Retrospective Studies, Substance Abuse, Intravenous, Vision, Low}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2014.03.037}, author = {Doan, Thuy and Vemulakonda, Gurunadh A and Choi, Deana and Keene, C Dirk and Akileswaran, Lakshmi and Van Gelder, Russell N and Chao, Jennifer R} }