Gut Bifidobacteria enrichment following oral Lactobacillus-supplementation is associated with clinical improvements in children with cystic fibrosis.

BACKGROUND: Relationships between gut microbiomes and airway immunity have been established in murine and human studies of allergy and asthma. Early life Lactobacillus supplementation alters the composition and metabolic productivity of the gut microbiome. However, little is known of how Lactobacillus supplementation impacts the gut microbiota in children with cystic fibrosis (CF) and whether specific microbiota states that arise following gut microbiome manipulation relate to pulmonary outcomes. METHODS: Stool samples were collected from CF patients enrolled in a multi-center, double-blind, randomized placebo-controlled trial of daily Lactobacillus rhamnosus strain GG (LGG) probiotic supplementation over a 12-month period. Fecal 16S rRNA biomarker sequencing was used to profile fecal bacterial microbiota and analyses were performed in QiiME. RESULTS: Bifidobacteria-dominated fecal microbiota were more likely to arise in LGG-treated children with CF (P = 0.04). Children with Bifidobacteria-dominated gut microbiota had a reduced rate of pulmonary exacerbations (IRR = 0.55; 95% CI 0.25 to 0.82; P = 0.01), improved pulmonary function (+ 20.00% of predicted value FEV1; 95% CI 8.05 to 31.92; P = 0.001), lower intestinal inflammation (Calprotectin; Coef = - 16.53 µg g-1 feces; 95% CI - 26.80 to - 6.26; P = 0.002) and required fewer antibiotics (IRR = 0.43; 95% CI 0.22 to 0.69; P = 0.04) compared to children with Bacteroides-dominated microbiota who were less likely to have received LGG. CONCLUSIONS: The majority of pediatric CF patients in this study possessed a Bacteroides- or Bifidobacteria-dominated gut microbiota. Bifidobacteria-dominated gut microbiota were more likely to be associated with LGG-supplementation and with better clinical outcomes.

Cross-Linking-Assisted Infection Reduction: A Randomized Clinical Trial Evaluating the Effect of Adjuvant Cross-Linking on Outcomes in Fungal Keratitis.

PURPOSE: To determine if there is a benefit to adjuvant corneal crosslinking (CXL) and to compare natamycin versus amphotericin B for filamentous fungal keratitis. DESIGN: Outcome-masked, 2×2 factorial design, randomized controlled clinical trial. PARTICIPANTS: Consecutive patients presenting with moderate vision loss from a smear-positive fungal ulcer at Aravind Eye Hospital, Madurai, India. METHODS: Study eyes were randomized to 1 of 4 treatment combinations using an adaptive randomization protocol. The treatment arms included (1) topical natamycin 5% alone, (2) topical natamycin 5% plus CXL, (3) topical amphotericin B 0.15% alone, and (4) topical amphotericin 0.15% plus CXL. MAIN OUTCOME MEASURES: The primary outcome of the trial was microbiological cure at 24 hours on repeat culture. Secondary outcomes included best spectacle-corrected visual acuity (BSCVA) at 3 weeks and 3 months, percentage of study participants with epithelial healing at 3 days, 3 weeks, and 3 months, infiltrate or scar size at 3 weeks and 3 months, 3-day smear and culture, and adverse events. RESULTS: Those randomized to CXL regardless of medication (topical natamycin or amphotericin) had 1.32-fold increased odds of 24-hour culture positivity, although this was not statistically significant (95% confidence interval [CI], 0.57-3.06; P = 0.51). We were also unable to find a difference in 24-hour culture positivity between those randomized to amphotericin and those randomized to natamycin when evaluating as a group regardless of whether or not they received CXL (coefficient 1.10; 95% CI, 0.47-2.54; P = 0.84). The BSCVA was approximately 0.22 logarithm of the minimum angle of resolution (logMAR) (2.2 Snellen lines) worse on average at 3 weeks among those receiving CXL regardless of medication (95% CI, -0.04 to 0.40; P = 0.04) and 0.32 logMAR (3.2 Snellen lines) worse visual acuity at 3 months after controlling for baseline visual acuity (95% CI, 0.03-0.54; P = 0.02). There was no difference in infiltrate or scar size, percentage of epithelialized or adverse events when comparing CXL with no CXL or the 2 topical medications. CONCLUSIONS: There appears to be no benefit of adjuvant CXL in the primary treatment of moderate filamentous fungal ulcers, and it may result in decreased visual acuity.

High-throughput sequencing of pooled samples to determine community-level microbiome diversity.

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'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's correlation as well as using Bland and Altman agreement analysis for three established diversity indices including richness, Simpson's and Shannon'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.

Linear growth in preschool children treated with mass azithromycin distributions for trachoma: A cluster-randomized trial.

BACKGROUND: Mass azithromycin distributions have been shown to reduce mortality among pre-school children in sub-Saharan Africa. It is unclear what mediates this mortality reduction, but one possibility is that antibiotics function as growth promoters for young children. METHODS AND FINDINGS: 24 rural Ethiopian communities that had received biannual mass azithromycin distributions over the previous four years were enrolled in a parallel-group, cluster-randomized trial. Communities were randomized in a 1:1 ratio to either continuation of biannual oral azithromycin (20mg/kg for children, 1 g for adults) or to no programmatic antibiotics over the 36 months of the study period. All community members 6 months and older were eligible for the intervention. The primary outcome was ocular chlamydia; height and weight were measured as secondary outcomes on children less than 60 months of age at months 12 and 36. Study participants were not masked; anthropometrists were not informed of the treatment allocation. Anthropometric measurements were collected for 282 children aged 0-36 months at the month 12 assessment and 455 children aged 0-59 months at the month 36 assessment, including 207 children who had measurements at both time points. After adjusting for age and sex, children were slightly but not significantly taller in the biannually treated communities (84.0 cm, 95%CI 83.2-84.8, in the azithromycin-treated communities vs. 83.7 cm, 95%CI 82.9-84.5, in the untreated communities; mean difference 0.31 cm, 95%CI -0.85 to 1.47, P = 0.60). No adverse events were reported. CONCLUSIONS: Periodic mass azithromycin distributions for trachoma did not demonstrate a strong impact on childhood growth. TRIAL REGISTRATION: The TANA II trial was registered on clinicaltrials.gov #NCT01202331.

Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa.

BACKGROUND: The MORDOR I trial (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) 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' original assignments. RESULTS: In the MORDOR II trial, the mean (±SD) azithromycin coverage was 91.3±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±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.).

Visual Impairment in Fungal Versus Bacterial Corneal Ulcers 4 Years After Successful Antimicrobial Treatment.

PURPOSE: To compare longitudinal outcomes of visual acuity after fungal corneal ulcers with those of bacterial ulcers. DESIGN: Prospective cohort study. METHODS: This study was conducted in a tertiary eye hospital in South India. The population consisted of 100 of 152 individuals whose fungal or bacterial keratitis had been diagnosed 4 years prior and had been enrolled in 1 of 2 concurrent randomized trials. Causative organisms of infectious keratitis were either bacterial or fungal. Presenting visual acuity consisted of best spectacle corrected visual acuity (BSCVA) and hard contact lens-corrected visual acuity (CLVA). RESULTS: Fifty study participants with prior fungal keratitis and 50 with prior bacterial keratitis were enrolled. Four years after treatment for keratitis, participants' presenting vision in the better eye was worse than 20/60 for 12 individuals (24.0%) in the fungal group and 10 individuals (20.0%) in the bacterial group. Median BSCVA in the affected eye at the 4-year visit in the fungal group was similar to that in the bacterial group (Snellen equivalent, 20/32 for each), although vision worse than 20/400 was more common in the fungal ulcer group after spectacle correction (odds ratio [OR] 4.19; 95% confidence interval [CI], 1.11-15.8) and contact lens correction (OR, 5.74; 95% CI, 1.37-24.1). CONCLUSIONS: In this South Indian population with a previous episode of fungal or bacterial keratitis, correctable bilateral visual impairment was common. Although long-term visual outcomes were, on average, similar between fungal and bacterial ulcers, fungal ulcers were more likely to produce severe visual impairment.

Effect of Commonly Used Pediatric Antibiotics on Gut Microbial Diversity in Preschool Children in Burkina Faso: A Randomized Clinical Trial.

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's α-diversity index. RESULTS: Post-treatment Simpson's diversity was significantly different across the 4 arms (P = .003). The mean Simpson'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; P = .0001). Diversity in children treated with amoxicillin (8.3; 95% CI, 7.0-9.6; P = .09) or cotrimoxazole (8.3; 95% CI, 8.2-9.7; P = .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.

Safety of azithromycin in infants under six months of age in Niger: A community randomized trial.

BACKGROUND: Mass azithromycin distribution reduces under-5 child mortality. Trachoma control programs currently treat infants aged 6 months and older. Here, we report findings from an infant adverse event survey in 1-5 month olds who received azithromycin as part of a large community-randomized trial in Niger. METHODS AND PRINCIPAL FINDINGS: Active surveillance of infants aged 1-5 months at the time of treatment was conducted in 30 randomly selected communities from within a large cluster randomized trial of biannual mass azithromycin distribution compared to placebo to assess the potential impact on child mortality. We compared the distribution of adverse events reported after treatment among azithromycin-treated versus placebo-treated infants. From January 2015 to February 2018, the caregivers of 1,712 infants were surveyed. Approximately one-third of caregivers reported at least one adverse event (azithromycin: 29.6%, placebo: 34.3%, risk ratio [RR] 0.86, 95% confidence interval [CI] 0.68 to 1.10, P = 0.23). The most commonly reported adverse events included diarrhea (azithromycin: 19.3%, placebo: 28.1%, RR 0.68, 95% CI 0.49 to 0.96, P = 0.03), vomiting (azithromycin: 15.9%, placebo: 21.0%, RR 0.76, 95% CI 0.56 to 1.02, P = 0.07), and skin rash (azithromycin: 12.3%, placebo: 13.6%, RR 0.90, 95% CI 0.59 to 1.37, P = 0.63). No cases of infantile hypertrophic pyloric stenosis were reported. CONCLUSIONS: Azithromycin given to infants aged 1-5 months appeared to be safe. Inclusion of younger infants in larger azithromycin-based child mortality or trachoma control programs could be considered if deemed effective. TRIAL REGISTRATION: ClinicalTrials.gov NCT02048007.

Mass Azithromycin Distribution and Community Microbiome: A Cluster-Randomized Trial.

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'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's α diversity. RESULTS: In the azithromycin arm, the gut microbial structures were significantly different than in the placebo arm (Euclidean PERMANOVA, P < .001). Further, the diversity of the gut microbiome in the azithromycin arm was significantly lower than in the placebo arm (inverse Simpson's index, P = .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.

Therapeutic Penetrating Keratoplasty Button Cultures in The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole Versus Placebo.

OBJECTIVE: To compare oral voriconazole vs placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis. DESIGN: Non-prespecified, secondary case-control analysis from a multicenter, double-masked, randomized placebo-controlled clinical trial. METHODS: Study Participants: Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 or worse who eventuated to therapeutic penetrating keratoplasty (TPK). INTERVENTION: Study participants were randomized to oral voriconazole vs oral placebo; all received topical antifungal drops. MAIN OUTCOME MEASURES: TPK button culture positivity. RESULTS: A total of 95 of 194 (49.5%) study participants enrolled at Madurai, Coimbatore, or Pondicherry, India eventuated to TPK in an average of 20.9 days (standard deviation 15.2 days, range 2-71 days). TPK button cultures were available for 67 of 95 (71%) of the TPKs performed and were positive for filamentous fungus in 45 of 67 (67%) cases. For each 1-day increase in the time to TPK there was 0.94-fold decreased odds of fungal culture positivity (95% confidence interval [CI] 0.90-0.98, P = .005). Those randomized to oral voriconazole had 1.26-fold increased odds of TPK button culture positivity after controlling for time to TPK and baseline organism, but this was not statistically significant (95% CI 0.32-4.87; P = .74). Those who underwent TPK for lack of response to medical therapy were 10.64-fold more likely to be culture positive than if the indication for surgery was perforation and this was statistically significant (95% CI 2.16-51.70; P = .003). CONCLUSIONS: There appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. Infection rather than inflammation appears to be the reason for the worsening clinical picture in many of these patients.

Regression Discontinuity and Randomized Controlled Trial Estimates: An Application to The Mycotic Ulcer Treatment Trials.

PURPOSE: We compare results from regression discontinuity (RD) analysis to primary results of a randomized controlled trial (RCT) utilizing data from two contemporaneous RCTs for treatment of fungal corneal ulcers. METHODS: Patients were enrolled in the Mycotic Ulcer Treatment Trials I and II (MUTT I & MUTT II) based on baseline visual acuity: patients with acuity ≤ 20/400 (logMAR 1.3) enrolled in MUTT I, and >20/400 in MUTT II. MUTT I investigated the effect of topical natamycin versus voriconazole on best spectacle-corrected visual acuity. MUTT II investigated the effect of topical voriconazole plus placebo versus topical voriconazole plus oral voriconazole. We compared the RD estimate (natamycin arm of MUTT I [N = 162] versus placebo arm of MUTT II [N = 54]) to the RCT estimate from MUTT I (topical natamycin [N = 162] versus topical voriconazole [N = 161]). RESULTS: In the RD, patients receiving natamycin had mean improvement of 4-lines of visual acuity at 3 months (logMAR -0.39, 95% CI: -0.61, -0.17) compared to topical voriconazole plus placebo, and 2-lines in the RCT (logMAR -0.18, 95% CI: -0.30, -0.05) compared to topical voriconazole. CONCLUSIONS: The RD and RCT estimates were similar, although the RD design overestimated effects compared to the RCT.

Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa.

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 (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±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 .).

The Significance of Repeat Cultures in the Treatment of Severe Fungal Keratitis.

PURPOSE: To identify fungal keratitis patients who are at risk of a poor outcome and may benefit from closer follow-up or more aggressive treatment. DESIGN: Secondary analysis of randomized clinical trial data. METHODS: We compared the clinical outcomes of patients who had positive 6-day fungal cultures with those who did not, using backward stepwise regression with covariates for all baseline clinical characteristics. SUBJECTS: Patients presenting with a smear-positive filamentous fungal ulcer and visual acuity of 20/400 or worse, and who subsequently had a 6-day fungal culture performed at the Aravind Eye Care system (India), Lumbini Eye Hospital (Nepal), or Bharatpur Eye Hospital (Nepal). MAIN OUTCOME MEASURES: The primary outcome is rate of corneal perforation and/or the need for therapeutic penetrating keratoplasty. Secondary outcomes include 3-month best spectacle-corrected visual acuity (BSCVA), 3-month infiltrate and/or scar size, and rate of re-epithelialization. RESULTS: Patients who tested positive at their 6-day culture had twice the hazard of experiencing a corneal perforation or the need for therapeutic penetrating keratoplasty (P = .002) than those who tested negative, even after controlling for baseline ulcer characteristics. These patients also had on average 0.26 logMAR lines worse BSCVA at 3 months (P = .001). Culture positivity at day 6 was not a statistically significant predictor of 3-month infiltrate/scar-size (-0.24 mm1; P = .45) or time to re-epithelialization (hazard ratio = .81; P = .31). CONCLUSIONS: Here we identify a uniquely valuable clinical tool, day 6 culture results, for the treatment of severe fungal keratitis. Risk stratification based on repeat culture positivity is an objective way to assess response to medical therapy and identify patients who are at high risk of a poor clinical outcome. This establishes a new standard of care for severe fungal keratitis management.

Predictors of Corneal Perforation or Need for Therapeutic Keratoplasty in Severe Fungal Keratitis: A Secondary Analysis of the Mycotic Ulcer Treatment Trial II.

Importance: Identifying patients with infectious keratitis who are at risk of experiencing a poor outcome may be useful to allocate resources toward high-risk patients, particularly in resource-poor settings. Objective: To determine baseline patient and ulcer characteristics that predict a high risk of developing corneal perforation and/or the need to undergo therapeutic penetrating keratoplasty (TPK). Design, Setting, and Participants: This is a secondary analysis of Mycotic Ulcer Treatment Trial II, a multicenter, double-masked, placebo-controlled randomized clinical trial that enrolled 240 patients with smear-positive filamentous fungal corneal ulcers who enrolled between May 2010 and August 2015. Participants had a baseline visual acuity of 20/400 or worse and were randomized to receive oral voriconazole or a placebo (all participants received topical voriconazole, 1%). After 39 participants (16.3%) were enrolled, topical natamycin, 5%, was also added. Main Outcomes and Measures: The primary outcome of this secondary analysis was the rate of corneal perforation or the need to undergo TPK. Results: The mean (SD) age at enrollment was 49 (13) years, 104 participants (43.3%) were women, and all were of Southeast Asian descent. The presence of hypopyon at baseline indicated 2.28 times the odds of the patient developing corneal perforation and/or needing TPK (95% CI, 1.18-4.40; P = .01). Study participants whose infiltrate involved the posterior one-third had a 71.4% risk of developing corneal perforation and/or needing TPK. For each 1-mm increase in the geometric mean of the infiltrate, there was 1.37 (95% CI, 1.12-1.67; P = .002) increased odds of developing perforation and/or needing TPK. Other clinical features such as visual acuity, baseline culture positivity, type of filamentous fungal organism and duration of symptoms, and demographic characteristics, such as sex and occupation, were not significant predictors in the multivariable regression analysis. Conclusions and Relevance: These results suggest that risk stratification from baseline ulcer characteristics can identify those at highest risk for developing corneal perforation and/or needing TPK. Trial Registration: clinicaltrials.gov Identifier: NCT00996736.

Association Between Thyroid Disease and Uveitis: Results From the Pacific Ocular Inflammation Study.

Importance: Common pathophysiological mechanisms may be responsible for immune dysregulation in both thyroid disease and uveitis. Studies investigating a possible association are limited. Objective: To determine the association between thyroid disease and uveitis. Design, Setting, and Participants: A retrospective, population-based case-control study was conducted from January 1, 2006, to December 31, 2007, among 217 061 members of the Kaiser Permanente Hawaii health system during the study period. A clinical diagnosis of uveitis was determined through a query of the electronic medical record followed by individual medical record review for confirmation by a uveitis specialist. Thyroid disease was determined based on International Classification of Diseases, Ninth Revision, coding. Two control groups were chosen at a 4:1 ratio for comparison with patients with uveitis. A logistic regression analysis was performed with uveitis as the main outcome variable and thyroid disease as the main predictor variable, while adjusting for age, sex, race, smoking status, and history of autoimmune disease. Data analysis was conducted between 2014 and 2016. Main Outcomes and Measures: A diagnosis of thyroid disease among patients with uveitis and respective controls. Results: Of the 224 patients with uveitis (127 women and 97 men; mean [SD] age, 54.1 [17.8] years) identified during the study period, 29 (12.9%) had a diagnosis of thyroid disease, compared with 62 of 896 patients (6.9%) in the control group (P = .01) and 78 of 896 patients (8.7%) in the ophthalmology clinic control group (P = .06). Using the general Kaiser Permanente Hawaii population control group, patients who had thyroid disease had a 1.7-fold (95% CI, 1.03-2.80; P = .04) higher odds of having uveitis compared with patients who did not have thyroid disease when controlling for age, sex, race, smoking status, and autoimmune disease. A similar association was found using the ophthalmology clinic control group (odds ratio, 1.8; 95% CI, 1.1-2.9; P = .02) while adjusting for these factors. Conclusions and Relevance: These findings suggest that a history of thyroid disease has a weak to moderate association with uveitis. Similar autoimmune mechanisms could explain the pathogenesis of both conditions. If future studies corroborate these findings, they may have further clinical implications in the laboratory workup of uveitis.

Adjunctive Oral Voriconazole Treatment of Fusarium Keratitis: A Secondary Analysis From the Mycotic Ulcer Treatment Trial II.

Importance: Fusarium keratitis is common and often results in poor outcomes. No new treatments since natamycin have become available. Objective: To explore the role of adjuvant oral voriconazole on clinical outcomes in Fusarium keratitis. Design, Setting, and Participants: In this prespecified subgroup analysis of a multicenter, double-masked, placebo-controlled randomized clinical trial, 240 patients from the Aravind Eye Care System in India, the Lumbini Eye Hospital and Bharatpur Eye Hospital in Nepal, and the University of California, San Francisco, who had culture-positive fungal ulcer and baseline visual acuity of 20/400 or worse were randomized to receive oral voriconazole vs placebo. Enrollment started May 24, 2010, and the last patient study visit was November 23, 2015. All patients received topical voriconazole, 1%, and after the results of the Mycotic Ulcer Treatment Trial (MUTT) II became available, topical natamycin, 5%, was added for all patients. Data analysis was performed from September 2 to October 28, 2016. Main Outcomes and Measures: The primary outcome of the trial was the rate of corneal perforation or the need for therapeutic penetrating keratoplasty. Secondary outcomes included rate of reepithelialization, best spectacle-corrected visual acuity, and infiltrate or scar size at 3 months. Results: Of the 240 study participants, 72 (30.4%) were culture positive for Fusarium species (41 [56.9%] male and 31 [43.1%] female; median [interquartile range] age, 50 [45-57] years). Of these, 33 (45.8%) were randomized to oral voriconazole and 39 (54.2%) to placebo. Fusarium ulcers randomized to oral voriconazole had a 0.43-fold decreased hazard of perforation or therapeutic penetrating keratoplasty compared with placebo after controlling for baseline infiltrate depth (95% CI, 0.22-fold to 0.84-fold; P = .01). Multiple linear regression revealed a 1.89-mm decreased infiltrate and/or scar size at 3 weeks (95% CI, -2.69 to -1.09 mm; P < .001) and a 0.83-mm decreased infiltrate and/or scar size at 3 months after correcting for baseline values (95% CI, -1.33 to -0.32 mm; P = .001) in eyes randomized to oral voriconazole vs placebo. Eyes treated with oral voriconazole also had a mean 0.29 decreased logMAR (improved) (Snellen equivalent 20/40) visual acuity at 3 months after controlling for baseline visual acuity, although this finding was not statistically significant (95% CI, -0.57 to 0.002; P = .052). Conclusions and Relevance: Although MUTT II could not find a benefit for all corneal ulcers, Fusarium keratitis may benefit from the addition of oral voriconazole to topical natamycin, and physicians should consider prescribing oral voriconazole in these cases. Trial Registration: clinicaltrials.gov Identifier: NCT00996736.

The Utility of Repeat Culture in Fungal Corneal Ulcer Management: A Secondary Analysis of the MUTT-I Randomized Clinical Trial.

PURPOSE: To determine whether patients who had a positive repeated culture was predictive of worse clinical outcome than those who achieved microbiological cure at 6 days in the Mycotic Ulcer Treatment Trial I (MUTT-I). DESIGN: Secondary analysis from a multicenter, double-masked, randomized clinical trial. METHODS: setting: Multiple hospital sites of the Aravind Eye Care System, India. STUDY POPULATION: Patients with culture-positive filamentous fungal ulcers and visual acuity of 20/40 to 20/400 reexamined 6 days after initiation of treatment. INTERVENTION: Corneal scraping and cultures were obtained from study participants at day 6 after enrollment. MAIN OUTCOME MEASURES: We assessed 3-month best spectacle-corrected visual acuity (BSCVA), 3-month infiltrate/scar size, corneal perforation, and re-epithelialization rates stratified by culture positivity at day 6. RESULTS: Of the 323 patients with smear-positive ulcers enrolled in MUTT-I, 299 (92.6%) were scraped and cultured 6 days after enrollment. Repeat culture positivity was 31% (92/299). Among patients who tested positive at enrollment, those with positive 6-day cultures had significantly worse 3-month BSCVA (0.39 logMAR; 95% confidence interval [CI]: 0.24-0.44; P < .001), had larger 3-month scar size (0.39 mm; 95% CI: 0.06-0.73; P = .02), were more likely to perforate or require therapeutic penetrating keratoplasty (odds ratio: 6.27; 95% CI: 2.73-14.40; P < .001), and were slower to re-epithelialize (hazard ratio: 0.33; 95% CI: 0.21-0.50; P < .001) than those with a negative 6-day culture result. CONCLUSIONS: Early microbiological cure on culture is a predictor of clinical response to treatment.

Gut Microbial Diversity in Antibiotic-Naive Children After Systemic Antibiotic Exposure: A Randomized Controlled Trial.

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's α-diversity index), with secondary outcomes of ß and γ Simpson's and Shannon'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'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'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'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 ß-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.

Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): A Randomized Clinical Trial.

Objective: To compare oral voriconazole with placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis. Design, Setting, and Participants: The Mycotic Ulcer Treatment Trial II (MUTT II), a multicenter, double-masked, placebo-controlled, randomized clinical trial, was conducted in India and Nepal, with 2133 individuals screened for inclusion. Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 (logMAR 1.3) or worse were randomized to receive oral voriconazole vs oral placebo; all participants received topical antifungal eyedrops. The study was conducted from May 24, 2010, to November 23, 2015. All trial end points were analyzed on an intent-to-treat basis. Interventions: Study participants were randomized to receive oral voriconazole vs oral placebo; a voriconazole loading dose of 400 mg was administered twice daily for 24 hours, followed by a maintenance dose of 200 mg twice daily for 20 days, with dosing altered to weight based during the trial. All participants received topical voriconazole, 1%, and natamycin, 5%. Main Outcomes and Measures: The primary outcome of the trial was rate of corneal perforation or the need for therapeutic penetrating keratoplasty (TPK) within 3 months. Secondary outcomes included microbiologic cure at 6 days, rate of re-epithelialization, best-corrected visual acuity and infiltrate and/or scar size at 3 weeks and 3 months, and complication rates associated with voriconazole use. Results: A total of 2133 patients in India and Nepal with smear-positive ulcers were screened; of the 787 who were eligible, 240 (30.5%) were enrolled. Of the 119 patients (49.6%) in the oral voriconazole treatment group, 65 were male (54.6%), and the median age was 54 years (interquartile range, 42-62 years). Overall, no difference in the rate of corneal perforation or the need for TPK was determined for oral voriconazole vs placebo (hazard ratio, 0.82; 95% CI, 0.57-1.18; P = .29). In prespecified subgroup analyses comparing treatment effects among organism subgroups, there was some suggestion that Fusarium species might have a decreased rate of perforation or TPK in the oral voriconazole-treated arm; however, this was not a statistically significant finding after Holms-Sidák correction for multiple comparisons (effect coefficient, 0.49; 95% CI, 0.26-0.92; P = .03). Patients receiving oral voriconazole experienced a total of 58 adverse events (48.7%) compared with 28 adverse events (23.1%) in the placebo group (P < .001 after Holms-Sidák correction for multiple comparisons). Conclusions and Relevance: There appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. All patients in this study were enrolled in India and Nepal; therefore, it is possible that organisms in this region may exhibit characteristics different from those in other regions of the world. Trial Registration: clinicaltrials.gov Identifier: NCT00996736.

Low Back Pain Response to Pelvic Tilt Position: An Observational Study of Chiropractic Patients.

OBJECTIVE: The aim of this study was to look for differences between patients with an increased pain response as compared with those with a decreased pain response. METHODS: Data were collected from consecutive new patients with lumbar or lumbopelvic pain in a chiropractic clinic. A pelvic tilt exercise was included in the initial examination, and pain response was noted. Analysis was made of pain and disability severity, as well as symptom location, chronicity, and other characteristics, before and after a course of chiropractic care. RESULTS: Patients with an increased pain response to pelvic tilt (n = 12) had higher levels of pain and disability at baseline than patients without (n = 34). There were no between-group differences in other aspects of their complaints; in age, sex, or body mass; or in the types of care they received (eg, manipulation, stretching, exercise instruction). On the average, both groups of patients showed improvement with chiropractic care, and there was no detectable difference in improvement between groups. CONCLUSIONS: This study found that patients experiencing pain in response to a pelvic tilt maneuver may have a poorer precare status than patients with a decreased pain response.