@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 {1596, title = {Comparison of antimicrobial resistance genes on the ocular surface of patients with corneal infections in California and Malawi.}, journal = {Int Health}, year = {2025}, month = {2025 Apr 29}, abstract = {

BACKGROUND: Antimicrobial resistance (AMR) determinants on the ocular surface may contribute to poor treatment responses.

METHODS: An exploratory comparative analysis of ocular surface AMR determinants, as determined by RNA-sequencing (RNA-seq), on patients presenting with corneal infections at the Proctor Medical Clinic at the University of California San Francisco in San Francisco, CA, USA, and the Queen Elizabeth Central Hospital at the Department of Ophthalmology of Kamuzu College of Health Sciences in Blantyre, Malawi, was conducted. All patients underwent swabbing of three sites on the ocular surface: cornea, ipsilateral conjunctiva, and contralateral conjunctiva.

RESULTS: Mutations conferring macrolide resistance were present on the ocular surface in 58\% (95\% CI 44 to 71\%) of the participants in Malawi and 32\% (95\% CI 20 to 46\%) of the participants in San Francisco. Aminoglycosides resistance genes were also common on the ocular surface with 58\% (95\% CI 44 to 71\%) prevalence in Malawi and 21\% (95\% CI 12 to 35\%) in San Francisco. AMR was associated with poorer visual outcomes in a subset of patients.

CONCLUSIONS: As determined by RNA-seq, ocular surface AMR gene mutations are common in patients with infectious keratitis. Surveillance may be important for infectious keratitis treatment selection as well as providing guidance for antibiotic stewardship.

}, issn = {1876-3405}, doi = {10.1093/inthealth/ihaf042}, author = {Seitzman, Gerami D and Kalua, Khumbo and Misanjo, Esther S and Chen, Cindi and Ouimette, Kevin and Zhong, Lina and Liu, YuHeng and Yu, Danny and Abraham, Thomas and Wu, Nathaniel and Yan, Daisy and Lietman, Thomas M and Hinterwirth, Armin and Doan, Thuy} } @article {1601, title = {A Distinguishable Peripheral Blood and Conjunctival Transcriptome and Gut Microbiome in Sj{\"o}gren{\textquoteright}s Disease: A Pilot Study.}, journal = {Eye Contact Lens}, year = {2025}, month = {2025 May 02}, abstract = {

OBJECTIVE: To create a comprehensive multi-tissue molecular atlas of Sj{\"o}gren{\textquoteright}s disease by using unbiased RNA sequencing to identify differentially expressed genes (DEGs) in peripheral blood and conjunctival transcriptomes, and to characterize the ocular surface and gut microbiome profiles in participants classified as Sj{\"o}gren{\textquoteright}s versus non-Sj{\"o}gren{\textquoteright}s disease.

METHODS: This exploratory study used high-throughput RNA sequencing to analyze peripheral blood, conjunctival swabs, and rectal swabs from participants (11 classified as Sj{\"o}gren{\textquoteright}s disease and four classified as non-Sj{\"o}gren{\textquoteright}s) to identify DEGs and microbial profiles that could distinguish these groups.

RESULTS: Differential gene expression analysis revealed upregulated type I interferon (IFI44L, OASL, USP18) and complement pathways (SERPING1) in peripheral blood, alongside activation of several novel pathways in the conjunctiva including intracellular vesicle trafficking (HIP1, GOLIM4, FIG4), immunometabolism (CERS5, HPRT1, ULK2), and cytoskeletal remodeling (MARK1, IQCB1) in Sj{\"o}gren{\textquoteright}s disease. In addition, distinct gut microbiome compositions were observed in Sj{\"o}gren{\textquoteright}s disease participants, characterized by an increased presence of Lactobacillus reuteri species.

CONCLUSIONS: Using unbiased RNA sequencing, we confirmed the role of type I interferon and complement pathways in the peripheral blood and identified novel molecular signatures in the conjunctiva of Sj{\"o}gren{\textquoteright}s disease participants. These newly identified pathways-involved in intracellular vesicle trafficking, immunometabolism, and cytoskeletal remodeling-expand our understanding of disease mechanisms beyond traditional immune pathways. In addition, we found distinct gut microbial profiles in Sj{\"o}gren{\textquoteright}s disease participants, although ocular surface microbiome showed no significant differences. Such findings may suggest possible new therapeutic targets and allow for Sj{\"o}gren{\textquoteright}s disease patient stratification. However, validation in larger cohorts is needed to establish clinical significance and potential applications in Sj{\"o}gren{\textquoteright}s disease.

}, issn = {1542-233X}, doi = {10.1097/ICL.0000000000001186}, author = {Nguyen, Robert D and Nortey, Jeremy and Gebreegziabher, Elisabeth and Hinterwirth, Armin and Zhong, Lina and Chen, Cindi and Doan, Thuy and Lietman, Thomas M and Gonzales, John A} } @article {1611, title = {Epstein-Barr Virus Associated with Unilateral Thygeson{\textquoteright}s Superficial Punctate Keratitis.}, journal = {Ophthalmology}, year = {2025}, month = {2025 May 31}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2025.04.029}, author = {Nesemann, John M and Doan, Thuy and Seitzman, Gerami D} } @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 {1576, title = {Reply to Comment on "Multiple Anterior Chamber Paracenteses May be Needed to Identify Cytomegalovirus Anterior Uveitis.".}, journal = {Am J Ophthalmol}, year = {2025}, month = {2025 Feb 11}, issn = {1879-1891}, doi = {10.1016/j.ajo.2025.02.011}, author = {Benador-Shen, Christine and Shantha, Jessica and Lee, Jennifer and Qian, Ying and Doan, Thuy and Gonzales, John A} } @article {1376, title = {Acute neuroretinitis as a delayed manifestation of tubulointerstitial nephritis and uveitis syndrome.}, journal = {Am J Ophthalmol Case Rep}, volume = {34}, year = {2024}, month = {2024 Jun}, pages = {102050}, abstract = {

PURPOSE: Tubulointerstitial nephritis syndrome with uveitis (TINU) is a rare, acquired syndrome characterized by interstitial nephritis with bilateral uveitis. We report a case of TINU with typical bilateral anterior uveitis complicated by an atypical, delayed-onset neuroretinitis in a 12-year old patient.

OBSERVATION: A 12-year-old female with a 21-month history of TINU featuring chronic bilateral anterior uveitis presented with one week of blurred vision in her left eye. On exam she was found to have new-onset disc edema in the right eye and neuroretinitis in the left eye. After a negative infectious disease workup, the patient was treated with a course of intravenous (IV) solumedrol with prednisone taper and advancement of her systemic immunosuppression. In follow up she demonstrated resolution of her disc edema and neuroretinitis with improved visual acuity and clinical exam.

CONCLUSION: This case stresses the importance of monitoring for additional ocular manifestations including neuroretinitis years after the onset of anterior uveitis in TINU. In comparison to the two published cases of TINU with neuroretinitis, this case shares features of uveitis progression, and thus highlights the value of further description of TINU-associated neuroretinitis.

}, issn = {2451-9936}, doi = {10.1016/j.ajoc.2024.102050}, author = {Vazquez, Sara E and Niemeyer, Katherine and Mentreddy, Akshay and Gonzales, John and Rasool, Nailyn and Acharya, Nisha R and Doan, Thuy and Shantha, Jessica G} } @article {1391, title = {Assessment of spillover of antimicrobial resistance to untreated children 7 to 12 years old after mass drug administration of azithromycin for child survival in Niger: a secondary analysis of the MORDOR cluster-randomized trial.}, journal = {Clin Infect Dis}, year = {2024}, month = {2024 May 13}, abstract = {

BACKGROUND: The risk of antibiotic resistance is complicated by the potential for spillover effects from one treated population to another. Azithromycin mass drug administration programs report higher rates of antibiotic resistance among treatment arms in targeted groups. This study aims to understand the risk of spillover of antibiotic resistance to non-target groups in these programs.

METHODS: Data was used from a cluster-randomized trial comparing the effect of biannual azithromycin and placebo distribution to children 1-59 months on child mortality. Nasopharyngeal samples from untreated children 7-12 years old were tested for genetic determinants of macrolide resistance (primary outcome) and resistance to other antibiotic classes (secondary outcomes). Linear regression was used to compare the community-level mean difference in prevalence by arm at the 24-month timepoint adjusting for baseline prevalence.

RESULTS: 1,103 children 7-12 years old in 30 communities were included in the analysis (15 azithromycin, 15 placebo). Adjusted mean differences in prevalence of resistance determinants for macrolides, beta-lactams and tetracyclines were 3.4\% (95\% CI -4.1\% to 10.8\%, P-value 0.37), -1.2\% (95\% CI -7.9\% to 5.5\%, P-value 0.72), and -3.3\% (95\% CI -9.5\% to 2.8\%, P-value 0.61), respectively.

CONCLUSIONS: We were unable to demonstrate a statistically significant increase in macrolide resistance determinants in untreated groups in an azithromycin mass drug administration program. While the result might be consistent with a small spillover effect, this study was not powered to detect such a small difference. Larger studies are warranted to better understand the potential for spillover effects within these programs.

}, issn = {1537-6591}, doi = {10.1093/cid/ciae267}, author = {Peterson, Brittany and Arzika, Ahmed M and Amza, Abdou and Maliki, Ramatou and Mankara Karamba, Alio and Moussa, Mariama and Kemago, Mariama and Liu, Zijun and Houpt, Eric and Liu, Jie and Pholwat, Suporn and Doan, Thuy and Porco, Travis and Keenan, Jeremy D and Lietman, Thomas M and O{\textquoteright}Brien, Kieran S} } @article {1456, title = {Association of weather variables with pathogens contributing to conjunctivitis worldwide.}, journal = {Clin Infect Dis}, year = {2024}, month = {2024 Aug 19}, abstract = {

PURPOSE: To identify weather variables associated with pathogens contributing to infectious conjunctivitis globally.

METHODS: Sample collection and pathogen identification from patients with acute infectious conjunctivitis was performed from 2017 to 2023. We linked pathogens identified from 13 sites across 8 countries with publicly available weather data by geographic coordinates. Mixed effects logistic regression analysis was performed to estimate the associations between temperature, precipitation, and relative humidity exposures, and the prevalence of infection types (RNA virus, DNA virus, bacteria, and fungus).

RESULTS: 498 cases from the United States, India, Nepal, Thailand, Burkina Faso, Niger, Vietnam, and Israel were included in the analysis. 8-day average precipitation (mm) was associated with increased odds of RNA virus infection (odds ratio (OR)=1.47, 95\% confidence interval (CI): 1.12 to 1.93, P=0.01) and decreased odds of DNA infection (OR=0.62, 95\% CI: 0.46 to 0.82, P\<0.001). Relative humidity (\%) was associated with increased odds of RNA virus infections (OR=2.64, 95\% CI: 1.51 to 4.61, P\<0.001), and fungal infections (OR=2.35, 95\% CI: 1.19 to 4.66, P=0.01), but decreased odds of DNA virus (OR=0.58, 95\%CI: 0.37 to 0.90, P=0.02) and bacterial infections (OR=0.42, 95\% CI: 0.25 to 0.71, P\<0.001). Temperature ({\textdegree}C) was not associated with ocular infections for any pathogen type.

CONCLUSIONS: This study suggests that weather factors affect pathogens differently. Particularly, humidity and precipitation were predictors for pathogens contributing to conjunctivitis worldwide. Additional work is needed to clarify the effects of shifts in weather and environmental factors on ocular infectious diseases.

}, issn = {1537-6591}, doi = {10.1093/cid/ciae417}, author = {Yan, Daisy and Prajna, N Venkatesh and Lalitha, Prajna and Sansanayudh, Wiwan and Satitpitakul, Vannarut and Laovirojjanakul, Wipada and Chaudhary, Meenu and Bountogo, Mamadou and Sie, Ali and Coulibaly, Boubacar and Amza, Abdou and Nassirou, Beido and Almou, Ibrahim and Tran, Huy and Tran, Yen and Tsui, Edmund and Onclinx, Tania and Sella, Ruti and Goren, Lee and McClean, Esmeralda and Tham, Vivien and Chen, Cindi and Ruder, Kevin and Zhong, Lina and Liu, YuHeng and Yu, Danny and Abraham, Thomas and Lebas, Elodie and Arnold, Benjamin F and McLeod, Stephen D and Deiner, Michael S and Porco, Travis C and Seitzman, Gerami D and Lietman, Thomas M and Shantha, Jessica and Hinterwirth, Armin and Doan, Thuy} } @article {1561, title = {Azithromycin to Reduce Mortality - An Adaptive Cluster-Randomized Trial.}, journal = {N Engl J Med}, volume = {391}, year = {2024}, month = {2024 Aug 22}, pages = {699-709}, abstract = {

BACKGROUND: Twice-yearly mass distribution of azithromycin to children is a promising intervention to reduce childhood mortality in sub-Saharan Africa. The World Health Organization recommended restricting distribution to infants 1 to 11 months of age to mitigate antimicrobial resistance, although this more limited treatment had not yet been tested.

METHODS: We randomly assigned rural communities in Niger to four twice-yearly distributions of azithromycin for children 1 to 59 months of age (child azithromycin group), four twice-yearly distributions of azithromycin for infants 1 to 11 months of age and placebo for children 12 to 59 months of age (infant azithromycin group), or placebo for children 1 to 59 months of age. Census workers who were not aware of the group assignments monitored mortality twice yearly over the course of 2 years. We assessed three primary community-level mortality outcomes (deaths per 1000 person-years), each examining a different age group and pairwise group comparison.

RESULTS: A total of 1273 communities were randomly assigned to the child azithromycin group (1229 were included in the analysis), 773 to the infant azithromycin group (751 included in the analysis), and 954 to the placebo group (929 included in the analysis). Among 382,586 children, 419,440 person-years and 5503 deaths were recorded. Lower mortality among children 1 to 59 months of age was observed in the child azithromycin group (11.9 deaths per 1000 person-years; 95\% confidence interval [CI], 11.3 to 12.6) than in the placebo group (13.9 deaths per 1000 person-years; 95\% CI, 13.0 to 14.8) (representing 14\% lower mortality with azithromycin; 95\% CI, 7 to 22; P\<0.001). Mortality among infants 1 to 11 months of age was not significantly lower in the infant azithromycin group (22.3 deaths per 1000 person-years; 95\% CI, 20.0 to 24.7) than in the placebo group (23.9 deaths per 1000 person-years; 95\% CI, 21.6 to 26.2) (representing 6\% lower mortality with azithromycin; 95\% CI, -8 to 19). Five serious adverse events were reported: three in the placebo group, one in the infant azithromycin group, and one in the child azithromycin group.

CONCLUSIONS: Azithromycin distributions to children 1 to 59 months of age significantly reduced mortality and was more effective than treatment of infants 1 to 11 months of age. Antimicrobial resistance must be monitored. (Funded by the Bill and Melinda Gates Foundation; AVENIR ClinicalTrials.gov number, NCT04224987.).

}, author = {O{\textquoteright}Brien, Kieran S and Arzika, Ahmed M and Amza, Abdou and Maliki, Ramatou and Aichatou, Bawa and Bello, Ismael Mamane and Beidi, Diallo and Galo, Nasser and Harouna, Naser and Karamba, Alio M and Mahamadou, Sani and Abarchi, Moustapha and Ibrahim, Almou and Lebas, Elodie and Peterson, Brittany and Liu, Zijun and Le, Victoria and Colby, Emily and Doan, Thuy and Keenan, Jeremy D and Oldenburg, Catherine E and Porco, Travis C and Arnold, Benjamin F and Lietman, Thomas M and AVENIR Study Group} } @article {1451, title = {Biomarker Detection and Validation for Corneal Involvement in Patients With Acute Infectious Conjunctivitis.}, journal = {JAMA Ophthalmol}, year = {2024}, month = {2024 Aug 15}, abstract = {

IMPORTANCE: Infectious conjunctivitis can lead to corneal involvement and result in ocular morbidity. The identification of biomarkers associated with corneal involvement has the potential to improve patient care.

OBJECTIVE: To identify biomarkers in patients with acute infectious conjunctivitis.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study took place from December 2016 to March 2024. Analyses were performed in 3 phases. First, logistic regression and machine learning algorithms were used to predict the probability of demonstrating corneal involvement in patients with presumed infectious conjunctivitis. Second, quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to confirm the most important biomarker gene identified by the algorithm. Third, the biomarker gene was validated in prospectively collected conjunctival samples of adult patients from 3 outpatient centers in Thailand and 1 in India. Patients with signs and symptoms of infectious conjunctivitis and onset within less than 14 days were eligible. Exclusion criteria were the inability to consent, presumed toxicity, or allergic conjunctivitis.

EXPOSURES: Acute infectious conjunctivitis.

MAIN OUTCOMES AND MEASURES: The identification and validation of ocular surface gene expression associated with corneal findings on slitlamp examination.

RESULTS: Thirteen genes exhibited a 1.5-log2 fold change in expression in patients with corneal involvement compared to patients without corneal involvement. Using the 13 genes to train and cross validate, logistic regression produced the highest mean area under the receiver operating characteristic curve (AUROC; 0.85; 95\% CI, 0.84-0.86) for corneal involvement. The removal of apolipoprotein E (APOE) from the gene ensemble led to a decline in predictive performance of the logistic regression classifier (from mean AUROC 0.85 [95\% CI, 0.84-0.86] to 0.74 [95\% CI, 0.73-0.75]; adjusted P = .001 [Tukey test]). Orthogonal testing of APOE expression level with RT-qPCR showed that APOE expression was higher in patients with corneal involvement compared to patients without (median [IQR], 0.23 [0.04-0.47] vs 0.04 [0.02-0.06]; P = .004 [Mann-Whitney U test]). Using a Youden index of 0.23 Δ threshold cycle, APOE had a sensitivity of 56\% (95\% CI, 33-77) and a specificity of 88\% (95\% CI, 79-93) in 106 samples with conjunctivitis at Aravind, India (P < .001 [Fisher exact test]). When applied to a different patient population in Thailand, the same criteria could discriminate between disease states (58 samples; sensitivity, 47\%; 95\% CI, 30-64 and specificity, 93\%; 95\% CI, 77-99; P = .001 [Fisher exact test]).

CONCLUSIONS AND RELEVANCE: The results from this study suggest that the host conjunctival immune response can be meaningfully interrogated to identify biomarkers for ocular surface diseases.

}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2024.2891}, author = {Seitzman, Gerami D and Prajna, Lalitha and Prajna, N Venkatesh and Sansanayudh, Wiwan and Satitpitakul, Vannarut and Laovirojjanakul, Wipada and Chen, Cindi and Zhong, Lina and Ouimette, Kevin and Redd, Travis and Deiner, Michael C and Porco, Travis C and McLeod, Stephen D and Lietman, Thomas M and Hinterwirth, Armin and Doan, Thuy} } @article {1401, title = {Could the effect of antimicrobials on antimicrobial resistance be saturated at high-antimicrobial consumption? A comparison of the MORDOR and ResistAZM studies.}, journal = {Int J Infect Dis}, volume = {145}, year = {2024}, month = {2024 May 03}, pages = {107082}, abstract = {

OBJECTIVES: Antimicrobial resistance poses a considerable threat in high-antimicrobial-consumption populations, such as men who have sex with men (MSM) taking HIV pre-exposure prophylaxis. While the ResistAZM trial found no increase in macrolide resistance genes in MSM with gonorrhea after azithromycin treatment, the MORDOR trial observed an increase in these genes after mass azithromycin distribution. We hypothesized that this could be due to saturation of the resistome. To test this hypothesis, we compared the abundance of macrolide resistance determinants in anorectal samples between the baselines of the two trials.

METHODS: Shotgun metagenome reads from the anorectal baseline samples from the ResistAZM (n = 42) and MORDOR (n = 30) trials were analyzed using AMRPlusPlus. Nonhost reads were mapped to the MEGARes database to detect antibiotic resistance genes (ARG). Antimicrobial resistance (AMR) was normalized using cumulative sum scaling, and ARG abundance was estimated.

RESULTS: Macrolide, lincosamides, and streptogramins determinants were approximately 10-fold more abundant in the ResistAZM than the MORDOR samples (P <= 0.001).

CONCLUSION: The findings are compatible with our hypothesis. Thus, in populations with high-antimicrobial use, the relationship between antimicrobial consumption and AMR may be diminished due to saturation. These findings are vital for future studies investigating the resistogencity of novel interventions, such as doxycycline post-exposure prophylaxis, in populations with high preceding consumption of antimicrobials.

}, issn = {1878-3511}, doi = {10.1016/j.ijid.2024.107082}, author = {Manoharan-Basil, Sheeba Santhini and Gestels, Zina and Abdelatti, Sa{\"\i}d and De Baetselier, Irith and Vanbaelen, Thibaut and Hinterwirth, Armin and Doan, Thuy and Lietman, Thomas and Kenyon, Chris} } @article {1416, title = {Coxsackievirus A24 Causing Acute Conjunctivitis in a 2023 outbreak in Vietnam.}, journal = {Int J Infect Dis}, year = {2024}, month = {2024 Jun 12}, pages = {107133}, abstract = {

OBJECTIVES: To determine the causative pathogen during the 2023 conjunctivitis outbreak in Vietnam METHODS: RNA-sequencing was used to identify pathogens before and during the outbreak.

RESULTS: 24 patients with infectious conjunctivitis between March and October 2023 from Hai Yen Vision Institute in Vietnam were swabbed. Coxsackievirus A24v was the most common pathogen identified. Phylogenetic analysis of these strains demonstrates similarities to the Coxsackievirus identified in the 2022 India outbreak. Human adenovirus D was also circulating. Ocular findings of tearing, purulence, and itching were common in this outbreak.

CONCLUSIONS: Multiple viruses can co-circulate during conjunctivitis outbreaks. Hemorrhagic conjunctivitis, commonly associated with coxsackievirus conjunctivitis, was not a common clinical sign in this outbreak. Repeat genetic surveillance, with the notable inclusion of RNA virus detection strategies, is important for outbreak detection.

}, issn = {1878-3511}, doi = {10.1016/j.ijid.2024.107133}, author = {Tran, Huy and Hạ, Thảo and Hoang, Linh and Tran, Yen and Ruder, Kevin and Zhong, Lina and Chen, Cindi and Liu, YuHeng and Yu, Danny and Abraham, Thomas and Hinterwirth, Armin and Deiner, Michael and Porco, Travis C and Lietman, Thomas M and Doan, Thuy and Seitzman, Gerami D} } @article {1446, title = {Deep sequencing as a diagnostic tool in patients with suspected primary vitreoretinal lymphoma.}, journal = {Br J Ophthalmol}, year = {2024}, month = {2024 Aug 09}, abstract = {

PURPOSE: To compare the diagnostic utility of metagenomic deep sequencing (MDS) to cytology, flow cytometry and gene rearrangement by PCR in ocular samples of patients with suspected vitreoretinal lymphoma (VRL).

METHODS: Patients with suspected VRL underwent ocular sampling of one or both eyes at the Emory Eye Center from September 2017 to June 2022. Ocular samples were evaluated with MDS and conventional diagnostics. MDS was performed at the Ralph and Sophie Heintz Laboratory at the F.I. Proctor Foundation. Relevant demographic and clinical data were retrospectively collected from medical records. Patients were diagnosed with VRL based on clinical assessment and conventional diagnostic testing.

RESULTS: This study included 13 patients with suspected VRL who underwent diagnostic vitrectomy, including 1 patient who had an additional subretinal biopsy. Six patients (46.2\%) were diagnosed with VRL. Among patients diagnosed with VRL, MDS detected pathogenic mutations in 5 out of 6 patients (83.3\%) while cytology was positive for VRL in 4 out of 6 patients (66.7\%), flow cytometry in 4 out of 4 patients (100.0\%) and PCR in 4 out of 4 patients (100.0\%). MDS detected mutations in in 2 out of 6 patients diagnosed with VRL. In 7 patients (53.8\%) not diagnosed with VRL, MDS detected pathogenic lymphoma mutations in 2 patients (28.6\%).

DISCUSSION: MDS detected pathogenic mutations in five out of six patients diagnosed with VRL, including in two patients with negative cytology, demonstrating its potential to improve diagnostic rates of VRL as an adjunctive test.

}, issn = {1468-2079}, doi = {10.1136/bjo-2023-324769}, author = {Choo, Charlene and Cote, Olivia and Bostwick, Karina and Regueiro, Matthew and Wells, Jill and Grossniklaus, Hans E and Gonzales, John and Yeh, Steven and Hinterwirth, Armin and Doan, Thuy and Shantha, Jessica G} } @article {1436, title = {Etiologies of Infectious Keratitis in Malawi.}, journal = {Am J Trop Med Hyg}, year = {2024}, month = {2024 Jul 16}, abstract = {

Infectious keratitis is a leading cause of corneal blindness worldwide with little information known about causative etiologies in Malawi, Africa. This area is resource-limited with ophthalmologist and microbiology services. The Department of Ophthalmology at the Kamuzu College of Health Sciences in Blantyre, Malawi, is a participating site of an international corneal ulcer consortium, capriCORN (Comprehensive Analysis of Pathogens, Resistomes, and Inflammatory-markers in the CORNea). In this study, 50 patients with corneal ulcers were swabbed for pathogen identification using RNA-sequencing. Corneal trauma was reported in 41\% and 19\% of the patients worked in agriculture. A pathogen was identified in 58\% of the cases. Fungal pathogens predominated, followed by viruses and bacteria. Aspergillus, Fusarium, HSV-1, and Gardnerella were the most common pathogens detected. 50\% of patients reported treatment with an antibiotic before presentation. Pathogens unusual for infectious keratitis, such as Subramaniula asteroids, Aureobasidium pullulans, and Gardnerella vaginalis, were also detected.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.24-0149}, author = {Kalua, Khumbo and Misanjo, Esther S and Lietman, Thomas M and Ruder, Kevin and Zhong, Lina and Chen, Cindi and Liu, YuHeng and Yu, Danny and Abraham, Thomas and Wu, Nathaniel and Yan, Daisy and Hinterwirth, Armin and Doan, Thuy and Seitzman, Gerami D} } @article {1361, title = {Gut Microbiome Diversity and Antimicrobial Resistance After a Single Dose of Oral Azithromycin in Children: A Randomized Placebo-Controlled Trial.}, journal = {Am J Trop Med Hyg}, year = {2024}, month = {2024 Jan 16}, abstract = {

Mass antibiotic distribution to preschool children resulted in alterations of the gut microbiome months after distribution. This individually randomized, placebo-controlled trial evaluated changes in the gut microbiome and resistome in children aged 8 days to 59 months after one dose of oral azithromycin in Burkina Faso. A total of 450 children were randomized in a 1:1 ratio to either placebo or azithromycin. Rectal samples were collected at baseline, 2 weeks, and 6 months after randomization and subjected to DNA deep sequencing. Gut microbiome diversity and normalized antimicrobial resistance determinants for different antibiotic classes were evaluated. Azithromycin decreased gut bacterial diversity (Shannon P < 0.0001; inverse Simpson P < 0.001) 2 weeks after treatment relative to placebo. Concurrently, the normalized abundance of macrolide resistance genetic determinants was 243-fold higher (95\% CI: 76-fold to 776-fold, P < 0.0001). These alterations did not persist at 6 months, suggesting that disruptions were transient. Furthermore, we were unable to detect resistance changes in other antibiotic classes, indicating that co-resistance with a single course of azithromycin when treated at the individual level was unlikely.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.23-0651}, author = {Doan, Thuy and Liu, Zijun and Sie, Ali and Dah, Clarisse and Bountogo, Mamadou and Ouattara, Mamadou and Coulibaly, Boubacar and Kiemde, Dramane and Zonou, Guillaume and Nebie, Eric and Brogdon, Jessica and Lebas, Elodie and Hinterwirth, Armin and Zhong, Lina and Chen, Cindi and Zhou, Zhaoxia and Porco, Travis and Arnold, Benjamin F and Oldenburg, Catherine E and Lietman, Thomas M} } @article {1396, title = {Human Conjunctival Transcriptome in Acanthamoeba Keratitis: An Exploratory Study.}, journal = {Cornea}, year = {2024}, month = {2024 May 21}, abstract = {

PURPOSE: The purpose of this study was to identify conjunctival transcriptome differences in patients with Acanthamoeba keratitis compared with keratitis with no known associated pathogen.

METHODS: The host conjunctival transcriptome of 9 patients with Acanthamoeba keratitis (AK) is compared with the host conjunctival transcriptome of 13 patients with pathogen-free keratitis. Culture and/or confocal confirmed Acanthamoeba in 8 of 9 participants with AK who underwent metagenomic RNA sequencing as the likely pathogen. Cultures were negative in all 13 cases where metagenomic RNA sequencing did not identify a pathogen.

RESULTS: Transcriptome analysis identified 36 genes differently expressed between patients with AK and patients with presumed sterile, or pathogen-free, keratitis. Gene enrichment analysis revealed that some of these genes participate in several biologic pathways important for cellular signaling, ion transport and homeostasis, glucose transport, and mitochondrial metabolism. Notable relatively differentially expressed genes with potential relevance to Acanthamoeba infection included CPS1, SLC35B4, STEAP2, ATP2B2, NMNAT3, and AKAP12.

CONCLUSIONS: This research suggests that the local transcriptome in Acanthamoeba keratitis may be sufficiently robust to be detected in the conjunctiva and that corneas infected with Acanthamoeba may be distinguished from the inflamed cornea where no pathogen was identified. Given the low sensitivity for corneal cultures, identification of differentially expressed genes may serve as a suggestive transcriptional signature allowing for a complementary diagnostic technique to identify this blinding parasite. Knowledge of differentially expressed genes may also direct investigation of disease pathophysiology and suggest novel pathways for therapeutic targets.

}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000003545}, author = {Seitzman, Gerami D and Keenan, Jeremy D and Lietman, Thomas M and Ruder, Kevin and Zhong, Lina and Chen, Cindi and Liu, YuHeng and Yu, Danny and Abraham, Thomas and Hinterwirth, Armin and Doan, Thuy} } @article {1366, title = {Mass Azithromycin Distribution to Prevent Child Mortality in Burkina Faso: The CHAT Randomized Clinical Trial.}, journal = {JAMA}, volume = {331}, year = {2024}, month = {2024 Feb 13}, pages = {482-490}, abstract = {

IMPORTANCE: Repeated mass distribution of azithromycin has been shown to reduce childhood mortality by 14\% in sub-Saharan Africa. However, the estimated effect varied by location, suggesting that the intervention may not be effective in different geographical areas, time periods, or conditions.

OBJECTIVE: To evaluate the efficacy of twice-yearly azithromycin to reduce mortality in children in the presence of seasonal malaria chemoprevention.

DESIGN, SETTING, AND PARTICIPANTS: This cluster randomized placebo-controlled trial evaluating the efficacy of single-dose azithromycin for prevention of all-cause childhood mortality included 341 communities in the Nouna district in rural northwestern Burkina Faso. Participants were children aged 1 to 59 months living in the study communities.

INTERVENTIONS: Communities were randomized in a 1:1 ratio to receive oral azithromycin or placebo distribution. Children aged 1 to 59 months were offered single-dose treatment twice yearly for 3 years (6 distributions) from August 2019 to February 2023.

MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause childhood mortality, measured during a twice-yearly enumerative census.

RESULTS: A total of 34 399 children (mean [SD] age, 25.2 [18] months) in the azithromycin group and 33 847 children (mean [SD] age, 25.6 [18] months) in the placebo group were included. A mean (SD) of 90.1\% (16.0\%) of the censused children received the scheduled study drug in the azithromycin group and 89.8\% (17.1\%) received the scheduled study drug in the placebo group. In the azithromycin group, 498 deaths were recorded over 60 592 person-years (8.2 deaths/1000 person-years). In the placebo group, 588 deaths were recorded over 58 547 person-years (10.0 deaths/1000 person-years). The incidence rate ratio for mortality was 0.82 (95\% CI, 0.67-1.02; P = .07) in the azithromycin group compared with the placebo group. The incidence rate ratio was 0.99 (95\% CI, 0.72-1.36) in those aged 1 to 11 months, 0.92 (95\% CI, 0.67-1.27) in those aged 12 to 23 months, and 0.73 (95\% CI, 0.57-0.94) in those aged 24 to 59 months.

CONCLUSIONS AND RELEVANCE: Mortality in children (aged 1-59 months) was lower with biannual mass azithromycin distribution in a setting in which seasonal malaria chemoprevention was also being distributed, but the difference was not statistically significant. The study may have been underpowered to detect a clinically relevant difference.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03676764.

}, issn = {1538-3598}, doi = {10.1001/jama.2023.27393}, author = {Oldenburg, Catherine E and Ouattara, Mamadou and Bountogo, Mamadou and Boudo, Valentin and Ouedraogo, Thierry and Compaor{\'e}, Guillaume and Dah, Clarisse and Zakane, Alphonse and Coulibaly, Boubacar and Bagagnan, Cheik and Hu, Huiyu and O{\textquoteright}Brien, Kieran S and Nyatigo, Fanice and Keenan, Jeremy D and Doan, Thuy and Porco, Travis C and Arnold, Benjamin F and Lebas, Elodie and Sie, Ali and Lietman, Thomas M} } @article {1441, title = {Neonatal Azithromycin Exposure and Childhood Growth: Long-Term Follow-Up of a Randomized Controlled Trial.}, journal = {Am J Trop Med Hyg}, year = {2024}, month = {2024 Jul 16}, abstract = {

Single-dose azithromycin is being considered by the WHO as an intervention for prevention of child mortality. However, concerns have emerged related to longer term unintended consequences of early life antibiotic use, particularly among infants. We conducted a long-term follow-up in a random sample of children who had been enrolled in a trial of neonatal azithromycin versus placebo for prevention of mortality to assess whether neonatal azithromycin exposure led to differences in child growth up to 4 years of age. We found no evidence of a difference in any anthropometric outcome among children who had received a single oral dose of azithromycin compared with placebo during the neonatal period. These results do not support long-term growth-promoting or deleterious effects of early life azithromycin exposure.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.24-0016}, author = {Bountogo, Mamadou and Ouermi, Lucienne and Dah, Clarisse and Sie, Ali and Coulibaly, Boubacar and Zakane, Alphonse and Ouedraogo, Thierry and Ouattara, Mamadou and Lebas, Elodie and Fetterman, Ian and Kimfuema, Aim{\'e}e and Doan, Thuy and Lietman, Thomas M and Oldenburg, Catherine E} } @article {1406, title = {Ocular manifestations of mpox.}, journal = {Curr Opin Ophthalmol}, year = {2024}, month = {2024 Jun 07}, abstract = {

PURPOSE OF REVIEW: To highlight the clinical features of mpox with an emphasis on ocular manifestations and to review treatment options for this re-emerging infectious disease.

RECENT FINDINGS: Ocular involvement of mpox varies by clade. The most recent 2022 outbreak appears to be associated with fewer conjunctivitis cases compared to previous outbreaks. However, the ocular findings occurring during this newly emerging clade can be visually threatening and include cases of keratitis, rapidly progressing scleritis, and necrotizing periorbital rashes.

SUMMARY: Ocular mpox is an important clinical feature of systemic mpox virus (MPXV) infection. Heightened clinical suspicion allows for a timely diagnosis and the initiation of antiviral treatment, when appropriate. Randomized clinical trials for mpox systemic and ocular treatment efficacy are lacking. Prior clinical experience with smallpox and in-vitro mpox data support the use of systemic antivirals such as tecovirimat, cidofovir, brincidofovir and topical use of trifluridine in ocular mpox management, though treatment-resistant infection can occur and portend a poor prognosis.

}, issn = {1531-7021}, doi = {10.1097/ICU.0000000000001066}, author = {Nguyen, Minh and Doan, Thuy and Seitzman, Gerami D} } @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 {1426, title = {Outcomes in Patients with Vogt-Koyanagi-Harada Disease from the First-line Antimetabolites for Steroid-sparing Treatment Uveitis Trial.}, journal = {Am J Ophthalmol}, year = {2024}, month = {2024 Jun 21}, abstract = {

PURPOSE: To compare the effectiveness of methotrexate (MTX) and mycophenolate mofetil (MMF) in achieving corticosteroid-sparing control of uveitis in patients with Vogt-Koyanagi-Harada (VKH) disease.

METHODS: A subanalysis of patients with VKH from the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial, a randomized, observer-masked, comparative effectiveness trial, with comparisons by treatment (MTX versus MMF) and disease stage (acute versus chronic). Individuals with noninfectious uveitis were placed on a standardized corticosteroid taper and block randomized 1:1 to either 25mg weekly oral MTX or 1.5g twice daily oral MMF. The primary outcome was treatment success defined by corticosteroid-sparing control of uveitis at 6 months. Additional outcomes included change in best spectacle-corrected visual acuity (BSCVA), retinal central subfield thickness (CST), and resolution of serous retinal detachment (SRD).

RESULTS: Ninety-three out of 216 enrolled patients had VKH; 49 patients were randomized to MTX and 44 to MMF, of which 85 patients (46 on MTX, 39 on MMF) contributed to the primary outcome. There was no significant difference in treatment success by antimetabolite (80.4\% for MTX compared to 64.1\% for MMF; P=.12) or in BSCVA improvement (P=.78). Methotrexate was superior to MMF in reducing CST (P=.003) and resolving SRD (P=.02). There was no significant difference in treatment success by disease stage (P=.25), but patients with acute VKH had greater improvement in BSCVA (P\<.001) and reduction of CST (P=.02) than chronic VKH patients.

CONCLUSIONS: MTX and MMF have comparable outcomes as corticosteroid-sparing immunosuppressive therapies for VKH. Visual acuity improvement was greater in acute vs chronic VKH.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00182929.

}, issn = {1879-1891}, doi = {10.1016/j.ajo.2024.06.004}, author = {Acharya, Nisha R and Rathinam, Sivakumar R and Thundikandy, Radhika and Kanakath, Anuradha and Balamurugan, S and Vedhanayaki, R and Gonzales, John A and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Doan, Thuy and Arellanes-Garcia, Lourdes and Coyne, Alison and Porco, Travis C and Shantha, Jessica G} } @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 {1571, title = {Seroepidemiology of trachoma in a low prevalence region receiving annual mass azithromycin distribution in Maradi, Niger.}, journal = {PLoS Negl Trop Dis}, volume = {18}, year = {2024}, month = {2024 Dec 09}, pages = {e0012727}, abstract = {

BACKGROUND: Trachoma programs use the indicator trachomatous inflammation--follicular (TF) to monitor indication for and response to treatment for trachoma at the district level. Alternative indicators, including serologic markers, are increasingly being evaluated for trachoma surveillance. We evaluated seroprevalence of IgG antibodies to the Pgp3 antigen in two districts in Maradi, Niger thought to have low TF prevalence.

METHODS: Data were collected as part of the baseline assessment of the Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) trial in September 2021. A random sample of 80 communities was selected from Mayahi and Guidan Roumdji districts, both of which had TF prevalence <20\% at their most recent trachoma impact survey in 2018. A random sample of 50 children per community was sampled. We collected field grades, conjunctival swabs for processing PCR for ocular Chlamydia trachomatis, and dried blood spots for serologic assessment.

RESULTS: Of 3,994 children sampled in 80 communities, 49\% were female and median age was 4 years. Overall TF prevalence was 4.6\% (95\% CI 3.5 to 5.8\%) and trachomatous inflammation-intense (TI) prevalence was 0.6\% (95\% 0.3 to 0.9\%). The prevalence of ocular chlamydia was 0.03\% (95\% CI 0.08\%). Seroprevalence for Pgp3 antibodies was 6.3\% (95\% CI 5.5 to 7.1\%) in 1-9-year-olds and 3.7\% (95\% CI 2.9 to 4.4\%) in 1-5-year-olds. TF and Pgp3 seroprevalence were better correlated in 1-5-year-olds (correlation coefficient 0.29) compared to 1-9-year-olds (correlation coefficient 0.09).

CONCLUSIONS: In this low trachoma prevalence setting in Niger, seroprevalence of antibodies to Pgp3 were consistent with little ongoing transmission of C. trachomatis.

}, issn = {1935-2735}, doi = {10.1371/journal.pntd.0012727}, author = {Amza, Abdou and Kadri, Boubacar and Nassirou, Beido and Arzika, Ahmed and Gebreegziabher, Elisabeth and Hu, Huiyu and Zhong, Lina and Chen, Cindi and Yu, Danny and Abraham, Thomas and Liu, YuHeng and Wickens, Karana and Doan, Thuy and Martin, Diana and Arnold, Benjamin F and Lietman, Thomas M and Oldenburg, Catherine E} } @article {1371, title = {Use of Large Language Models to Assess the Likelihood of Epidemics From the Content of Tweets: Infodemiology Study.}, journal = {J Med Internet Res}, volume = {26}, year = {2024}, month = {2024 Mar 01}, pages = {e49139}, abstract = {

BACKGROUND: Previous work suggests that Google searches could be useful in identifying conjunctivitis epidemics. Content-based assessment of social media content may provide additional value in serving as early indicators of conjunctivitis and other systemic infectious diseases.

OBJECTIVE: We investigated whether large language models, specifically GPT-3.5 and GPT-4 (OpenAI), can provide probabilistic assessments of whether social media posts about conjunctivitis could indicate a regional outbreak.

METHODS: A total of 12,194 conjunctivitis-related tweets were obtained using a targeted Boolean search in multiple languages from India, Guam (United States), Martinique (France), the Philippines, American Samoa (United States), Fiji, Costa Rica, Haiti, and the Bahamas, covering the time frame from January 1, 2012, to March 13, 2023. By providing these tweets via prompts to GPT-3.5 and GPT-4, we obtained probabilistic assessments that were validated by 2 human raters. We then calculated Pearson correlations of these time series with tweet volume and the occurrence of known outbreaks in these 9 locations, with time series bootstrap used to compute CIs.

RESULTS: Probabilistic assessments derived from GPT-3.5 showed correlations of 0.60 (95\% CI 0.47-0.70) and 0.53 (95\% CI 0.40-0.65) with the 2 human raters, with higher results for GPT-4. The weekly averages of GPT-3.5 probabilities showed substantial correlations with weekly tweet volume for 44\% (4/9) of the countries, with correlations ranging from 0.10 (95\% CI 0.0-0.29) to 0.53 (95\% CI 0.39-0.89), with larger correlations for GPT-4. More modest correlations were found for correlation with known epidemics, with substantial correlation only in American Samoa (0.40, 95\% CI 0.16-0.81).

CONCLUSIONS: These findings suggest that GPT prompting can efficiently assess the content of social media posts and indicate possible disease outbreaks to a degree of accuracy comparable to that of humans. Furthermore, we found that automated content analysis of tweets is related to tweet volume for conjunctivitis-related posts in some locations and to the occurrence of actual epidemics. Future work may improve the sensitivity and specificity of these methods for disease outbreak detection.

}, issn = {1438-8871}, doi = {10.2196/49139}, author = {Deiner, Michael S and Deiner, Natalie A and Hristidis, Vagelis and McLeod, Stephen D and Doan, Thuy and Lietman, Thomas M and Porco, Travis C} } @article {1271, title = {Apollo Rising: Acute Conjunctivitis Outbreak in India, 2022}, journal = {Cornea Open}, year = {2023}, month = {08/2023}, abstract = {

Purpose: The purpose of this study was to identify pathogens associated with the 2022 conjunctivitis outbreak in Tamil Nadu, India. Methods: This prospective study was conducted in November 2022. Patients with presumed acute infectious conjunctivitis presenting to the Aravind Eye Clinic in Madurai, India, were eligible. Anterior nares and conjunctival samples from participants were obtained and processed for metagenomic RNA deep sequencing (RNA-seq). Results: Samples from 29 patients were sequenced. A pathogen was identified in 28/29 (97\%) patients. Coxsackie virus A24v, a highly infectious RNA virus, was the predominant pathogen and detected in 23/29 patients. Human adenovirus D (HAdV-D), a DNA virus commonly associated with conjunctivitis outbreaks, was detected in the remaining patients (5/29). Hemorrhagic conjunctiva was documented in both HAdV-D and Coxsackie virus A24v affected patients but was not the predominant clinical presentation. Phylogenetic analysis of Coxsackie virus A24v revealed a recent divergence from the 2015 outbreak. Conclusions: Coxsackie virus A24v and HAdV-D were cocirculating during the 2022 conjunctivitis outbreak in Tamil Nadu, India. Clinical findings were similar between patients with HAdV-D and Coxsackie virus A24v{\textendash}associated conjunctivitis. As high-throughput sequencing technologies become more readily available and cost-effective, unbiased pathogen surveillance may prove useful for outbreak surveillance and control.

}, issn = {2833-6992}, author = {Prajna, Namperumalsamy Venkatesh and Prajna, Lalitha and Teja, Vishnu and Gunasekaran, Ramesh and Ruder, Kevin and Zhong, Lina and Yu, Danny and Liu, David and Abraham, Thomas and Ao, Wendy and Deiner, Michael and Hinterwirth, Armin and Seitzman, Gerami D. and Doan, Thuy and Lietman, Thomas M. and on behalf of the, Scorpio Study Group} } @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 {1181, title = {Association between Quality of Life and Visual Acuity in a Randomized Clinical Trial of Patients with Uveitis Taking Antimetabolites.}, journal = {Ocul Immunol Inflamm}, year = {2023}, month = {2023 Feb 07}, pages = {1-9}, abstract = {

PURPOSE: To evaluate how changes in visual acuity are associated with changes in quality of life (QoL) among patients with non-infectious uveitis taking antimetabolites.

METHODS: This secondary analysis of the multicenter First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial involves 216 participants randomized to methotrexate or mycophenolate mofetil. Vision-related (NEI-VFQ and IND-VFQ) and health-related (PCS and MCS SF-36v2) QoL and visual acuity were measured at baseline and 6-month primary endpoint.

RESULTS: Visual acuity was significantly associated and correlated with all QoL measures (Spearman correlation coefficients\ =\ 0.5, 0.5, 0.3, and 0.4 for NEI-VFQ, IND-VFQ, SF-36v2 MCS and PCS, respectively). All observed changes in QoL met or exceeded the minimal clinically important difference definition on each scale. Treatment group was not significantly associated with any QoL measure.

CONCLUSION: By adding insight beyond visual acuity, QoL provides a more comprehensive picture of the patient experience during uveitis treatment. QoL = quality of life; VR-QoL = vision-related quality of life; HR-QoL = health-related quality of life; FAST = First-line Antimetabolites as Corticosteroid Sparing Treatment; NEI-VFQ = National Eye Institute Visual Functioning Questionnaire; IND-VFQ = Indian Visual Functioning Questionnaire; SF-36v2 = Medical Outcomes Study 36-Item Short Form Survey; PCS = physical component score; MCS = mental component score; 95\% CI = 95\% confidence interval; MCID = minimal clinically important difference.

}, issn = {1744-5078}, doi = {10.1080/09273948.2023.2169714}, author = {Chattopadhyay, Aheli and Rathinam, S R and Gonzales, John A and Kelly, Nicole K 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 Ebert, Caleb D and Porco, Travis C and Acharya, Nisha R} } @article {1191, title = {Case Series: Unbiased Deep Sequencing Analysis of Acute Infectious Conjunctivitis in an Ambulatory Eye Center in Berkeley, California.}, journal = {Optom Vis Sci}, year = {2023}, month = {2023 Mar 07}, abstract = {

SIGNIFICANCE: Acute infectious conjunctivitis poses significant challenges to eye care providers. It can be highly transmissible and as etiology is often presumed, correct treatment and management can be difficult. This study utilizes unbiased deep sequencing to identify causative pathogens of infectious conjunctivitis, potentially allowing for improved approaches to diagnosis and management.

PURPOSES: To identified associated pathogens of acute infectious conjunctivitis in a single ambulatory eye care center.Case ReportsThis study included patients who presented to the University of California Berkeley eye center with signs and symptoms suggestive of infectious conjunctivitis. From December 2021 to July 2021, samples were collected from 7 subjects (ages ranging from 18 to 38 years old). Deep sequencing identified associated pathogens in 5 out of 7 samples, including human adenovirus D (HAdV), Haemophilus influenzae, Chlamydia trachomatis, and human coronavirus 229E (HCoV-229E).

CONCLUSIONS: Unbiased deep sequencing identified some unexpected pathogens in subjects with acute infectious conjunctivitis. HAdV was recovered from only one patient in this series. While all samples were obtained during the COVID-19 pandemic, only one case of HCoV-229E and no SARS-CoV-2was identified.

}, issn = {1538-9235}, doi = {10.1097/OPX.0000000000002010}, author = {Kanai, Kuniyoshi and Whiteside, Meredith and Wong, Michel and La, Tammy and Nassiri, Maryam and Lee, Sam and Yeung, Sze Kei and Coulter, Adrienne and Ruder, Kevin and Chen, Cindi and Liu, David and Abraham, Thomas and Hinterwirth, Armin and Lietmanb, Thomas M and Doan, Thuy and Seitzman, Gerami D} } @article {1351, title = {Comprehensive Profile of Pathogens and Antimicrobial Resistance in Conjunctivitis Cases from Niger.}, journal = {Am J Trop Med Hyg}, volume = {109}, year = {2023}, month = {2023 Dec 06}, pages = {1333-1338}, 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.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.23-0498}, author = {Amza, Abdou and Nassirou, Beido and Kadri, Boubacar and Ali, Saley and Mariama, Boubacar and Ibrahim, Ciss{\'e} Mamadou and Roufaye, Lamine Aboubacar and Lebas, Elodie and Colby, Emily and Zhong, Lina and Chen, Cindi and Ruder, Kevin and Yu, Danny and Liu, YuHeng and Abraham, Thomas and Chang, Aaron and Mai, Lina and Hinterwirth, Armin and Seitzman, Gerami D and Lietman, Thomas M and Doan, Thuy} } @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 {1226, title = {Metagenomic Deep Sequencing for Orbital Inflammatory Disease.}, journal = {Ocul Immunol Inflamm}, year = {2023}, month = {2023 Apr 17}, pages = {1-4}, abstract = {

PURPOSE: Orbital inflammatory disease (OID) is a heterogeneous group of immunologic disorders whose etiology is often non-specific despite routine investigation. In this proof-of-concept study, metagenomic deep sequencing (MDS) is applied to examine host gene expression in two subtypes of OID.

METHODS: Prospectively collected lacrimal gland tissue from patients with OID was processed for MDS. Differential gene expression analysis was performed to evaluate for host transcriptome signatures. Proof-of-concept comparison was made between histologically confirmed samples of idiopathic dacryoadenitis and IgG4-related disease (IgG4-RD).

RESULTS: Twelve genes were identified to be differentially expressed between idiopathic dacryoadenitis and IgG4-RD. Differences in innate humoral immunity gene expression were observed. Several additional genes of interests were also found to be upregulated in idiopathic dacryoadenitis.

CONCLUSIONS: A unique transcriptome signature was found when comparing idiopathic dacryoadenitis to IgG4-RD. This suggests that MDS can identify differentially expressed genes in OID. Such insight could potentially provide a better understanding of host gene expression and the inflammatory pathways involved in OID.

}, issn = {1744-5078}, doi = {10.1080/09273948.2023.2199061}, author = {Vagefi, M Reza and Idowu, Oluwatobi O and Miller, Amanda and Doan, Thuy and Chen, Cindi and Hinterwirth, Armin and Zhong, Lina and Ahmad, Meleha and Ashraf, Davin C and Grob, Seanna R and Kersten, Robert C and Winn, Bryan J} } @article {1411, title = {Pathogen Profiles of Infectious Conjunctivitis in Ho Chi Minh City, Vietnam.}, journal = {Cornea Open}, volume = {2}, year = {2023}, month = {2023 Dec}, abstract = {

PURPOSE: Conjunctivitis epidemics and pandemics remain a global burden. This study aims to comprehensively identify pathogens associated with conjunctivitis in Vietnam.

METHODS: Patients with acute conjunctivitis presented to an outpatient clinic in Ho Chi Minh City, Vietnam, were enrolled from September 2022 to March 2023. Swabs were obtained from conjunctiva and anterior nares of all patients. Unbiased RNA deep sequencing (RNA-seq) was used to identify any replicating pathogens in the samples.

RESULTS: Samples from 35 patients were analyzed. A pathogen was identified in 80\% of the patients. 72\% (95\% confidence interval: 54\% to 85\%) were infected with either HAdV-D or HAdV-B. RNA viruses detected were rhinoviruses and human coronavirus 229E. Bacteria etiologies included , , and One patient had co-infection of rhinovirus A and HAdV-B. , a fungus, was identified in one patient. Corneal sub-epithelial infiltrates, pseudomembranes, or pre-auricular lymphadenopathy were not reported in any patient.

CONCLUSIONS: Human adenoviruses are the common circulating pathogens associated with infectious conjunctivitis in Vietnam. HAdV species, however, appear to vary between geographic locations within Vietnam. Other under-recognized pathogens identified in this study, such as RNA viruses, suggest broader pathogen surveillance may be beneficial.

}, issn = {2833-6992}, doi = {10.1097/coa.0000000000000025}, author = {Tran, Huy and Hoang, Linh and Tran, Yen and Hạ, Thảo and Ruder, Kevin and Zhong, Lina and Chen, Cindi and Yu, Danny and Liu, YuHeng and Abraham, Thomas and Hinterwirth, Armin and Deiner, Michael and Porco, Travis and Lietman, Thomas M and Seitzman, Gerami D and Doan, Thuy} } @article {1356, title = {Pathogen Surveillance for Acute Infectious Conjunctivitis.}, journal = {JAMA Ophthalmol}, year = {2023}, month = {2023 Nov 02}, abstract = {

IMPORTANCE: Acute infectious conjunctivitis is a common ocular condition with major public health consequences.

OBJECTIVE: To assess regional variations and microbial etiologies of acute infectious conjunctivitis to guide treatment.

DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, patients with presumed acute infectious conjunctivitis were enrolled in the study at 5 sites (Honolulu, Hawaii; Los Angeles, San Francisco, and San Diego, California; and Petah-Tikva, Israel) from March 2021 to March 2023. Patients with allergic or toxic conjunctivitis were excluded.

MAIN OUTCOMES AND MEASURES: Pathogens were identified by unbiased RNA deep sequencing.

RESULTS: In all, 52 patients (mean [range] age, 48 [7-80] years; 31 females [60\%]) were enrolled at 5 sites (6 patients from Honolulu, 9 from San Diego, 11 from Los Angeles, 13 from San Francisco, and 13 from Petah-Tikva). RNA deep sequencing detected human adenovirus species D in one-quarter of patients (13 of 52). A wide range of pathogens, including human coronavirus 229E, SARS-CoV-2, and herpes simplex virus type 1, was also identified, as well as several bacteria and fungi. Moreover, 62\% (32 of 52) of patients presented with purulent discharge, while only 8\% (4 of 52) of patients had confirmed bacterial pathogens.

CONCLUSION AND RELEVANCE: In this cross-sectional study, pathogens associated with acute infectious conjunctivitis varied between all 5 sites in the US and Israel. Purulent discharge was a common presenting sign in this study, with a low specificity for bacteria-associated conjunctivitis, suggesting that further diagnostic workup may be necessary to inform antibiotic stewardship. Additional research on cost-effectiveness of using RNA deep sequencing is needed to ascertain whether it is better to monitor patients clinically until resolution of disease.

}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2023.4785}, author = {Tsui, Edmund and Sella, Ruti and Tham, Vivien and Kong, Alan W and McClean, Esmeralda and Goren, Lee and Bahar, Irit and Cherian, Nina and Ramirez, Joana and Hughes, Reginald E and Privratsky, Joseph K and Onclinx, Tania and Feit-Leichman, Rachel and Cheng, Angel and Molina, Iliana and Kim, Phillip and Yu, Carol and Ruder, Kevin and Tan, Alexander and Chen, Cindi and Liu, YuHeng and Abraham, Thomas and Hinterwirth, Armin and Zhong, Lina and Porco, Travis C and Lietman, Thomas M and Seitzman, Gerami D and Doan, Thuy} } @article {1171, title = {Reduced Dose Methotrexate and Mycophenolate Mofetil in Noninfectious Uveitis: A Sub-Analysis from the First-Line Antimetabolites as Steroid Sparing Therapy (FAST) Trial.}, journal = {Ocul Immunol Inflamm}, year = {2023}, month = {2023 Jan 26}, pages = {1-6}, abstract = {

PURPOSE: Some patients taking methotrexate (MTX) or mycophenolate mofetil (MMF) experience intolerable side effects at full doses. We evaluated whether dose reduction affected treatment outcomes in uveitis patients.

METHODS: Subanalysis of the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial. Patients were randomized to receive MTX (25 mg weekly) or MMF (3\ g daily). A pre-specified dose reduction protocol could be employed for intolerable side effects. Primary analysis was performed at 6\ months.

RESULTS: 43/194 patients (22\%) required dose reduction. 88/151 patients (58\%) on maximum doses and 32/43 patients (74\%) on reduced doses were deemed treatment successes at 6 months. The odds ratio point estimate (1.60, 95\% CI 0.72-3.74) favored dose-reduction but this was not significant. Following reduction, adverse events improved at the subsequent study visit (79 events reduced to 63 events).

CONCLUSION: Dose reduction of antimetabolites was not associated with worse outcomes in this subanalysis of a uveitis trial.

}, issn = {1744-5078}, doi = {10.1080/09273948.2023.2165949}, author = {Sura, Amol A and Sun, Yuwei and Reddy, Amit K and Rathinam, S R and Gonzales, John A and Thundikandy, Radhika and Vedhanayaki, Rajesh and Kanakath, Anuradha and Murugan, Bala and Doan, Thuy A and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Acharya, Nisha R} } @article {1231, title = {Risk of failing both methotrexate and mycophenolate mofetil from the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial.}, journal = {J Ophthalmic Inflamm Infect}, volume = {13}, year = {2023}, month = {2023 Jun 09}, pages = {29}, abstract = {

BACKGROUND: The antimetabolites methotrexate (MTX) and mycophenolate mofetil (MMF) are commonly used as initial corticosteroid-sparing treatment for uveitis. There is little data examining risk factors for failing both MTX and MMF. The objective of this study is to determine risk factors for failing both MTX and MMF in patients with non-infectious uveitis.

MAIN BODY: This is a sub-analysis of the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial, which was an international, multicenter, block-randomized, observer-masked, comparative effectiveness trial comparing MTX and MMF as initial treatments for non-infectious uveitis. This study was undertaken at multiple referral centers in India, the United States, Australia, Saudi Arabia and Mexico between 2013 and 2017. A total of 137 patients who completed all 12 months of follow-up from the FAST trial, were included in this study. The primary outcome was failing both antimetabolites over the 12 months of the trial. Potential predictors included: age, sex, bilateral involvement, anatomic location of the uveitis, presence of cystoid macular edema (CME) and retinal vasculitis at baseline visit, uveitis duration, and country/study sites as risk factors for failing both MTX and MMF. The presence of retinal vasculitis posterior to the equator on fluorescein angiogram was associated with failing both MTX and MMF.

CONCLUSION: Retinal vasculitis may be a risk factor for failing multiple antimetabolites. Clinicians could consider more quickly advancing these patients to other medication classes, such as biologics.

}, issn = {1869-5760}, doi = {10.1186/s12348-023-00350-5}, author = {Reddy, Amit K and Miller, D Claire and Sura, Amol A and Rathinam, S R and Gonzales, John A and Thundikandy, Radhika and Kanakath, Anuradha and Murugan, Bala and Vedhanayaki, Rajesh and Lim, Lyndell L and Suhler, Eric B and Doan, Thuy and Al-Dhibi, Hassan A and Goldstein, Debra A and Arellanes-Garcia, Lourdes and Acharya, Nisha R} } @article {1291, title = {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.}, journal = {Am J Trop Med Hyg}, year = {2023}, month = {2023 Oct 02}, 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.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.23-0431}, author = {Hazel, Ashley and Arzika, Ahmed M and Abdou, Amza and Lebas, Elodie and Porco, Travis C and Maliki, Ramatou and Doan, Thuy and Lietman, Thomas M and Keenan, Jeremy D and Blumberg, Seth} } @article {1276, title = {Transmission of yellow fever vaccine virus through blood transfusion and organ transplantation in the USA in 2021: report of an investigation}, journal = {The Lancet Microbe}, year = {2023}, month = {08/2023}, abstract = {

In 2021, four patients who had received solid organ transplants in the USA developed encephalitis beginning 2{\textendash}6 weeks after transplantation from a common organ donor. We describe an investigation into the cause of encephalitis in these patients. Methods From Nov 7, 2021, to Feb 24, 2022, we conducted a public health investigation involving 15 agencies and medical centres in the USA. We tested various specimens (blood, cerebrospinal fluid, intraocular fluid, serum, and tissues) from the organ donor and recipients by serology, RT-PCR, immunohistochemistry, metagenomic next-generation sequencing, and host gene expression, and conducted a traceback of blood transfusions received by the organ donor. Findings We identified one read from yellow fever virus in cerebrospinal fluid from the recipient of a kidney using metagenomic next-generation sequencing. Recent infection with yellow fever virus was confirmed in all four organ recipients by identification of yellow fever virus RNA consistent with the 17D vaccine strain in brain tissue from one recipient and seroconversion after transplantation in three recipients. Two patients recovered and two patients had no neurological recovery and died. 3 days before organ procurement, the organ donor received a blood transfusion from a donor who had received a yellow fever vaccine 6 days before blood donation. Interpretation This investigation substantiates the use of metagenomic next-generation sequencing for the broad-based detection of rare or unexpected pathogens. Health-care workers providing vaccinations should inform patients of the need to defer blood donation for at least 2 weeks after receiving a yellow fever vaccine. Despite mitigation strategies and safety interventions, a low risk of transfusion-transmitted infections remains.

}, issn = {2666-5247}, doi = {https://doi.org/10.1016/S2666-5247(23)00170-2}, author = {Gould, Carolyn V. and Free, Rebecca J. and Bhatnagar, Julu and Soto, Raymond A. and Royer, Tricia L. and Maley, Warren R. and Moss, Sean and Berk, Matthew A. and Craig-Shapiro, Rebecca and Kodiyanplakkal, Rosy Priya L. and Westblade, Lars F. and Muthukumar, Thangamani and Puius, Yoram A. and Raina, Amresh and Hadi, Azam and Gyure, Kymberly A. and Trief, Danielle and Pereira, Marcus and Kuehnert, Matthew J. and Ballen, Vennus and Kessler, Debra A. and Dailey, Kimberly and Omura, Charles and Doan, Thuy and Miller, Steve and Wilson, Michael R. and Lehman, Jennifer A. and Ritter, Jana M. and Lee, Elizabeth and Silva-Flannery, Luciana and Reagan-Steiner, Sarah and Velez, Jason O. and Laven, Janeen J. and Fitzpatrick, Kelly A. and Panella, Amanda and Davis, Emily H. and Hughes, Holly R. and Brault, Aaron C. and St George, Kirsten and Dean, Amy B. and Ackelsberg, Joel and Basavaraju, Sridhar V. and Chiu, Charles Y. and Staples, J. Erin and Ajaimy, Maria and Al Azzi, Yorg and Annambhotla, Pallavi and Backenson, Bryon and Belden, Katherine and Colovai, Adriana and Coppock, Dagan and Du, Lydia and Estetter, Lindsey and Le, Marie and Martines, Roosecelis B. and Pettengill, Matthew and Szymczak, Wendy and Vareechon, Chairut} } @article {1166, title = {Viruses Associated with Acute Conjunctivitis in Vanuatu.}, journal = {Am J Trop Med Hyg}, year = {2023}, month = {2023 Jan 16}, abstract = {

The first manifestation of a viral infection may be conjunctivitis. There are limited data on the etiology of viral conjunctivitis in Vanuatu, a country in the South Pacific Ocean. Patients presenting to one of two Vanuatu health centers with presumed infectious conjunctivitis were eligible if symptom onset was within 14 days of screening. Conjunctival and anterior nasal swabs were obtained and subjected to unbiased RNA deep sequencing (RNA-seq) to identify DNA and RNA viruses. For samples collected from May to November 2021, RNA-seq identified a viral etiology in 12/48 patients. Human adenovirus species were the most common viruses (58\%) detected, followed by human herpes viruses (cytomegalovirus, varicella zoster virus, and human herpes 7 virus). Rhinovirus C, Epstein-Barr virus, and bocavirus were also detected. In summary, the etiology for viral conjunctivitis in Vanuatu appears broad. Unbiased testing may be useful for disease surveillance.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.22-0600}, author = {Johnson, Kasso and Taleo, Fasihah and Willie, Kalbule and Amel, Edwin and Nanu, Madopule and Alguet, Marie and Wass, Jose and Rymill, Prudence and Solomon, Anthony and Ruder, Kevin and Chen, Cindi and Zhong, Lina and Hinterwirth, Armin and Liu, David and Abraham, Thomas and Seitzman, Gerami and Lietman, Thomas and Doan, Thuy} } @article {1281, title = {Wastewater-Based Surveillance of Antimicrobial Resistance in Niger: An Exploratory Study.}, journal = {Am J Trop Med Hyg}, year = {2023}, month = {2023 Aug 28}, 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.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.23-0204}, author = {Ousmane, Sani and Kollo, Issifi A and Jambou, Ronan and Boubacar, Rakia and Arzika, Ahmed M and Maliki, Ramatou and Amza, Abdou and Liu, Zijun and Lebas, Elodie and Colby, Emily and Zhong, Lina and Chen, Cindi and Hinterwirth, Armin and Doan, Thuy and Lietman, Thomas M and O{\textquoteright}Brien, Kieran S} } @article {1021, title = {Bilateral anterior and intermediate uveitis in SARS-CoV-2 associated multisystem inflammatory syndrome in a pediatric patient.}, journal = {Pediatr Rheumatol Online J}, volume = {20}, year = {2022}, month = {2022 Jul 30}, pages = {59}, abstract = {

PURPOSE: To report a case of bilateral anterior intermediate uveitis after recovery from SARS-CoV-2 associated multisystem inflammatory syndrome in children (MIS-C).

CASE REPORT: A 9-year-old male presented with bilateral anterior intermediate uveitis with fluorescein angiography (FA) leakage of the disc and peripheral vasculature 1 month after recovery from MIS-C. He was treated with difluprednate 0.05\% in both eyes with resolution of FA leakage, but our patient has required an extended treatment of topical therapy and the need long term immunosuppression.

CONCLUSIONS: This is a case of uveitis presenting after recent MIS-C related to SARS-CoV-2. Ongoing follow up and monitoring is required, and it is important for the ophthalmologist and rheumatologist to be aware of this rare complication during the current COVID-19 pandemic.

}, issn = {1546-0096}, doi = {10.1186/s12969-022-00712-8}, author = {Shantha, Jessica and Reddy, Amit K and Sura, Amol and Tsang, Adrian and Moussa, Kareem and Acharya, Nisha and Gonzales, John and Doan, Thuy} } @article {936, title = {Biomarkers for primary open-angle glaucoma progression.}, journal = {Exp Eye Res}, year = {2022}, month = {2022 Mar 09}, pages = {109025}, abstract = {

Glaucoma is a heterogeneous group of progressive optic neurodegenerative. Although most patients with primary open angle glaucoma (POAG) are stable for many years, certain subgroups of POAG patients could progress over time even with treatment. This study is to identify aqueous humor (AH) biomarkers that may be associated with disease progression in POAG patients. Gene differential expression study of prospectively collected AH from patients with stable or progressive POAG. Metagenomic deep sequencing (MDS) was performed on the aqueous fluid of 20 patients with stable POAG and 20 patients with progressive POAG. Differential gene expression analysis was performed to identify host transcriptome signatures. A total of 21 transcripts were differentially expressed between groups. Differential transcripts identified by MDS. Twenty transcripts were up-regulated and 1 transcript was down-regulated in progressive POAG patients compared to stable patients. Of those, 11 transcripts were eye-related, and 5 transcripts were related to glaucomatous phenotypes (Fibronectin type III domain containing 3B (FNDC3B), Clusterin (CLU), Proprotein convertase subtilisin/kexin type 6 (PCSK6), Cadherin EGF LAG seven-pass G-type receptor 1 (Celsr1), and Rho guanine nucleotide exchange factor 4 (ARHGEF4)). Biomarkers associated with POAG progression can be identified from aqueous fluid. Identification of the biomarkers may improve glaucoma surveillance for progressive POAG.

}, issn = {1096-0007}, doi = {10.1016/j.exer.2022.109025}, author = {Zhao, Mengya and Ma, Ping and Xie, Qinghong and Bui, Anh and Yonamine, Sean and Hinterwirth, Armin and Zhong, Lina and Chen, Cindi and Doan, Thuy and Han, Ying} } @article {1176, title = {Case-Control Study Examining the Composition of the Gut Microbiome in Individuals With and Without Immune-Mediated Dry Eye.}, journal = {Cornea}, year = {2022}, month = {2022 Dec 13}, abstract = {

PURPOSE: Gut microbiome alterations have been associated with various autoimmune diseases. There are limited data, however, on relationships between gut dysbiosis and immune-related dry eye (DE). Our aim was to compare the gut microbiome composition of individuals with early and late markers of Sj{\"o}gren syndrome (SS) with controls without DE.

METHODS: We compared 20 individuals with positive early markers [antisalivary protein 1 (SP1), antiparotid secretory protein (PSP), anticarbonic anhydrase 6 (CA6) IgG, IgA, and IgM, n = 19)], or late markers (anti-Ro/SS-A and anti-La/SS-B, n = 1) of SS with no comorbid autoimmune diagnoses and 20 age-matched and sex-matched controls. Collected stool samples underwent deep RNA sequencing. The main outcomes measured included gut microbiome composition and diversity.

RESULTS: A total of 20 cases [Dry Eye Questionnaire-5 15.2 {\textpm} 3.4, Ocular Surface Disease Index 55.1 {\textpm} 22.8, and Schirmer 7.1 {\textpm} 5.2 mm] were compared with 20 controls (Dry Eye Questionnaire-5 4.8 {\textpm} 3.8, Ocular Surface Disease Index 14.2 {\textpm} 12.3, and Schirmer 20.4 {\textpm} 9.2 mm). No differences were observed in α-diversity (P = 0.97) or overall community structure (P = 0.62). Between groups, 32 species were differentially abundant (P \< 0.01). Among cases, 27 were relatively more abundant, including 10 Lactobacillus and 4 Bifidobacterium species. A relative depletion of 5 species was found in cases compared with controls, notably Fusobacterium varium and Prevotella stercorea.

CONCLUSIONS: Differences in gut microbiome composition were found in individuals with mostly early markers of SS compared with controls. However, their clinical significance to DE manifestations remains unclear. Further studies are needed to elucidate the role of gut dysbiosis on immune dysregulation and disease activity in the various forms of immune-mediated DE.

}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000003195}, author = {Goodman, Courtney F and Doan, Thuy and Mehra, Divy and Betz, Jason and Locatelli, Elyana and Mangwani-Mordani, Simran and Kalahasty, Karthik and Hernandez, Mireya and Hwang, Jodi and Galor, Anat} } @article {941, title = {Concordance of ompA types in children re-infected with ocular Chlamydia trachomatis following mass azithromycin treatment for trachoma.}, journal = {PLoS Negl Trop Dis}, volume = {16}, year = {2022}, month = {2022 Mar}, pages = {e0010237}, abstract = {

BACKGROUND: The chlamydial major outer membrane protein, encoded by the ompA gene, is a primary target for chlamydial vaccine research. However, human studies of ompA-specific immunity are limited, and prior studies have been limited in differentiating re-infection from persistent infection. The purpose of this study was to assess whether children living in trachoma-endemic communities with re-infections of ocular chlamydia were more likely to be infected with a different or similar genovar.

METHODOLOGY AND FINDINGS: The study included 21 communities from a trachoma-hyperendemic area of Ethiopia that had been treated with a mass azithromycin distribution for trachoma. Conjunctival swabbing was offered to all children younger than 5 years of age at baseline (i.e., pre-treatment), and then at follow-up visits 2 and 6 months later. Swabs were subjected to polymerase chain reaction (PCR) to detect C. trachomatis. A random sample of 359 PCR-positive swabs, stratified by study visit and study community, was chosen for ompA sequencing. In addition, ompA sequencing was performed on all swabs of 24 children who experienced chlamydial re-infection (i.e., positive chlamydial test before treatment, negative test 2 months following mass distribution of azithromycin, and again a positive test 6 months post-treatment). ompA sequencing was successful for 351 of 359 swabs of the random sample and 44 of 48 swabs of the re-infection sample. In the random sample, ompA types clustered within households more than would be expected by chance. Among the 21 re-infected children with complete ompA data, 14 had the same ompA type before and after treatment.

CONCLUSION: The high frequency of ompA concordance suggests incomplete genovar-specific protective immunity and the need for multiple antigens as vaccine targets.

}, issn = {1935-2735}, doi = {10.1371/journal.pntd.0010237}, author = {Mosenia, Arman and Chin, Stephanie A and Alemayehu, Wondu and Melese, Muluken and Lakew, Takele and Zhou, Zhaoxia and Doan, Thuy and Cevallos, Vicky and Lietman, Thomas M and Keenan, Jeremy D} } @article {891, title = {Deep sequencing analysis of acute conjunctivitis in Burkina Faso, Africa.}, journal = {Int Health}, year = {2022}, month = {2022 Jan 24}, abstract = {

BACKGROUND: Seasonal and epidemic conjunctivitis (pink eye) infections are highly contagious and impose a significant economic burden worldwide. Long-term visual impairment can occur.

METHODS: This study used metagenomic deep sequencing to evaluate pathogens causing acute infectious conjunctivitis in Burkina Faso.

RESULTS: We found that pathogens causing conjunctivitis in Burkina Faso are diverse, with human adenoviruses responsible for a small fraction of the samples tested.

CONCLUSIONS: These results are unexpected and suggest the importance of regional surveillance.

}, issn = {1876-3405}, doi = {10.1093/inthealth/ihac001}, author = {Bountogo, Mamadou and Sie, Ali and Coulibaly, Boubacar and Ruder, Kevin and Chen, Cindi and Zhong, Lina and Colby, Emily and Lebas, Elodie and Deiner, Michael and Hinterwirth, Armin and Lietman, Thomas M and Seitzman, Gerami D and Doan, Thuy} } @article {1056, title = {Deep sequencing analysis of clinical samples from patients with acute infectious conjunctivitis during the COVID-19 delta surge in Madurai, India.}, journal = {J Clin Virol}, volume = {157}, year = {2022}, month = {2022 Oct 05}, pages = {105318}, abstract = {

BACKGROUND: Seasonal 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.

METHODS: This 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).

RESULTS: Samples 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.

CONCLUSIONS: During 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.

}, issn = {1873-5967}, doi = {10.1016/j.jcv.2022.105318}, author = {Lalitha, Prajna and Prajna, N Venkatesh and Gunasekaran, Rameshkumar and Teja, Gonugunta Vishnu and Sharma, Sankalp S and Hinterwirth, Armin and Ruder, Kevin and Zhong, Lina and Chen, Cindi and Deiner, Michael and Huang, ChunHong and Pinsky, Benjamin A and Lietman, Thomas M and Doan, Thuy and Seitzman, Gerami D} } @article {976, title = {Detection of Leptospirosis Genome from the Aqueous Humor of a Patient with Bilateral Uveitis.}, journal = {Ocul Immunol Inflamm}, year = {2022}, month = {2022 Apr 29}, pages = {1-3}, abstract = {

BACKGROUND: Leptospira species are difficult to culture. Thus, when there is suspicion for an infectious etiology to uveitis, bacterial cultures may fail to identify Leptospira. We describe a case of leptospirosis-associated uveitis that evaded culture and molecular assays. DNA sequencing of the aqueous fluid showed the presence of Leptospira spp.

METHODS: Retrospective case review of clinical and laboratory features of a patient with ocular leptospirosis is presented.

RESULTS: DNA sequencing identified the genome of Leptospirosis spp. in the aqueous humor.

CONCLUSION: Metagenomic sequencing, by virtue of its unbiased nature, can be a helpful adjunctive test when a strong clinical suspicion for intraocular infection persists despite negative routine culture and molecular assays.

}, issn = {1744-5078}, doi = {10.1080/09273948.2022.2067779}, author = {Gonzales, John A and Sundararajan, Miel and Qian, Ying and Hwang, Thomas and Doan, Thuy} } @article {931, title = {Effect of biannual azithromycin distribution on antibody responses to malaria, bacterial, and protozoan pathogens in Niger.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 02 21}, pages = {976}, abstract = {

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5\% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1-59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29\% (hazard ratio = 0.71, 95\% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger.

}, issn = {2041-1723}, doi = {10.1038/s41467-022-28565-5}, author = {Arzika, Ahmed M and Maliki, Ramatou and Goodhew, E Brook and Rogier, Eric and Priest, Jeffrey W and Lebas, Elodie and O{\textquoteright}Brien, Kieran S and Le, Victoria and Oldenburg, Catherine E and Doan, Thuy and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M and Martin, Diana L and Arnold, Benjamin F} } @article {1036, title = {Effect of Single-dose Azithromycin on Pneumococcal Carriage and Resistance: A Randomized Controlled Trial.}, journal = {Pediatr Infect Dis J}, volume = {41}, year = {2022}, month = {2022 Sep 01}, pages = {728-730}, abstract = {

We evaluated antibiotic resistance selection in Streptococcus pneumoniae isolates from children participating in an individually randomized trial of single-dose azithromycin versus placebo. After 14 days, the prevalence of resistance to erythromycin, oxacillin, and clindamycin was elevated in the azithromycin versus placebo group. There was no difference at 6 months.

}, issn = {1532-0987}, doi = {10.1097/INF.0000000000003585}, author = {Coulibaly, Boubacar and Kiemde, Dramane and Zonou, Guillaume and Sie, Ali and Dah, Clarisse and Bountogo, Mamadou and Brogdon, Jessica and Hu, Huiyu and Lebas, Elodie and Porco, Travis C and Doan, Thuy and Lietman, Thomas M and Oldenburg, Catherine E} } @article {1156, title = {Gut Microbiome among Children with Uncomplicated Severe Acute Malnutrition in a Randomized Controlled Trial of Azithromycin versus Amoxicillin.}, journal = {Am J Trop Med Hyg}, year = {2022}, month = {2022 Dec 12}, abstract = {

Antibiotics are routinely used as part of the management of severe acute malnutrition and are known to reduce gut microbial diversity in non-malnourished children. We evaluated gut microbiomes in children participating in a randomized controlled trial (RCT) of azithromycin versus amoxicillin for severe acute malnutrition. Three hundred one children aged 6 to 59 months with uncomplicated severe acute malnutrition (mid-upper arm circumference \< 11.5 cm and/or weight-for-height Z-score \< -3 without clinical complications) were enrolled in a 1:1 RCT of single-dose azithromycin versus a 7-day course of amoxicillin (standard of care). Of these, 109 children were randomly selected for microbiome evaluation at baseline and 8 weeks. Rectal swabs were processed with metagenomic DNA sequencing. We compared alpha diversity (inverse Simpson{\textquoteright}s index) at 8 weeks and evaluated relative abundance of microbial taxa using DESeq2. Of 109 children enrolled in the microbiome study, 95 were followed at 8 weeks. We found no evidence of a difference in alpha diversity between the azithromycin and amoxicillin groups at 8 weeks controlling for baseline diversity (mean difference -0.6, 95\% CI -1.8 to 0.6, P = 0.30). Gut microbiomes did not diversify during the study. Differentially abundant genera at the P \< 0.01 level included Salmonella spp. and Shigella spp., both of which were overabundant in the azithromycin compared with amoxicillin groups. We found no evidence to support an overall difference in gut microbiome diversity between azithromycin and amoxicillin among children with uncomplicated severe acute malnutrition, but potentially pathogenic bacteria that can cause invasive diarrhea were more common in the azithromycin group. Trial Registration: ClinicalTrials.gov NCT03568643.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.22-0381}, author = {Oldenburg, Catherine E and Hinterwirth, Armin and Dah, Clarisse and Millogo, Ourohir{\'e} and Coulibaly, Boubacar and Ou{\'e}draogo, Moussa and Sie, Ali and Chen, Cindi and Zhong, Lina and Ruder, Kevin and Lebas, Elodie and Nyatigo, Fanice and Arnold, Benjamin F and O{\textquoteright}Brien, Kieran S and Doan, Thuy} } @article {1031, title = {Gut Resistome after Antibiotics among Children with Uncomplicated Severe Acute Malnutrition: A Randomized Controlled Trial.}, journal = {Am J Trop Med Hyg}, volume = {107}, year = {2022}, month = {2022 Jul 13}, pages = {59-64}, abstract = {

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

}, keywords = {Amoxicillin, Anti-Bacterial Agents, Azithromycin, Child, Drug Resistance, Bacterial, Humans, Macrolides, Severe Acute Malnutrition}, issn = {1476-1645}, doi = {10.4269/ajtmh.22-0007}, author = {Oldenburg, Catherine E and Hinterwirth, Armin and Ourohir{\'e}, Millogo and Dah, Clarisse and Ou{\'e}draogo, Moussa and Sie, Ali and Boudo, Valentin and Chen, Cindi and Ruder, Kevin and Zhong, Lina and Lebas, Elodie and Nyatigo, Fanice and Arnold, Benjamin F and O{\textquoteright}Brien, Kieran S and Doan, Thuy} } @article {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 {966, title = {Interepidemic Respiratory Syncytial Virus during the COVID-19 Pandemic.}, journal = {Microbiol Spectr}, year = {2022}, month = {2022 Apr 25}, pages = {e0094722}, issn = {2165-0497}, doi = {10.1128/spectrum.00947-22}, author = {Huang, ChunHong and Sahoo, Malaya K and Verghese, Michelle and Sibai, Mamdouh and Solis, Daniel and Mfuh, Kenji O and Kurzer, Jason and Hogan, Catherine A and Doan, Thuy A and Pinsky, Benjamin A} } @article {961, title = {Intraocular Inflammation Associated with IRAK4 Deficiency.}, journal = {Ocul Immunol Inflamm}, year = {2022}, month = {2022 Apr 20}, pages = {1-3}, issn = {1744-5078}, doi = {10.1080/09273948.2022.2059523}, author = {Gonzales, John A and Nortey, Jeremy and Reddy, Amit and Doan, Thuy and Acharya, Nisha R} } @article {1006, title = {Neonatal azithromycin administration for prevention of infant mortality.}, journal = {NEJM Evid}, volume = {1}, year = {2022}, month = {2022 Apr}, pages = {EVIDoa2100054}, abstract = {

Background: Biannual mass azithromycin administration reduces all-cause childhood mortality in some sub-Saharan African settings, with the largest effects in children aged 1-5 months. Azithromycin has not been distributed to children \<1 month due to risk of infantile hypertrophic pyloric stenosis (IHPS).

Methods: This 1:1 placebo-controlled trial, randomized neonates aged 8-27 days to a single oral dose of azithromycin (20 mg/kg) or equivalent volume of placebo in 5 regions of Burkina Faso during 2019 and 2020. The primary outcome was all-cause mortality at 6 months of age. Infants were evaluated at 21 days after treatment and at 3 and 6 months of age for vital status; family and provider surveillance for IHPS continued throughout.

Results: Of 21,832 enrolled neonates, 10,898 were allocated to azithromycin and 10,934 to placebo. At 6 months of age, 92 infants had died, 42 (0.44\%) in the azithromycin group and 50 (0.52\%) in the placebo group (hazard ratio 0.85, 95\% confidence interval 0.56 to 1.28, =0.46). A single IHPS case was detected, which was in the azithromycin arm. Serious adverse events, including death and hospitalization within 28 days of treatment, occurred in 0.27\% of infants in the azithromycin group and 0.14\% in the placebo group, for an absolute risk difference 0.14 percentage points, 95\% confidence interval 0.01 to 0.26.

Conclusions: Overall mortality was lower than anticipated when the trial was designed, thus limiting its power. The available data do not support the routine use of azithromycin for prevention of mortality in neonates in sub-Saharan African settings similar to the one in which this trial was conducted.

Trial registration: ClinicalTrials.gov NCT03682653.

}, issn = {2766-5526}, doi = {10.1056/EVIDoa2100054}, author = {Oldenburg, Catherine E and Sie, Ali and Bountogo, Mamadou and Zakane, Alphonse and Compaor{\'e}, Guillaume and Ouedraogo, Thierry and Koueta, Fla and Lebas, Elodie and Brogdon, Jessica and Nyatigo, Fanice and Doan, Thuy and Porco, Travis C and Arnold, Benjamin F and Lietman, Thomas M} } @article {971, title = {Occult cause of uveitis-glaucoma-hyphema syndrome diagnosed during treatment with endocyclophotocoagulation (ECP).}, journal = {Am J Ophthalmol Case Rep}, volume = {26}, year = {2022}, month = {2022 Jun}, pages = {101537}, abstract = {

Purpose: To describe uveitis-glaucoma-hyphema (UGH) syndrome secondary to a posterior chamber intraocular lens (PCIOL) within the capsular bag in which pathogenic changes to the ciliary body were observed and treated with endocyclophotocoagulation (ECP).

Observations: An 85-year-old woman who had cataract surgery in her right eye four years ago presented with recurrent, unilateral, open-angle, hypertensive uveitis in her right eye. Her presentations were characterized by decreased vision, elevated intraocular pressure, corneal edema, a mixed anterior chamber reaction, and pigmented anterior vitreous cells. She had a frank vitreous hemorrhage during two episodes. Ultrasound biomicroscopy revealed a dense Soemmerring ring in her right eye without evidence of PCIOL-iris or PCIOL-ciliary body chafe. Subsequent ECP revealed whitened and atrophic ciliary processes adjacent to a tilted haptic within the capsular bag, consistent with chronic PCIOL-ciliary body chafe. ECP was applied to the affected ciliary processes, which successfully eliminated recurrences.

Conclusions and importance: UGH can rarely occur due to an PCIOL within the capsular bag. In cases where ultrasound biomicroscopy (UBM) does not show abnormalities and clinical suspicion remains high, ECP can be a useful adjunct to observe and treat abnormalities of the ciliary body.

}, issn = {2451-9936}, doi = {10.1016/j.ajoc.2022.101537}, author = {Sura, Amol A and Reddy, Amit K and Babic, Kelly and Saifee, Murtaza and Acharya, Nisha R and Gonzales, John A and Han, Ying and Doan, Thuy A} } @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 {921, title = {Outcomes of uveitic macular edema in the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial.}, journal = {Ophthalmology}, year = {2022}, month = {2022 Feb 07}, abstract = {

PURPOSE: To evaluate the outcomes of uveitic macular edema at 6 months and 12 months in patients treated with methotrexate or mycophenolate mofetil.

DESIGN: Subanalysis of a block-randomized, observer-masked, multi-center clinical trial.

SUBJECTS/PARTICIPANTS: Patients were enrolled into the First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial between August 2013 and August 2017.

METHODS/INTERVENTION/TESTING: Patients were randomized to oral methotrexate 25mg weekly or mycophenolate mofetil 1.5g twice daily for 12 months, along with a corticosteroid taper. In addition to standardized clinical examination, all patients underwent spectral domain optical coherence tomography imaging at each visit. At the 6-month primary endpoint, patients who achieved treatment success continued the same treatment for a subsequent 6 months and treatment failures switched to the other treatment group.

MAIN OUTCOME MEASURES: Pre-specified primary outcome at 6 months and 12 months outcomes of central subfield thickness and visual acuity.

RESULTS: Of 216 patients in the FAST Trial, 42 eyes of 30 patients in the methotrexate group and 55 eyes of 41 patients in the mycophenolate group had uveitic macular edema. Baseline median central subfield thickness was 359μm and 342μm in the methotrexate and mycophenolate groups, respectively. At 12 months, for those who stayed on the same treatment, macular thickness decreased from baseline by 23 μm (IQR, -39.0 to 13) and 18 μm (IQR, -68.5 to 9), in the methotrexate and mycophenolate groups, respectively, (P=0.76). In patients who switched treatment at 6 months, macular thickness decreased from baseline by 12.5 μm (IQR, -29.8 to -2.3) and 92 μm (IQR, -240 to -18) in the methotrexate and mycophenolate groups, respectively, (P=0.23). At 12 months, 7/19 (37\%) eyes on methotrexate had resolution of macular edema compared to 15/25 (60\%) eyes on mycophenolate (P=0.10). For those that switched treatments, 8/17 (47\%) eyes on methotrexate and 6/11 (55\%) eyes on mycophenolate had improvement of macular edema, (P=0.92) CONCLUSIONS: Treatment with methotrexate or mycophenolate mofetil for uveitic macular edema results in similar improvements in macular thickness at 6 and 12 months. At 12 months, approximately half of eyes in each antimetabolite group still had persistent macular edema.

}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2022.02.002}, author = {Tsui, Edmund and Rathinam, Sivakumar R and Gonzales, John A and Thundikandy, Radhika and Kanakath, Anuradha and Balamurugan, S and Vedhanayaki, R and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Doan, Thuy and Keenan, Jeremy and Ebert, Caleb D and Kim, Eric and Madow, Brian and Porco, Travis C and Acharya, Nisha R} } @article {1046, title = {Outpatient human coronavirus associated conjunctivitis in India.}, journal = {J Clin Virol}, volume = {157}, year = {2022}, month = {2022 Sep 27}, pages = {105300}, abstract = {

BACKGROUND: Viral conjunctivitis (pink eye) can be highly contagious and is of public health importance. There remains significant debate whether SARS-CoV-2 can present as a primary conjunctivitis. The aim of this study was to identify pathogens associated with outpatient infectious conjunctivitis during the COVID-19 Delta surge.

METHODS: This prospective study was conducted in the spring and summer months of 2021. 106 patients with acute conjunctivitis who presented to the Aravind Eye Center in Madurai, India were included. One anterior nasal swab and one conjunctival swab of each eye were obtained for each enrolled patient. Samples were subsequently processed for unbiased metagenomic RNA deep sequencing (RNA-seq). Outcomes included clinical findings and codetection of other pathogens with SARS-CoV-2 in patients with conjunctivitis.

RESULTS: Among the 13 patients identified with human coronavirus RNA fragments in their swabs, 6 patients had SARS-CoV-2 infection, 5 patients had coinfections of SARS-CoV-2 and human adenovirus (HAdV), 1 patient had a coinfection with human coronavirus OC43 and HAdV, and 1 patient had a coinfection of Vittaforma corneae and SARS-CoV-2. 30\% had bilateral disease and symptoms on presentation. Petechial hemorrhage was noted in 33\% of patients with SARS-CoV-2 infection. No patients with SARS-CoV-2 or SARS-CoV-2 and HAdV infections had subepithelial infiltrates on presentation. All patients denied systemic symptoms.

CONCLUSIONS: Among the patients presented with conjunctivitis associated with human coronavirus infection, over 50\% of the patients had co-infections with other circulating pathogens, suggesting the public-health importance of broad pathogen testing and surveillance in the outpatient conjunctivitis population.

}, issn = {1873-5967}, doi = {10.1016/j.jcv.2022.105300}, author = {Prajna, N Venkatesh and Lalitha, Prajna and Teja, Gonugunta Vishnu and Gunasekaran, Rameshkumar and Sharma, Sankalp S and Hinterwirth, Armin and Ruder, Kevin and Zhong, Lina and Chen, Cindi and Deiner, Michael and Huang, ChunHong and Pinsky, Benjamin A and Lietman, Thomas M and Seitzman, Gerami D and Doan, Thuy} } @article {1041, title = {Role of Ophthalmology in Emerging Infectious Diseases.}, journal = {JAMA Ophthalmol}, year = {2022}, month = {2022 Sep 07}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2022.4017}, author = {Rose-Nussbaumer, Jennifer and Doan, Thuy} } @article {896, title = {Time to Uveitis Control with Methotrexate and Mycophenolate Mofetil.}, journal = {Ophthalmology}, year = {2022}, month = {2022 Jan 24}, abstract = {

This subanalysis from the First-line Antimetabolites as Steroid-sparing Treatment Trial found no significant difference in the time to achieve a corticosteroid-sparing dosage of prednisone for patients with noninfectious uveitis treated with methotrexate versus mycophenolate mofetil.

}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2022.01.020}, author = {Bui, Anh D and Kong, Christina L and Kelly, Nicole K and Rathinam, S R and Gonzales, John A and Thundikandy, Radhika and Kanakath, Anuradha and Murugan, Bala and Vedhanayaki, R and Lim, Lyndell L and Suhler, Eric B and Al-Dhibi, Hassan A and Doan, Thuy and Acharya, Nisha R} } @article {946, title = {Vaccine-Associated Measles Encephalitis in Immunocompromised Child, California, USA.}, journal = {Emerg Infect Dis}, volume = {28}, year = {2022}, month = {2022 Apr}, pages = {906-908}, abstract = {

We report a fatal case of vaccine-associated measles encephalitis in an immunocompromised child in California, USA. The infection was confirmed by whole-genome RNA sequencing of measles virus from brain tissue. We observed biased matrix-gene hypermutation consistent with persistent measles virus central nervous system infection.

}, issn = {1080-6059}, doi = {10.3201/eid2804.212357}, author = {Costales, Cristina and Sahoo, Malaya K and Huang, ChunHong and Guimaraes, Carolina V and Born, Donald and Kushner, Lauren and Gans, Hayley A and Doan, Thuy A and Pinsky, Benjamin A} } @article {916, title = {Very late onset LASIK flap Acremonium fungal keratitis confirmed by metagenomic deep sequencing.}, journal = {Am J Ophthalmol Case Rep}, volume = {25}, year = {2022}, month = {2022 Mar}, pages = {101294}, abstract = {

Purpose: To describe a unique case of LASIK flap fungal keratitis confirmed by next generation sequencing.

Observations: A 56-year-old female presented with refractory keratitis involving her LASIK flap 21 years after surgery. Confocal was positive for filamentous structures. The patient underwent immediate flap amputation followed by topical antifungal treatment. Corneal culture was positive for sp. Metagenomic deep sequencing confirmed as the primary source of infection and also identified as a likely contributor of a mixed fungal infection. Sequencing also identified hay as the likely source of the infection. Treatment resulted in eradication of the infection. The patient{\textquoteright}s final best corrected visual acuity was 20/30 with rigid contact lens overrefraction.

Conclusions: Metagenomic deep sequencing is a novel diagnostic tool that is increasingly being utilized for diagnosis of refractory keratitis. This case demonstrates the diagnostic potential of deep sequencing for identifying post-LASIK keratitis and reinforces the utility of LASIK flap amputation in the setting of tectonic flap instability due to keratolysis.

Importance: This case highlights several important clinical points for treating LASIK flap keratitis and highlights the emerging role metagenomic sequencing has in the diagnosis of infectious keratitis. This is first known case using next generation sequencing to diagnose a post-LASIK infectious keratitis.

}, issn = {2451-9936}, doi = {10.1016/j.ajoc.2022.101294}, author = {Greenwald, Miles F and Redd, Travis K and Doan, Thuy and McLeod, Stephen D and Seitzman, Gerami D} } @article {861, title = {Acute Keratoconjunctivitis Resulting From Coinfection With Avian Newcastle Virus and Human Adenovirus.}, journal = {Cornea}, year = {2021}, month = {2021 Sep 04}, abstract = {

PURPOSE: The aim of this study was to report a case of human keratoconjunctivitis caused by both Newcastle disease virus (NDV) and human adenovirus.

METHODS: A 32-year-old-man presented with an acute unilateral keratoconjunctivitis that resolved with corneal scarring. On presentation, his conjunctival swab was collected for metagenomic sequencing.

RESULTS: The highest number of pathogen sequencing reads in the conjunctival sample mapped to the NDV. The second highest number of reads mapped to human adenovirus. Confirmation testing with directed reverse-transcription polymerase chain reaction also identified NDV in the specimen.

CONCLUSIONS: Newcastle conjunctivitis has not been reported for more than 40 years. Mixed infections, including zoonotic pathogens, may be more common than realized.

}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000002853}, author = {Prajna, N Venkatesh and Lalitha, Prajna and Chen, Cindi and Zhong, Lina 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 {871, title = {Changes to ophthalmic clinical care during the coronavirus disease 2019 pandemic.}, journal = {Curr Opin Ophthalmol}, year = {2021}, month = {2021 Aug 26}, abstract = {

PURPOSE OF REVIEW: Given the impact that society as a whole, and medicine specifically, has experienced as a result of the COVID-19 pandemic, an examination of clinical care changes enacted in the field of ophthalmology is of interest to the specialty.

RECENT FINDINGS: In order to adapt to the reality of the COVID-19 pandemic, measures, such as broadening telehealth capabilities, adopting universal masking, careful sanitation procedures, applying virtual teaching in academic environments, and deferring elective surgeries were put in place. These were aimed at reducing person-to-person spread of SARS-CoV-2. Though best efforts were made at triaging ophthalmic emergencies during these times, unfortunate delays in care were observed in some circumstances. Finally, a prospective study interrogating the risk of spread at slit lamp distances for short periods of time was encouraging, suggesting low risk of transmissibility, though limited by a small case-positive sample size.

SUMMARY: Significant changes have been made in the design and delivery of ophthalmic care during the COVID-19 pandemic. Some of these, such as telemedicine, may provide value in a postpandemic world.

}, issn = {1531-7021}, doi = {10.1097/ICU.0000000000000797}, author = {Sundararajan, Miel and Schallhorn, Julie M and Doan, Thuy and Seitzman, Gerami D} } @article {731, title = {Comprehensive pathogen detection for ocular infections.}, journal = {J Clin Virol}, volume = {136}, year = {2021}, month = {2021 Feb 11}, pages = {104759}, abstract = {

BACKGROUND: Molecular diagnostics such as pathogen-directed PCRs have transformed testing for ocular infections since the late 1990s. Although these assays remain important diagnostic tools for samples with low biomass, the lack of diagnostic range motivates alternative molecular approaches for ocular infections. The aim of this study was to determine the performance of a high-throughput RNA sequencing approach, RNA-seq, to detect infectious agents in ocular samples from patients with presumed ocular infections.

METHODS: We compared the performance of RNA-seq to pathogen-directed PCRs using remnant nucleic acids from 41 aqueous or vitreous samples of patients with presumed ocular infections. Pathogen-directed PCRs were performed at the CLIA-certified Stanford Clinical Virology Laboratory. RNA-seq was performed in a masked manner at the Proctor Foundation at the University of California San Francisco. Percent positive and negative agreement between the two testing approaches were calculated. Discordant results were subjected to orthogonal testing.

RESULTS: The positive percent agreement between RNA-seq and pathogen-directed PCRs was 100\% (95\% confidence interval (CI): 78.5\%-100\%). The negative percent agreement was 92.6\% (95\% CI: 76.6\%-97.9\%). RNA-seq identified pathogens not on the differential diagnosis for 9.7\% (4/41) of the samples. Two pathogens solely identified with RNA-seq were confirmed with orthogonal testing.

CONCLUSIONS: RNA-seq can accurately identify common and rare pathogens in aqueous and vitreous samples of patients with presumed ocular infections. Such an unbiased approach to testing has the potential to improve diagnostics although practical clinical utility warrants additional studies.

}, issn = {1873-5967}, doi = {10.1016/j.jcv.2021.104759}, author = {Doan, Thuy and Sahoo, Malaya K and Ruder, Kevin and Huang, ChunHong and Zhong, Lina and Chen, Cindi and Hinterwirth, Armin and Lin, Charles and Gonzales, John A and Pinsky, Benjamin A and Acharya, Nisha R} } @article {846, title = {Detection of Tropheryma whipplei Genome From the Aqueous Humor by Metagenomic Sequencing.}, journal = {Ann Intern Med}, year = {2021}, month = {06/2021}, issn = {1539-3704}, doi = {10.7326/L20-1470}, author = {Gonzales, John A and Doan, Thuy and VanZante, Annemieke and Stewart, Jay M and Sura, Amol and Reddy, Amit and Rasool, Nailyn} } @article {281, title = {Dual Molecular Diagnosis of Microsporidia (Encephalitozoon hellem) Keratoconjunctivitis in an Immunocompetent Adult.}, journal = {Cornea}, volume = {40}, year = {2021}, month = {2021 Feb 01}, pages = {242-244}, abstract = {

PURPOSE: To report a case of microsporidia (Encephalitozoon hellem) keratoconjunctivitis acquired through avian transmission in an immunocompetent adult, diagnosed by metagenomic deep sequencing (MDS), and confirmed by polymerase chain reaction.

METHODS: A case report.

RESULTS: An 18-year-old woman was referred with unilateral keratoconjunctivitis unresponsive to topical and systemic therapy after exposure to birdcage debris. Slit-lamp examination of the left eye revealed a follicular papillary reaction of the palpebral conjunctiva and multiple corneal punctate epithelial opacities that stained minimally with fluorescein. In vivo confocal microscopy revealed bright double-walled structures and smaller bright round structures in the superficial epithelial debris and epithelium. Molecular diagnosis with MDS of E. hellem was confirmed by polymerase chain reaction. Clinical resolution and normalization of in vivo confocal microscopy was observed after a 6-week course of topical azithromycin. The patient elected a 3-week course of topical voriconazole 1\% for definitive antimicrosporidial treatment, with no evidence of persistent infection 1 month later.

CONCLUSIONS: Microsporidial (E. hellem) keratoconjunctivitis can occur through avian transmission in immunocompetent hosts. Topical azithromycin may be effective against this pathogen. MDS has utility in the diagnosis of atypical keratoconjunctivitis.

}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000002466}, author = {Ma, Kevin K and Kinde, Benyam and Doan, Thuy and Jacobs, Deborah S and Ong Tone, Stephan} } @article {866, title = {Effect of a single dose of oral azithromycin on malaria parasitaemia in children: a randomized controlled trial.}, journal = {Malar J}, volume = {20}, year = {2021}, month = {2021 Aug 31}, pages = {360}, abstract = {

BACKGROUND: Azithromycin has recently been shown to reduce all-cause childhood mortality in sub-Saharan Africa. One potential mechanism of this effect is via the anti-malarial effect of azithromycin, which may help treat or prevent malaria infection. This study evaluated short- and longer-term effects of azithromycin on malaria outcomes in children.

METHODS: Children aged 8 days to 59 months were randomized in a 1:1 fashion to a single oral dose of azithromycin (20\ mg/kg) or matching placebo. Children were evaluated for malaria via thin and thick smear and rapid diagnostic test (for those with tympanic temperature >= 37.5\ {\textdegree}C) at baseline and 14 days and 6 months after treatment. Malaria outcomes in children receiving azithromycin versus placebo were compared at each follow-up timepoint separately.

RESULTS: Of 450 children enrolled, 230 were randomized to azithromycin and 220 to placebo. Children were a median of 26 months and 51\% were female, and 17\% were positive for malaria parasitaemia at baseline. There was no evidence of a difference in malaria parasitaemia at 14 days or 6 months after treatment. In the azithromycin arm, 20\% of children were positive for parasitaemia at 14 days compared to 17\% in the placebo arm (P = 0.43) and 7.6\% vs. 5.6\% in the azithromycin compared to placebo arms at 6 months (P = 0.47).

CONCLUSIONS: Azithromycin did not affect malaria outcomes in this study, possibly due to the individually randomized nature of the trial. Trial registration\ This study is registered at clinicaltrials.gov (NCT03676751; registered 19 September 2018).

}, issn = {1475-2875}, doi = {10.1186/s12936-021-03895-9}, author = {Coulibaly, Boubacar and Sie, Ali and Dah, Clarisse and Bountogo, Mamadou and Ouattara, Mamadou and Compaor{\'e}, Adama and Nikiema, Moustapha and Tiansi, J{\'e}r{\^o}me Nankon{\'e} and Sibiri, Nestor Demb{\'e}l{\'e} and Brogdon, Jessica M and Lebas, Elodie and Doan, Thuy and Porco, Travis C and Lietman, Thomas M and Oldenburg, Catherine E} } @article {856, title = {Effect of Azithromycin on the Ocular Surface Microbiome of Children in a High Prevalence Trachoma Area.}, journal = {Cornea}, year = {2021}, month = {2021 Sep 04}, abstract = {

PURPOSE: The aim of this study was to evaluate the effect of the 4 times per year mass azithromycin distributions on the ocular surface microbiome of children in a trachoma endemic area.

METHODS: In this cluster-randomized controlled trial, children aged 1 to 10 years in rural communities in the Goncha Seso Enesie district of Ethiopia were randomized to either no treatment or treatment with a single dose of oral azithromycin (height-based dosing to approximate 20 mg/kg) every 3 months for 1 year. Post hoc analysis of ocular surface Chlamydia trachomatis load, microbial community diversity, and macrolide resistance determinants was performed to evaluate differences between treatment arms.

RESULTS: One thousand two hundred fifty-five children from 24 communities were included in the study. The mean azithromycin coverage in the treated communities was 80\% (95\% CI: 73\%-86\%). The average age was 5 years (95\% CI: 4-5). Ocular surface C. trachomatis load was reduced in children treated with the 4 times per year azithromycin (P = 0.0003). Neisseria gonorrhoeae, Neisseria lactamica, and Neisseria meningitidis were more abundant in the no-treatment arm compared with the treated arm. The macrolide resistance gene ermB was not different between arms (P = 0.63), but mefA/E was increased (P = 0.04) in the azithromycin-treated arm.

CONCLUSIONS: We found a reduction in the load of C. trachomatis and 3 Neisseria species in communities treated with azithromycin. These benefits came at the cost of selection for macrolide resistance.

}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000002863}, author = {Doan, Thuy and Gebre, Teshome and Ayele, Berhan and Zerihun, Mulat and Hinterwirth, Armin and Zhong, Lina and Chen, Cindi and Ruder, Kevin and Zhou, Zhaoxia and Emerson, Paul M and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M} } @article {851, title = {Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection: A Randomized Clinical Trial.}, journal = {JAMA}, year = {2021}, month = {2021 Jul 16}, abstract = {

Importance: Azithromycin has been hypothesized to have activity against SARS-CoV-2.

Objective: To determine whether oral azithromycin in outpatients with SARS-CoV-2 infection leads to absence of self-reported COVID-19 symptoms at day 14.

Design, Setting, and Participants: Randomized clinical trial of azithromycin vs matching placebo conducted from May 2020 through March 2021. Outpatients from the US were enrolled remotely via internet-based surveys and followed up for 21 days. Eligible participants had a positive SARS-CoV-2 diagnostic test result (nucleic acid amplification or antigen) within 7 days prior to enrollment, were aged 18 years or older, and were not hospitalized at the time of enrollment. Among 604 individuals screened, 297 were ineligible, 44 refused participation, and 263 were enrolled. Participants, investigators, and study staff were masked to treatment randomization.

Interventions: Participants were randomized in a 2:1 fashion to a single oral 1.2-g dose of azithromycin (n = 171) or matching placebo (n = 92).

Main Outcomes and Measures: The primary outcome was absence of self-reported COVID-19 symptoms at day 14. There were 23 secondary clinical end points, including all-cause hospitalization at day 21.

Results: Among 263 participants who were randomized (median age, 43 years; 174 [66\%] women; 57\% non-Hispanic White and 29\% Latinx/Hispanic), 76\% completed the trial. The trial was terminated by the data and safety monitoring committee for futility after the interim analysis. At day 14, there was no significant difference in proportion of participants who were symptom free (azithromycin: 50\%; placebo: 50\%; prevalence difference, 0\%; 95\% CI, -14\% to 15\%; P \> .99). Of 23 prespecified secondary clinical end points, 18 showed no significant difference. By day 21, 5 participants in the azithromycin group had been hospitalized compared with 0 in the placebo group (prevalence difference, 4\%; 95\% CI, -1\% to 9\%; P = .16).

Conclusions and Relevance: Among outpatients with SARS-CoV-2 infection, treatment with a single dose of azithromycin compared with placebo did not result in greater likelihood of being symptom free at day 14. These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection.

Trial Registration: ClinicalTrials.gov Identifier: NCT04332107.

}, issn = {1538-3598}, doi = {10.1001/jama.2021.11517}, author = {Oldenburg, Catherine E and Pinsky, Benjamin A and Brogdon, Jessica and Chen, Cindi and Ruder, Kevin and Zhong, Lina and Nyatigo, Fanice and Cook, Catherine A and Hinterwirth, Armin and Lebas, Elodie and Redd, Travis and Porco, Travis C and Lietman, Thomas M and Arnold, Benjamin F and Doan, Thuy} } @article {821, title = {Gut resistome of preschool children after prolonged mass azithromycin distribution: a cluster-randomized trial.}, journal = {Clin Infect Dis}, year = {2021}, month = {2021 May 26}, abstract = {

We evaluated the gut resistome of children from communities treated with 10 twice-yearly azithromycin distributions. While 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.

}, issn = {1537-6591}, doi = {10.1093/cid/ciab485}, author = {Arzika, Ahmed M and Maliki, Ramatou and Abdou, Amza and Mankara, Alio K and Harouna, Abdoul N and Cook, Catherine and Hinterwirth, Armin and Worden, Lee and Zhong, Lina and Chen, Cindi and Ruder, Kevin and Zhou, Zhaoxia and Lebas, Elodie and O{\textquoteright}Brien, Kieran S and Oldenburg, Catherine E and Le, Victoria and Arnold, Benjamin F and Porco, Travis and Keenan, Jeremy D and Lietman, Thomas M and Doan, Thuy} } @article {906, title = {Keeping an eye on pink eye: a global conjunctivitis outbreak expert survey.}, journal = {Int Health}, year = {2021}, month = {2021 Aug 19}, abstract = {

BACKGROUND: Recurrent conjunctivitis epidemics are prevalent worldwide. Aetiologies are often undetermined.

METHODS: We surveyed conjunctivitis researchers about perceived trends in prevalence, incidence and aetiologies of conjunctivitis epidemics.

RESULTS: Of the 155 participants, 7\% endorsed globally variable and dynamic microbial aetiologies of conjunctivitis epidemics. Increased incidence of conjunctivitis epidemics over the last decade were reported by 21\% of respondents. Peak seasons differed between the northern and southern hemispheres.

CONCLUSIONS: There is regional equipoise regarding the increasing incidence and emerging underlying aetiologies of epidemic conjunctivitis. Further investigation of global surveillance and microbial characterization of conjunctivitis outbreaks could improve prevention and outcomes.

}, issn = {1876-3405}, doi = {10.1093/inthealth/ihab049}, author = {Kaur, Gurbani and Seitzman, Gerami D and Lietman, Thomas M and McLeod, Stephen D and Porco, Travis C and Doan, Thuy and Deiner, Michael S} } @article {761, title = {Peripheral Blood Transcriptome in Patients with Sarcoidosis-Associated Uveitis.}, journal = {Ocul Immunol Inflamm}, year = {2021}, month = {2021 Mar 04}, pages = {1-4}, abstract = {

: To identify peripheral blood transcriptome differences in uveitis patients with sarcoidosis compared to those with Vogt-Koyanagi-Harada (VKH) syndrome and controls.: Ten patients with uveitis compatible with sarcoidosis (eight with pulmonary sarcoidosis, one with central nervous system sarcoidosis, and one with conjunctival sarcoidosis), nine patients with VKH, and nine healthy controls were prospectively enrolled.: Ten genes exhibited a four-fold difference in expression in sarcoidosis patients compared to controls, many being involved in regulating inflammatory processes or cellular responses to microbes.: This research suggests that the transcriptome in sarcoidosis is robust enough to be detected in the peripheral blood and that sarcoidosis can be distinguished from healthy controls. Differentially expressed genes may serve as candidates warranting further investigation with respect to disease pathophysiology and may provide additional information, such as ability to stratify patients based on associated disease severity and anatomical location of inflammation within the eye.

}, issn = {1744-5078}, doi = {10.1080/09273948.2020.1861306}, author = {Gonzales, John A and Takhar, Jaskirat S and Joye, Ashlin and Acharya, Nisha R and Chen, Cindi and Hinterwirth, Armin and Doan, Thuy} } @article {776, title = {Poultry Ownership and Genetic Antibiotic Resistance Determinants in the Gut of Preschool Children.}, journal = {Am J Trop Med Hyg}, year = {2021}, month = {2021 Mar 22}, abstract = {

Zoonotic transmission is likely a pathway for antibiotic resistance. Data from a randomized trial of pediatric antibiotic administration were secondarily evaluated to determine if poultry ownership was significantly associated with the presence of gut genetic antibiotic resistance determinants among 118 children in Burkina Faso. Antimicrobial resistance (AMR) determinants were classified using DNA sequencing. We measured the relationship between genetic resistance determinants and chicken ownership using a logistic regression model adjusted for confounding variables. Children in households reporting poultry ownership had four times the odds of tetracycline resistance determinants in the gut compared with those without household poultry (OR: 4.08, 95\% CI: 1.08-15.44, P = 0.04). There was no statistically significant difference found for other antibiotic classes. Understanding the origins of antibiotic resistance may help spur the development of interventions to combat the global AMR crisis.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.20-1384}, author = {Brogdon, Jessica M and Sie, Ali and Dah, N Clarisse and Ouermi, Lucienne and Coulibaly, Boubacar and Lebas, Elodie and Zhong, Lina and Chen, Cindi and Lietman, Thomas M and Keenan, Jeremy D and Doan, Thuy and Oldenburg, Catherine E} } @article {781, title = {Single-dose azithromycin for child growth in Burkina Faso: a randomized controlled trial.}, journal = {BMC Pediatr}, volume = {21}, year = {2021}, month = {2021 Mar 17}, pages = {130}, abstract = {

BACKGROUND: In lower resource settings, previous randomized controlled trials have demonstrated evidence of increased weight gain following antibiotic administration in children with acute illness. We conducted an individually randomized trial to assess whether single dose azithromycin treatment causes weight gain in a general population sample of children in Burkina Faso.

METHODS: Children aged 8 days to 59 months were enrolled in November 2019 and followed through June 2020 in Nouna Town, Burkina Faso. Participants were randomly assigned to a single oral dose of azithromycin (20 mg/kg) or matching placebo. Anthropometric measurements were collected at baseline and 14 days and 6 months after enrollment. The primary anthropometric outcome was weight gain velocity in g/kg/day from baseline to 14 days and 6 months in separate linear regression models.

RESULTS: Of 450 enrolled children, 230 were randomly assigned to azithromycin and 220 to placebo. Median age was 26 months (IQR 16 to 38 months) and 51\% were female. At 14 days, children in the azithromycin arm gained a mean difference of 0.9 g/kg/day (95\% CI 0.2 to 1.6 g/kg/day, P = 0.01) more than children in the placebo arm. There was no difference in weight gain velocity in children receiving azithromycin compared to placebo at 6 months (mean difference 0.04 g/kg/day, 95\% CI - 0.05 to 0.13 g/kg/day, P = 0.46). There were no significant differences in other anthropometric outcomes.

CONCLUSIONS: Transient increases in weight gain were observed after oral azithromycin treatment, which may provide short-term benefits.

CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT03676751 . Registered 19/09/2018.

}, issn = {1471-2431}, doi = {10.1186/s12887-021-02601-7}, author = {Sie, Ali and Coulibaly, Boubacar and Dah, Clarisse and Bountogo, Mamadou and Ouattara, Mamadou and Compaor{\'e}, Guillaume and Brogdon, Jessica M and Godwin, William W and Lebas, Elodie and Doan, Thuy and Arnold, Benjamin F and Porco, Travis C and Lietman, Thomas M and Oldenburg, Catherine E} } @article {736, title = {Vitreoretinal Lymphoma: A Literature Review and Introduction of a New Diagnostic Method.}, journal = {Asia Pac J Ophthalmol (Phila)}, volume = {10}, year = {2021}, month = {2021 01 19}, pages = {93-98}, abstract = {

PURPOSE: The aim of this study was to briefly review the clinical and diagnostic features of vitreoretinal lymphoma (VRL) and to introduce the recent introduction of metagenomic deep sequencing in this ocular lymphomatous disease.

DESIGN AND METHODS: Review and description of the process of using metagenomic deep sequencing for ocular specimens at the Proctor Foundation, University of California, San Francisco, CA.

RESULTS: VRL masquerades as a uveitis, but clinical signs of subretinal lesions, and vitritis should prompt the inclusion of VRL in a differential diagnosis. Imaging features such as hyporeflective infiltrative lesions between the retinal pigment epithelium and Bruch{\textquoteright}s membrane are compatible with VRL, but diagnosis requires satisfying specific cytopathological and immunohistochemical or molecular features. Diagnosis, then, is subject to the cellularity, viability, and volume of the specimen submitted for these tests. Metagenomic deep sequencing has the ability to detect numerous lymphoma-associated mutations and is able to utilize minute volume samples and cell-free nucleic acid, so is well-suited for ocular tissues.

CONCLUSIONS: Metagenomic deep sequencing may offer an additional tool in the future with which to diagnose VRL.

}, issn = {2162-0989}, doi = {10.1097/APO.0000000000000365}, author = {Takhar, Jaskirat and Doan, Thuy and Gonzales, John A} } @article {216, title = {Adverse Events and Clinic Visits following a Single Dose of Oral Azithromycin among Preschool Children: A Randomized Placebo-Controlled Trial.}, journal = {Am J Trop Med Hyg}, year = {2020}, month = {2020 Dec 21}, abstract = {

Biannual mass azithromycin distribution reduces all-cause child mortality in some settings in sub-Saharan Africa; however, adverse events and short-term infectious outcomes following treatment have not been well characterized. Children aged 0-59 months were recruited in Nouna Town, Burkina Faso, and randomized 1:1 to a single directly observed oral 20 mg/kg dose of azithromycin or placebo. At 14 days after treatment, caregivers were interviewed about adverse event symptoms their child experienced since treatment and if they had sought health care for their child. All children had tympanic temperature measured at the 14-day visit. We compared adverse events and clinic visits using logistic regression models between azithromycin- and placebo-controlled children. Of 450 children enrolled, 230 were randomized to azithromycin and 220 to placebo. On average, children were aged 28 months, and 50.9\% were female. Caregivers of 20\% of children reported that their child experienced at least one adverse event, with no significant difference between study arms (19.9\% azithromycin; 20.0\% placebo, logistic regression = 0.96). Vomiting was more often reported by caregivers of azithromycin-treated children than by those of placebo-treated children (7.2\% azithromycin, 1.9\% placebo, logistic regression = 0.01). There were no significant differences in other adverse events or clinic visits. Adverse events following a single oral dose of azithromycin in preschool children were rare and mild. Azithromycin administration appears safe in this population.

}, issn = {1476-1645}, doi = {10.4269/ajtmh.20-1002}, author = {Sie, Ali and Dah, Clarisse and Bountogo, Mamadou and Ouattara, Mamadou and Nebie, Eric and Coulibaly, Boubacar and Brogdon, Jessica M and Godwin, William W and Lebas, Elodie and Doan, Thuy and Arnold, Benjamin F and Porco, Travis C and Lietman, Thomas M and Oldenburg, Catherine E} } @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 {181, title = {Clinical Course of Preexisting Uveitis during Treatment of Lung Cancer with Durvalumab.}, journal = {Ocul Immunol Inflamm}, volume = {28}, year = {2020}, month = {2020 05 18}, pages = {566-570}, issn = {1744-5078}, doi = {10.1080/09273948.2019.1678652}, author = {Ahmad, Tessnim R and Doan, Thuy and Gonzales, John A and Acharya, Nisha R and Tsui, Edmund} } @article {81, title = {Clinical metagenomics for infectious corneal ulcers: Rags to riches?}, journal = {Ocul Surf}, volume = {18}, year = {2020}, month = {2020 01}, pages = {1-12}, abstract = {

The emergence of clinical metagenomics as an unbiased, hypothesis-free approach to diagnostic testing is set to fundamentally alter the way infectious diseases are detected. Long envisioned as the solution to the limitations of culture-based conventional microbiology, next generation sequencing methods will soon mature, and our attention will inevitably turn to how they can be applied to areas of medicine which need it most urgently. In ophthalmology, the demand for this technology is particularly pressing for the care of infectious corneal ulcers, where current diagnostic tests may fail to identify a causative organism in over half of cases. However, the optimism found in the budding discourse surrounding clinical metagenomics belies the reality that clinicians and scientists will soon be inundated by oppressive volumes of sequencing data, much of which will be foreign and unfamiliar. Therefore, our success in translating clinical metagenomics is likely to hinge on how we make sense of these data, and understanding its implications for the interpretation and implementation of sequencing into routine clinical care. In this consortium-led review, we provide an outline of these data-related issues and how they may be used to inform technical workflows, with the hope that we may edge closer to realizing the potential of clinical metagenomics for this important unmet need.

}, issn = {1937-5913}, doi = {10.1016/j.jtos.2019.10.007}, author = {Ung, Lawson and Bispo, Paulo J M and Doan, Thuy and Van Gelder, Russell N and Gilmore, Michael S and Lietman, Thomas and Margolis, Todd P and Zegans, Michael E and Lee, Cecilia S and Chodosh, James} } @article {176, title = {Evaluation of Metagenomic Deep Sequencing as a Diagnostic Test for Infectious Keratitis.}, journal = {Ophthalmology}, year = {2020}, month = {2020 Jul 17}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2020.07.030}, author = {Lalitha, Prajna and Prajna, N Venkatesh and Sikha, Misra and Gunasekaran, Rameshkumar and Hinterwirth, Armin and Worden, Lee and Chen, Cindi and Zhong, Lina and Liu, Zijun and Lietman, Thomas M and Seitzman, Gerami D 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 {201, title = {Indirect effect of oral azithromycin on the gut resistome of untreated children: a randomized controlled trial.}, journal = {Int Health}, year = {2020}, month = {2020 Jun 17}, abstract = {

BACKGROUND: Antibiotic use by one individual may affect selection for antimicrobial resistance in close contacts. Here we evaluated whether oral antibiotic treatment of one child within a household affected the gut resistome of an untreated cohabiting child.

METHODS: Households with at least two children \<5\ y of age were randomized in a 1:1 fashion to a 5d course of azithromycin or placebo. To evaluate indirect effects of azithromycin treatment on the gut resistome, we randomly assigned one child in the house to azithromycin and one to placebo. In placebo households, each child received placebo. We performed DNA sequencing of rectal swabs collected 5\ d after the last antibiotic dose. We estimated risk ratios for the presence of genetic resistance determinants at the class level using modified Poisson models for children in azithromycin households compared with placebo households and assessed the composition of the resistome using permutational analysis of variance (PERMANOVA).

RESULTS: Of 58 children (n = 30 azithromycin households, n = 28 placebo households) with post-treatment rectal swabs, genetic resistance determinants were common but there was no significant difference at the class (p = 0.54 for macrolides) or gene (p = 0.94 for structure by PERMANOVA, p = 0.94 for diversity) level between untreated children in azithromycin households compared with placebo households.

CONCLUSIONS: The results are encouraging that one child{\textquoteright}s antibiotic use may not influence the resistome of another child. Trial registration: ClinicalTrials.gov NCT03187834.

}, issn = {1876-3405}, doi = {10.1093/inthealth/ihaa029}, author = {Oldenburg, Catherine E and Hinterwirth, Armin and Worden, Lee and Sie, Ali and Dah, Clarisse and Ouermi, Lucienne and Coulibaly, Boubacar and Zhong, Lina and Chen, Cindi and Ruder, Kevin 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 {156, title = {Metagenomic Deep Sequencing to Investigate for an Infectious Etiology of Iridocorneal Endothelial Syndrome.}, journal = {Cornea}, volume = {39}, year = {2020}, month = {2020 Oct}, pages = {1307-1310}, abstract = {

PURPOSE: Iridocorneal endothelial (ICE) syndrome is a group of rare ocular conditions that result from abnormal corneal endothelial cells, leading to secondary glaucoma, iris distortions, and corneal edema. The etiology of ICE is unknown, although it has been associated with viral infections, such as herpes simplex virus. In this study, we sought to identify an infectious etiology for ICE using advanced molecular techniques.

METHODS: Metagenomic RNA sequencing (MDS) is a high-throughput sequencing approach that can identify all pathogens in any clinical sample, including RNA viruses. Descemet membrane and aqueous fluid from patients with ICE syndrome were subjected to MDS testing.

RESULTS: Samples from 3 patients with ICE were analyzed. MDS was performed on the aqueous fluid of 3 patients and Descemet membrane and endothelial cell tissue from 1 patient. Viral pathogens were not identified in any of the samples.

CONCLUSIONS: We were unable to identify a viral etiology in the tissues of patients with the Chandler variant of ICE syndrome, although this study was limited by sample size.

}, issn = {1536-4798}, doi = {10.1097/ICO.0000000000002368}, author = {Sutra, Plern and Rose-Nussbaumer, Jennifer and Gonzales, John A and Wang, Kaidi and Hinterwirth, Armin and Seitzman, Gerami and Bloomer, Michele and Acharya, Nisha and Doan, Thuy} } @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 {76, title = {A double masked randomised 4-week, placebo-controlled study in the USA, Thailand and Taiwan to compare the efficacy of oral valganciclovir and topical 2\% ganciclovir in the treatment of cytomegalovirus anterior uveitis: study protocol.}, journal = {BMJ Open}, volume = {9}, year = {2019}, month = {2019 12 19}, pages = {e033175}, abstract = {

INTRODUCTION: Cytomegalovirus (CMV) anterior uveitis is a recognised cause of anterior uveitis in immunocompetent patients and is preventable cause of vision loss. Ocular sequelae include corneal endothelial damage which can cause corneal oedema and failure, as well as glaucoma. Recurrences of inflammation are common and therefore patients are often exposed to long-term therapy. Oral therapy is available in the form of valganciclovir, although with the caveat of systemic side effects such as bone marrow suppression and renal failure necessitating regular interval laboratory monitoring. Recent reports have demonstrated that topical 2\% ganciclovir solution may offer promising treatment outcomes in patients with CMV anterior uveitis with superior safety, cost-effectiveness and convenience profiles. An investigation into the relative equipoise of these therapies is warranted for these reasons.

METHODS AND ANALYSIS: The Systemic and Topical Control of Cytomegalovirus Anterior uveitis: Treatment Outcomes (STACCATO) trial is designed as a multicentre, block randomised by site, double-masked, placebo-controlled trial comparing the efficacy of oral valganciclovir, 2\% topical ganciclovir and placebo in treating PCR-proven CMV anterior uveitis. Participant clinical evaluation will occur at three study time points by a masked study ophthalmologist over a 28-day period to assess resolution of ocular inflammation (secondary outcome). A control group will provide additional information about the possible impact that the infected host{\textquoteright}s immune response may play in controlling local viral replication. The primary analysis is an analysis of covariance (three arms) correcting for baseline to compare quantitative CMV viral load in the anterior chamber (AC) aqueous fluid before and 7 days after treatment.

ETHICS AND DISSEMINATION: The University of California San Francisco Committee on Human Research and the Khon Kaen University Institutional Review Board have given ethical approval. The results of this trial will be presented at local and international meetings and submitted for peer-reviewed journals for publication.

TRIAL REGISTRATION NUMBER: NCT03576898.

}, keywords = {Administration, Oral, Administration, Topical, Antiviral Agents, Cytomegalovirus Infections, Double-Blind Method, Ganciclovir, Humans, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Taiwan, Thailand, United States, Uveitis, Anterior, Valganciclovir, Viral Load}, issn = {2044-6055}, doi = {10.1136/bmjopen-2019-033175}, author = {Takhar, Jaskirat S and Joye, Ashlin S and Somkijrungroj, Thanapong and Laovirojjanakul, Wipada and Lin, Chang-Ping and Lietman, Thomas M and Porco, Travis C and Keenan, Jeremy D and Gebreegziabher, Elisabeth A and Seitzman, Gerami D and Rose-Nussbaumer, Jennifer and Thuy A Doan and Acharya, Nisha R and Gonzales, John A} } @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 {196, title = {Indirect Effect of Azithromycin Use on the Intestinal Microbiome Diversity of Untreated Children: A Randomized Trial.}, journal = {Open Forum Infect Dis}, volume = {6}, year = {2019}, month = {2019 Mar}, pages = {ofz061}, abstract = {

Cohabiting children may share components of their intestinal microbiome. We evaluated whether receipt of azithromycin in one sibling confers changes to the intestinal microbiome in an untreated sibling compared with placebo in a randomized controlled trial. We found no evidence of an indirect effect of antibiotic use in cohabiting children. NCT03187834.

}, issn = {2328-8957}, doi = {10.1093/ofid/ofz061}, author = {Oldenburg, Catherine E 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 Cummings, Susie and Zhong, Lina and Lietman, Thomas M and Keenan, Jeremy D 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 {111, title = {Letermovir for the Management of Cytomegalovirus-associated Uveitis.}, journal = {Ocul Immunol Inflamm}, year = {2019}, month = {2019 Oct 22}, pages = {1-6}, abstract = {

: To investigate the use of letermovir 480 mg daily for the treatment of cytomegalovirus (CMV)-associated uveitis (AU). : Retrospective case series of CMV-AU patients on letermovir. : Six eyes of five patients (mean age 54 years) were included. Mean follow-up time was 10 months. Four patients had CMV anterior uveitis and one patient had bilateral CMV retinitis. All were treated initially with valganciclovir 900 mg twice daily. Transition to letermovir was due to cytopenias (n = 3), transaminitis (n = 1), and persistent inflammation on valganciclovir (n = 1). At the initiation of letermovir, mean visual acuity (VA) was 0.35 logMAR and IOP was 14 mmHg. One of the six eyes had a recurrence of anterior uveitis due to self-discontinuation of letermovir. No adverse events were observed. At last follow-up, no patients had active inflammation. Mean VA was 0.08 logMAR and IOP was 9 mmHg. : Letermovir may be an alternative treatment for CMV-AU in patients with persistent inflammation or side effects on valganciclovir.

}, issn = {1744-5078}, doi = {10.1080/09273948.2019.1662062}, author = {Tsui, Edmund and Gonzales, John A and Shantha, Jessica G and Acharya, Nisha and Doan, Thuy} } @article {121, title = {Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa.}, journal = {N Engl J Med}, volume = {380}, year = {2019}, month = {2019 Jun 06}, pages = {2207-2214}, abstract = {

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

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

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

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

}, keywords = {Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Drug Administration Schedule, Female, Humans, Infant, Infant Mortality, Male, Mass Drug Administration, Niger}, issn = {1533-4406}, doi = {10.1056/NEJMoa1817213}, author = {Keenan, Jeremy D and Arzika, Ahmed M and Maliki, Ramatou and Boubacar, Nameywa and Elh Adamou, Sanoussi and Moussa Ali, Maria and Cook, Catherine and Lebas, Elodie and Lin, Ying and Ray, Kathryn J and O{\textquoteright}Brien, Kieran S and Doan, Thuy and Oldenburg, Catherine E and Callahan, E Kelly and Emerson, Paul M and Porco, Travis C and Lietman, Thomas M} } @article {141, title = {Macrolide Resistance and Longer-Term Assessment of Azithromycin in MORDOR I. Reply.}, journal = {N Engl J Med}, volume = {381}, year = {2019}, month = {2019 11 28}, pages = {2184-2185}, keywords = {Africa, Anti-Bacterial Agents, Azithromycin, Child Mortality, Drug Resistance, Bacterial, Macrolides}, issn = {1533-4406}, doi = {10.1056/NEJMc1910014}, author = {Lietman, Thomas M and Doan, Thuy and Keenan, Jeremy D} } @article {136, title = {Macrolide Resistance in MORDOR I - A Cluster-Randomized Trial in Niger.}, journal = {N Engl J Med}, volume = {380}, year = {2019}, month = {2019 Jun 06}, pages = {2271-2273}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Child, Preschool, Drug Resistance, Bacterial, Humans, Infant, Macrolides, Niger, Pneumococcal Infections, Streptococcus pneumoniae}, issn = {1533-4406}, doi = {10.1056/NEJMc1901535}, author = {Doan, Thuy and Arzika, Ahmed M and Hinterwirth, Armin and Maliki, Ramatou and Zhong, Lina and Cummings, Susie and Sarkar, Samarpita and Chen, Cindi and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M} } @article {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 {91, title = {Primary vitreoretinal lymphoma: empowering our clinical suspicion.}, journal = {Curr Opin Ophthalmol}, volume = {30}, year = {2019}, month = {2019 Nov}, pages = {491-499}, abstract = {

PURPOSE OF REVIEW: Vitreoretinal lymphoma (VRL) is well known as a masquerade syndrome. However, delays in diagnosis are common particularly because of the small volume of tissue that is used for investigative studies. We outline the current diagnostic tests available to clinicians and provide a glimpse of possible future novel diagnostics.

RECENT FINDINGS: The use of spectral domain ocular coherence tomography to identify subretinal lesions has proven to be a reliable ally to clinicians. Nevertheless, the diagnostic gold standard remains cytology, which requires a skilled pathologist. Molecular tests, including MYD88 polymerase chain reaction testing has further refined our diagnostic capabilities. Metagenomic deep sequencing is a newer molecular test that offers the ability to identify any mutation associated with lymphoma development and may offer more sensitive testing in the future.

SUMMARY: Clinicians have developed a strong acumen for suspecting VRL based upon clinical features, which can further be supported by a variety of imaging modalities. Delays in diagnosis continue to occur particularly because of the small volume of ocular fluid available for testing and because current tests offer a biased approach in terms of limited scope of detecting a specific mutation or cytopathologic feature(s). Newer molecular techniques feature an expanded scope of detecting any mutation associated with lymphomatous development.

}, keywords = {Eye Neoplasms, Humans, Intraocular Lymphoma, Molecular Diagnostic Techniques, Myeloid Differentiation Factor 88, Retinal Neoplasms, Vitreous Body}, issn = {1531-7021}, doi = {10.1097/ICU.0000000000000620}, author = {Takhar, Jaskirat S and Thuy A Doan and Gonzales, John A} } @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 {146, title = {When to Consider Bisphosphonates in Patients on Steroids for Chronic Ocular Inflammatory Conditions.}, journal = {J Ocul Pharmacol Ther}, volume = {35}, year = {2019}, month = {2019 09}, pages = {379-380}, keywords = {Adrenal Cortex Hormones, Adult, Aged, Aged, 80 and over, Bone Density Conservation Agents, Diphosphonates, Eye Diseases, Female, Humans, Male, Middle Aged, Osteoporotic Fractures}, issn = {1557-7732}, doi = {10.1089/jop.2019.0058}, author = {Takhar, Jaskirat S and Pawar, Varun K and Marneris, Athanasios G and Thuy A Doan and Acharya, Nisha R and Gonzales, John A} } @article {56, title = {Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa.}, journal = {N Engl J Med}, volume = {378}, year = {2018}, month = {2018 Apr 26}, pages = {1583-1592}, abstract = {

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

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

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

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

}, keywords = {Administration, Oral, Anti-Bacterial Agents, Azithromycin, Child Mortality, Child, Preschool, Communicable Disease Control, Communicable Diseases, Drug Resistance, Bacterial, Female, Humans, Infant, Infant Mortality, Malawi, Male, Mass Drug Administration, Niger, Public Health, Tanzania}, issn = {1533-4406}, doi = {10.1056/NEJMoa1715474}, author = {Keenan, Jeremy D and Bailey, Robin L and West, Sheila K and Arzika, Ahmed M and Hart, John and Weaver, Jerusha and Kalua, Khumbo and Mrango, Zakayo and Ray, Kathryn J and Cook, Catherine and Lebas, Elodie and O{\textquoteright}Brien, Kieran S and Emerson, Paul M and Porco, Travis C and Lietman, Thomas M} } @article {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 {261, title = {Effect of Commonly Used Pediatric Antibiotics on Gut Microbial Diversity in Preschool Children in Burkina Faso: A Randomized Clinical Trial.}, journal = {Open Forum Infect Dis}, volume = {5}, year = {2018}, month = {2018 Nov}, pages = {ofy289}, abstract = {

Background: Exposure to antibiotics may result in alterations to the composition of intestinal microbiota. However, few trials have been conducted, and observational studies are subject to confounding by indication. We conducted a randomized controlled trial to determine the effect of 3 commonly used pediatric antibiotics on the intestinal microbiome in healthy preschool children.

Methods: Children aged 6-59 months were randomized (1:1:1:1) to a 5-day course of 1 of 3 antibiotics, including amoxicillin (25 mg/kg/d twice-daily doses), azithromycin (10 mg/kg dose on day 1 and then 5 mg/kg once daily for 4 days), cotrimoxazole (240 mg once daily), or placebo. Rectal swabs were obtained at baseline and 5 days after the last dose and were processed using 16S rRNA gene sequencing. The prespecified primary outcome was inverse Simpson{\textquoteright}s α-diversity index.

Results: Post-treatment Simpson{\textquoteright}s diversity was significantly different across the 4 arms ( = .003). The mean Simpson{\textquoteright}s α-diversity among azithromycin-treated children was significantly lower than in placebo-treated children (6.6; 95\% confidence interval [CI], 5.5-7.8; vs 9.8; 95\% CI, 8.7-10.9; = .0001). Diversity in children treated with amoxicillin (8.3; 95\% CI, 7.0-9.6; = .09) or cotrimoxazole (8.3; 95\% CI, 8.2-9.7; = .08) was not significantly different than placebo.

Conclusions: Azithromycin affects the composition of the pediatric intestinal microbiome. The effect of amoxicillin and cotrimoxazole on microbiome composition was less clear.

Clinical Trials Registration: clinicaltrials.gov NCT03187834.

}, issn = {2328-8957}, doi = {10.1093/ofid/ofy289}, author = {Oldenburg, Catherine E and Sie, Ali and Coulibaly, Boubacar and Ouermi, Lucienne and Dah, Clarisse and Tapsoba, Charlemagne and B{\"a}rnighausen, Till and Ray, Kathryn J and Zhong, Lina and Cummings, Susie and Lebas, Elodie and Lietman, Thomas M and Keenan, Jeremy D and Doan, Thuy} } @article {221, title = {Mass Azithromycin Distribution and Community Microbiome: A Cluster-Randomized Trial.}, journal = {Open Forum Infect Dis}, volume = {5}, year = {2018}, month = {2018 Aug}, pages = {ofy182}, abstract = {

Background: Mass distributions of oral azithromycin have long been used to eliminate trachoma, and they are now being proposed to reduce childhood mortality. The observed benefit appears to be augmented with each additional treatment, suggesting a possible community-level effect. Here, we assess whether 2 biannual mass treatments of preschool children affect the community{\textquoteright}s gut microbiome at 6 months after the last distribution.

Methods: In this cluster-randomized controlled trial, children aged 1-60 months in the Dossa region of Niger were randomized at the village level to receive a single dose of azithromycin or placebo every 6 months. Fecal samples were collected 6 months after the second treatment for metagenomic deep sequencing. The prespecified primary outcome was the Euclidean PERMANOVA of the gut microbiome, or effectively the distance between the genus-level centroid at the community level, with the secondary outcome being the Simpson{\textquoteright}s α diversity.

Results: In the azithromycin arm, the gut microbial structures were significantly different than in the placebo arm (Euclidean PERMANOVA, \< .001). Further, the diversity of the gut microbiome in the azithromycin arm was significantly lower than in the placebo arm (inverse Simpson{\textquoteright}s index, = .005).

Conclusions: Two mass azithromycin administrations, 6 months apart, in preschool children led to long-term alterations of the gut microbiome structure and community diversity. Here, long-term microbial alterations in the community did not imply disease but were associated with an improvement in childhood mortality.

Clinical Trials Registration: NCT02048007.

}, issn = {2328-8957}, doi = {10.1093/ofid/ofy182}, author = {Doan, Thuy and Hinterwirth, Armin and Arzika, Ahmed M and Cotter, Sun Y and Ray, Kathryn J and O{\textquoteright}Brien, Kieran S and Zhong, Lina and Chow, Eric D and Zhou, Zhaoxia and Cummings, Susie L and Fry, Dionna and Oldenburg, Catherine E and Worden, Lee and Porco, Travis C and Keenan, Jeremy D and Lietman, Thomas M} } @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 {291, title = {C-terminal threonines and serines play distinct roles in the desensitization of rhodopsin, a G protein-coupled receptor.}, journal = {Elife}, volume = {4}, year = {2015}, month = {2015 Apr 24}, abstract = {

Rod photoreceptors generate measurable responses to single-photon activation of individual molecules of the G protein-coupled receptor (GPCR), rhodopsin. Timely rhodopsin desensitization depends on phosphorylation and arrestin binding, which quenches G protein activation. Rhodopsin phosphorylation has been measured biochemically at C-terminal serine residues, suggesting that these residues are critical for producing fast, low-noise responses. The role of native threonine residues is unclear. We compared single-photon responses from rhodopsin lacking native serine or threonine phosphorylation sites. Contrary to expectation, serine-only rhodopsin generated prolonged step-like single-photon responses that terminated abruptly and randomly, whereas threonine-only rhodopsin generated responses that were only modestly slower than normal. We show that the step-like responses of serine-only rhodopsin reflect slow and stochastic arrestin binding. Thus, threonine sites play a privileged role in promoting timely arrestin binding and rhodopsin desensitization. Similar coordination of phosphorylation and arrestin binding may more generally permit tight control of the duration of GPCR activity.

}, keywords = {Animals, Arrestin, Binding Sites, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphorylation, Receptors, G-Protein-Coupled, Retinal Rod Photoreceptor Cells, Rhodopsin, Serine, Threonine}, issn = {2050-084X}, doi = {10.7554/eLife.05981}, author = {Azevedo, Anthony W and Doan, Thuy and Moaven, Hormoz and Sokal, Iza and Baameur, Faiza and Vishnivetskiy, Sergey A and Homan, Kristoff T and Tesmer, John J G and Gurevich, Vsevolod V and Chen, Jeannie and Rieke, Fred} } @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} } @article {751, title = {A woman with bilateral maculopathy and acquired vitamin B12 deficiency.}, journal = {Eye (Lond)}, volume = {28}, year = {2014}, month = {2014 Jul}, pages = {905-6}, keywords = {Color Vision Defects, Electroretinography, Female, Fluorescein Angiography, Humans, Magnetic Resonance Imaging, Middle Aged, Paresthesia, Retinal Diseases, Tomography, Optical Coherence, Visual Acuity, Vitamin B 12, Vitamin B 12 Deficiency, Vitamin B Complex}, issn = {1476-5454}, doi = {10.1038/eye.2014.82}, author = {Doan, T and Chao, J R} } @article {741, title = {Arrestin competition influences the kinetics and variability of the single-photon responses of mammalian rod photoreceptors.}, journal = {J Neurosci}, volume = {29}, year = {2009}, month = {2009 Sep 23}, pages = {11867-79}, abstract = {

Reliable signal transduction via G-protein-coupled receptors requires proper receptor inactivation. For example, signals originating from single rhodopsin molecules vary little from one to the next, requiring reproducible inactivation of rhodopsin by phosphorylation and arrestin binding. We determined how reduced concentrations of rhodopsin kinase (GRK1) and/or arrestin1 influenced the kinetics and variability of the single-photon responses of mouse rod photoreceptors. These experiments revealed that arrestin, in addition to its role in quenching the activity of rhodopsin, can tune the kinetics of rhodopsin phosphorylation by competing with GRK1. This competition influenced the variability of the active lifetime of rhodopsin. Biasing the competition in favor of GRK1 revealed that rhodopsin remained active through much of the single-photon response under the conditions of our experiments. This long-lasting rhodopsin activity can explain the characteristic time course of single-photon response variability. Indeed, explaining the late time-to-peak of the variance required an active lifetime of rhodopsin approximately twice that of the G-protein transducin. Competition between arrestins and kinases may be a general means of influencing signals mediated by G-protein-coupled receptors, particularly when activation of a few receptors produces signals of functional importance.

}, keywords = {Animals, Arrestin, G-Protein-Coupled Receptor Kinase 1, Kinetics, Markov Chains, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Neurological, Phosphorylation, Photic Stimulation, Photons, Retinal Rod Photoreceptor Cells, Rhodopsin, Signal Transduction, Time Factors}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0819-09.2009}, author = {Doan, Thuy and Azevedo, Anthony W and Hurley, James B and Rieke, Fred} } @article {746, title = {Deletion of PrBP/delta impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segments.}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, year = {2007}, month = {2007 May 22}, pages = {8857-62}, abstract = {

The mouse Pde6d gene encodes a ubiquitous prenyl binding protein, termed PrBP/delta, of largely unknown physiological function. PrBP/delta was originally identified as a putative rod cGMP phosphodiesterase (PDE6) subunit in the retina, where it is relatively abundant. To investigate the consequences of Pde6d deletion in retina, we generated a Pde6d(-/-) mouse by targeted recombination. Although manifesting reduced body weight, the Pde6d(-/-) mouse was viable and fertile and its retina developed normally. Immunocytochemistry showed that farnesylated rhodopsin kinase (GRK1) and prenylated rod PDE6 catalytic subunits partially mislocalized in Pde6d(-/-) rods, whereas rhodopsin was unaffected. In Pde6d(-/-) rod single-cell recordings, sensitivity to single photons was increased and saturating flash responses were prolonged. Pde6d(-/-) scotopic paired-flash electroretinograms indicated a delay in recovery of the dark state, likely due to reduced levels of GRK1 in rod outer segments. In Pde6d(-/-) cone outer segments, GRK1 and cone PDE6alpha{\textquoteright} were present at very low levels and the photopic b-wave amplitudes were reduced by 70\%. Thus the absence of PrBP/delta in retina impairs transport of prenylated proteins, particularly GRK1 and cone PDE, to rod and cone outer segments, resulting in altered photoreceptor physiology and a phenotype of a slowly progressing rod/cone dystrophy.

}, keywords = {Animals, Catalytic Domain, Cyclic Nucleotide Phosphodiesterases, Type 6, Electroretinography, G-Protein-Coupled Receptor Kinase 1, Gene Deletion, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoprene, Phosphoric Diester Hydrolases, Photoreceptor Cells, Vertebrate, Protein Transport}, issn = {0027-8424}, doi = {10.1073/pnas.0701681104}, author = {Zhang, H and Li, S and Doan, T and Rieke, F and Detwiler, P B and Frederick, J M and Baehr, W} } @article {726, title = {Multiple phosphorylation sites confer reproducibility of the rod{\textquoteright}s single-photon responses.}, journal = {Science}, volume = {313}, year = {2006}, month = {2006 Jul 28}, pages = {530-3}, abstract = {

Although signals controlled by single molecules are expected to be inherently variable, rod photoreceptors generate reproducible responses to single absorbed photons. We show that this unexpected reproducibility-the consistency of amplitude and duration of rhodopsin activity-varies in a graded and systematic manner with the number but not the identity of phosphorylation sites on rhodopsin{\textquoteright}s C terminus. These results indicate that each phosphorylation site provides an independent step in rhodopsin deactivation and that collectively these steps tightly control rhodopsin{\textquoteright}s active lifetime. Other G protein cascades may exploit a similar mechanism to encode accurately the timing and number of receptor activation.

}, keywords = {Animals, Arrestin, Electrophysiology, Mice, Mice, Transgenic, Models, Biological, Mutation, Patch-Clamp Techniques, Phosphorylation, Photons, Retinal Rod Photoreceptor Cells, Rhodopsin, Vision, Ocular}, issn = {1095-9203}, doi = {10.1126/science.1126612}, author = {Doan, Thuy and Mendez, Ana and Detwiler, Peter B and Chen, Jeannie and Rieke, Fred} }