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Portable perimetric testing could be useful for community-based glaucoma screening programs. Frequency doubling technology (FDT) and the Moorfields motion displacement test (MDT) are portable perimeters which have shown promise as potential screening tools for glaucoma. This study's goal was to determine the diagnostic accuracy of FDT and MDT for visual field defects and glaucoma.Prospective, cross-sectional, diagnostic accuracy study.A consecutive series of patients aged ≥50 years who presented to a glaucoma clinic in South India and had never undergone Humphrey field analyzer (HFA) visual field testing in the past.Participants underwent 24-2 SITA Standard HFA perimetry, FDT perimetry, MDT perimetry, and iPad perimetry using visualFields Easy in random order. Ophthalmologist grades of HFA and optic nerve head photographs were used as the reference standards for glaucoma and field defect presence. Receiver operating characteristic curves were constructed to assess diagnostic accuracy of various parameters for each test.Sensitivity, specificity, area under the receiver operating characteristic curve (AUROC) RESULTS: 292 eyes from 173 participants were included, with 112 eyes classified as moderate or worse glaucoma. For moderate or worse glaucoma detection, the best parameter on FDT was mean deviation (MD) (AUROC 0.84, 95% CI 0.79 to 0.89), and the best parameter on MDT was global probability of true damage (GPTD) (AUROC 0.87, 95% CI 0.82 to 0.91). When specificity was set to 90%, the sensitivity for detection of moderate or worse glaucoma was 55% (95% CI 39 to 68%) for FDT MD and 62% (95% CI 52 to 71%) for MDT GPTD.FDT and MDT perimetry had fair diagnostic accuracy for glaucoma detection when administered to naïve test-takers in this South Indian population. Although not appropriate for use as a sole glaucoma screening test, these perimetric tests may be useful as ancillary tests.

Corneal ulcers are a common cause of blindness in low-income and middle-income countries, usually resulting from traumatic corneal abrasions during agricultural work. Antimicrobial prophylaxis of corneal abrasions can help prevent corneal ulcers, but delays in the initiation of therapy are frequent. We aimed to assess whether a community-based programme for corneal ulcer prevention would reduce the incidence of corneal ulceration.A cluster-randomised trial was performed in village development committees (VDCs) in Nepal. VDCs in the catchment area of Bharatpur Eye Hospital, Nepal with less than 15 000 people were eligible for inclusion. We randomly assigned (1:1) VDCs to either an intervention group or a control group. In the intervention VDCs, existing female community health volunteers (FCHVs) were trained to diagnose corneal abrasions and provide a 3-day course of ophthalmic antimicrobials to their patients. In the control VDCs, FCHVs did not provide this intervention. Participants were not masked given the nature of the intervention. Both groups were followed up for 3 years for photographic evidence of corneal ulceration. The primary outcome was the incidence of corneal ulceration, determined by masked assessment of corneal photographs. The analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT01969786.We assessed 112 VDCs, of which 24 were enrolled. The study was performed between Feb 4, 2014, and Oct 20, 2017. 12 VDCs were randomly assigned to the intervention group and 12 to the control group. 252 539 individuals were included in the study (130 579 in the intervention group and 121 960 in the control group). FCHVs diagnosed and provided antimicrobials for 4777 corneal abrasions. The census identified 289 corneal ulcers among 246 893 person-years in the intervention group (incidence 1·21 cases [95% CI 0·85-1·74] per 1000 person-years) and 262 corneal ulcers among 239 170 person-years in the control group (incidence 1·18 cases [0·82-1·70] per 1000 person-years; incidence rate ratio 1·03 [95% CI 0·63-1·67]; p=0·93). Medication allergy was self-reported in 0·2% of participants.We did not detect a reduction in the incidence of corneal ulceration during the first 3 years of a community-based corneal ulcer prevention programme. Further study might be warranted in more rural areas where basic eye care facilities are not available.National Eye Institute.

Observational studies have linked early-life antibiotic exposure to increased risk of obesity in children in high income settings. We evaluated whether neonatal antibiotic exposure led to changes in infant growth at 6 months of age in Burkina Faso. Neonates aged 8 to 27 days of age who weighed at least 2,500 g at the time of enrollment were randomized in a 1:1 fashion to a single oral 20-mg/kg dose of azithromycin or equivalent volume of placebo from April 2019 through December 2020. Weight, length, and mid-upper-arm circumference (MUAC) were measured at baseline and 6 months of age. Growth outcomes, including weight gain in grams per day, length change in millimeters per day, and changes in weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ), and MUAC were compared among neonates randomized to azithromycin compared with placebo. Among 21,832 neonates enrolled in the trial, median age at enrollment was 11 days, and 50% were female. We found no evidence of a difference in weight gain (mean difference −0.009 g/day, 95% confidence interval [CI]: −0.16 to 0.14, P = 0.90), length change (mean difference 0.003 mm/day, 95% CI: −0.002 to 0.007, P = 0.23), or WAZ (mean difference −0.005 SD, 95% CI: −0.03 to 0.02, P = 0.72), WLZ (mean difference −0.01 SD, 95% CI: −0.05 to 0.02, P = 0.39), LAZ (mean difference 0.01, 95% CI: −0.02 to 0.04, P = 0.47), or MUAC (mean difference 0.01 cm, 95% CI: −0.02 to 0.04, P = 0.49). These results do not suggest that azithromycin has growth-promoting properties in infants when administered during the neonatal period. Trial registration: ClinicalTrials.gov NCT03682653.

Purpose To determine the diagnostic accuracy of potential screening tests for moderate to advanced glaucoma. Design Prospective diagnostic test accuracy study. Participants The study enrolled a consecutive series of patients aged ≥50 years who presented to a glaucoma clinic in South India without ever having received automated visual field testing. Methods All participants underwent 8 index tests: OCT of the peripapillary retinal nerve fiber layer, optic disc photography, Moorfield’s Motion Displacement Test (MDT), frequency doubling technique perimetry, noncontact tonometry, pneumatonometry, presenting visual acuity, and best-corrected visual acuity. Participants also underwent stereoscopic photographs and Humphrey visual fields, which were used by 2 ophthalmologists to arrive at the reference standard diagnosis of moderate to advanced glaucoma. Main Outcome Measures Sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio. Results A total of 217 people were enrolled; 321 eyes from 180 participants had all tests performed. Of these, 127 eyes (40%) were classified as having moderate to advanced glaucoma. Among the 8 tests, OCT best optimized sensitivity (84%, 95% confidence interval [CI], 76–90) and specificity (75%, 95% CI, 68–81). Moorfield’s Motion Displacement Test was the best perimetric test, with a sensitivity of 91% (95% CI, 85–96) and specificity of 53% (95% CI, 44–61). Pressure and vision tests were not sensitive (e.g., sensitivity of 16%, 95% CI, 9–23 for noncontact tonometry and 23%, 95% CI, 15–31 for best-corrected visual acuity). Moorfield’s Motion Displacement Test identified 16 of 127 eyes (13%) with glaucoma that were not captured by OCT, but also had false-positive results in 65 of 194 eyes (34%) without glaucoma that OCT correctly classified as negative. Conclusions OCT had moderate sensitivity and fair specificity for diagnosing moderate to advanced glaucoma and should be prioritized during an initial assessment for glaucoma.

The purpose of this study was to investigate the social determinants of health for keratoconus.In this retrospective cohort study of patients with keratoconus, the electronic health record was reviewed for keratometry, treatments received, clinical comorbidities, and social characteristics. Outcomes included severe keratoconus at presentation (steep keratometry ≥52 diopters), disease progression (≥0.75 diopters increase from the first to the most recent clinical visit), and corneal transplantation. Logistic regression was used to evaluate factors associated with severity at presentation and corneal transplantation. Cox proportional hazards modeling was used to evaluate progression.A total of 1038 patients with keratoconus were identified, 725 (70%) of whom had baseline imaging. Compared with commercially insured patients, Medicaid recipients were more likely to have severe keratoconus, independent of social and clinical confounders [odds ratio (OR) 1.94, 95% confidence interval (CI), 1.12-3.35, P = 0.017]. Male sex was independently associated with progression (hazard ratio = 1.38, 95% CI, 1.03-1.84, P = 0.030). Medicare and Medicaid recipients were more likely to require transplantation compared with commercially insured patients (OR 2.71, 95% CI, 1.65-4.46, P0.001 and OR 1.74, 95% CI, 1.08-2.80, P = 0.022, respectively). Other social determinants of health, including non-White race/ethnicity, limited English proficiency, and unemployment, were associated with the outcomes only in univariate analysis. Obstructive sleep apnea, atopy, body mass index, and tobacco use were not associated with any outcome.Socioeconomic factors were more consistent predictors of keratoconus severity and corneal transplantation compared with clinical factors that have received relatively greater attention in the keratoconus literature.

Infant undernutrition is thought to contribute to growth failure and mortality. We evaluated the patterns in underweight in a population-based sample of children aged 1–11 months in rural northwestern Burkina Faso. Data were collected during the baseline assessment of a community-randomized trial evaluating mass azithromycin distribution in Nouna District, Burkina Faso. A door-to-door census was undertaken for all households in all communities. Infants aged 1–11 months were weighed for weight-based dosing in the trial and their weights were used to calculate weight-for-age Z-scores (WAZ). Underweight was defined as WAZ ≤ 2. We evaluated the age patterns in WAZ and underweight by demographic, seasonal, and geographic characteristics. Of 7,109 infants, 6,077 had accurate weight and global positioning system (GPS) coordinate data (85.5%). Infants were a median of 6 months old (interquartile range [IQR] 3–8) and 48.4% were female. Mean WAZ was −0.68 (SD 1.6) and 19.0% were underweight. The WAZ decreased with increasing age, and the prevalence of underweight increased from 2.5% among 1-month-olds to 27.6% among 11-month-olds. Underweight was more common among boys than girls (22.1% among boys versus 15.6% among girls). Improved latrine use by the household was associated with increased WAZ, and this effect was stronger in male compared with female infants. Given the large burden of underweight among infants, interventions addressing undernutrition should specifically include infants.

Glaucoma drainage devices (GDD) are increasingly utilized in the management of childhood glaucoma. This systematic review and meta-analysis assesses the efficacy of first-time Ahmed or Baerveldt implantation in children. PubMed, Embase, and Cochrane Library were searched for relevant English-language, peer-reviewed literature. Postoperative outcomes were pooled using random effects regression models with restricted maximum likelihood estimation. Thirty-two studies (1221 eyes, 885 children) were included. Mean ± standard deviation preoperative IOP was 31.8±3.4 mmHg. Pooled mean IOP at 12 and 24 months postoperatively were 16.5 mmHg (95% CI 15.5–17.6) and 17.6 mmHg (95% CI 16.4–18.7), respectively. Pooled proportions of success were 0.87 (95% CI 0.83–0.91) at 12 months, 0.77 (95% CI 0.71–0.83) at 24 months, 0.54 (95% CI 0.44–0.65) at 48 months, 0.60 (95% CI 0.48–0.71) at 60 months, and 0.37 (95% CI 0.32–0.42) at 120 months. There were no differences in proportion of success at 12 and 24 months among eyes that received Ahmed and Baerveldt tube shunts, nor between eyes with primary glaucoma, glaucoma following cataract surgery or other secondary glaucoma. Our findings show that Ahmed and Baerveldt shunts substantially reduced IOP for at least 24 months in childhood glaucoma, with similar findings among device types and glaucoma etiologies.

PurposeTo determine whether exposure to unclean cooking fuels was associated with subsequent cataract progression as reported in previous cross-sectional studies.DesignProspective cohort study.MethodsThis is a secondary observational analysis of the community-based Antioxidants in Prevention of Cataracts trial (ClinicalTrials.gov ID NCT01664819). The exposure of interest was cooking fuel type, measured at baseline. Main outcome measures were baseline cataract severity and self-reported cataract surgery at a 15-year visit.ResultsBaseline and 15-year follow-up data were available for 798 and 579 participants, respectively. Wood or kerosene was used by 711 of 798 (89.1%) baseline participants, including 539 of 579 (93.1%) participants with complete follow-up. Cooking fuel type was not associated with cataract severity at baseline (P=.443). Of 8334 person-years of follow-up, 90 cataract surgeries were observed over 15 years (1.08 surgeries per 100 person-years; 95% CI=0.87-1.32). Use of wood or kerosene was not associated with 15-year incidence of cataract surgery relative to use of propane (adjusted P=.154). Cataract surgery was more common in older individuals (HR=1.1 per year, 95% CI=1.1-1.2, P < .001), those with baseline myopia (HR=2.1, 95% CI=1.2-3.5, P=.009), and women (HR=3.5, 95% CI=1.2-10.1, P=.019).ConclusionsThis study found no association between unclean cooking fuels and cataract progression over a 15-year period. No other modifiable risk factors were associated with incident self-reported cataract surgery.

Risk of death from undernutrition is thought to be higher in younger than in older children, but evidence is mixed. Research also demonstrates sex differences whereby boys have a higher prevalence of undernutrition than girls. This analysis described mortality risk associated with anthropometric deficits (wasting, underweight and stunting) in children 6–59 months by age and sex. We categorised children into younger (6–23 months) and older (24–59 months) age groups. Age and sex variations in near-term (within 6 months) mortality risk, associated with individual anthropometric deficits were assessed in a secondary analysis of multi-country cohort data. A random effects meta-analysis was performed. Data from seven low-or-middle-income-countries collected between 1977 and 2013 were analysed. One thousand twenty deaths were recorded for children with anthropometric deficits. Pooled meta-analysis estimates showed no differences by age in absolute mortality risk for wasting (RR 1.08, p = 0.826 for MUAC < 125 mm; RR 1.35, p = 0.272 for WHZ < −2). For underweight and stunting, absolute risk of death was higher in younger (RR 2.57, p < 0.001) compared with older children (RR 2.83, p < 0.001). For all deficits, there were no differences in mortality risk for girls compared with boys. There were no differences in the risk of mortality between younger and older wasted children, supporting continued inclusion of all children under-five in wasting treatment programmes. The risk of mortality associated with underweight and stunting was higher among younger children, suggesting that prevention programmes might be justified in focusing on younger children where resources are limited. There were no sex differences by age in mortality risk for all deficits.

International audience; HARMONI is the first light, adaptive optics assisted, integral field spectrograph for the European Southern Observatory’s Extremely Large Telescope (ELT). A work-horse instrument, it provides the ELT’s diffraction limited spectroscopic capability across the near-infrared wavelength range. HARMONI will exploit the ELT’s unique combination of exquisite spatial resolution and enormous collecting area, enabling transformational science. The design of the instrument is being finalized, and the plans for assembly, integration and testing are being detailed. We present an overview of the instrument’s capabilities from a user perspective, and provide a summary of the instrument’s design. We also include recent changes to the project, both technical and programmatic, that have resulted from red-flag actions. Finally, we outline some of the simulated HARMONI observations currently being analyzed.

Because transmission of ocular strains of Chlamydia trachomatis is greatest among preschool-aged children, limiting azithromycin distributions to this age group may conserve resources and result in less antimicrobial resistance, which is a potential advantage in areas with hypoendemic trachoma and limited resources.To determine the efficacy of mass azithromycin distributions to preschool-aged children as a strategy for trachoma elimination in areas with hypoendemic disease.In this cluster randomized clinical trial performed from November 23, 2014, until July 31, 2017, thirty rural communities in Niger were randomized at a 1:1 ratio to biannual mass distributions of either azithromycin or placebo to children aged 1 to 59 months. Participants and study personnel were masked to treatment allocation. Data analyses for trachoma outcomes were performed from October 19, 2021, through June 10, 2022.Every 6 months, a single dose of either oral azithromycin (20 mg/kg using height-based approximation for children who could stand or weight calculation for small children) or oral placebo was provided to all children aged 1 to 59 months.Trachoma was a prespecified outcome of the trial, assessed as the community-level prevalence of trachomatous inflammation-follicular and trachomatous inflammation-intense through masked grading of conjunctival photographs from a random sample of 40 children per community each year during the 2-year study period. A secondary outcome was the seroprevalence of antibodies to C trachomatis antigens.At baseline, 4726 children in 30 communities were included; 1695 children were enrolled in 15 azithromycin communities and 3031 children were enrolled in 15 placebo communities (mean [SD] proportions of boys, 51.8% [4.7%] vs 52.0% [4.2%]; mean [SD] age, 30.8 [2.8] vs 30.6 [2.6] months). The mean coverage of study drug for the 4 treatments was 79% (95% CI, 75%-83%) in the azithromycin group and 82% (95% CI, 79%-85%) in the placebo group. The mean prevalence of trachomatous inflammation-follicular at baseline was 1.9% (95% CI, 0.5%-3.5%) in the azithromycin group and 0.9% (95% CI, 0-1.9%) in the placebo group. At 24 months, trachomatous inflammation-follicular prevalence was 0.2% (95% CI, 0-0.5%) in the azithromycin group and 0.8% (95% CI, 0.2%-1.6%) in the placebo group (incidence rate ratio adjusted for baseline: 0.18 [95% CI, 0.01-1.20]; permutation P = .07).The findings of this trial do not show that biannual mass azithromycin distributions to preschool-aged children were more effective than placebo, although the underlying prevalence of trachoma was low. The sustained absence of trachoma even in the placebo group suggests that trachoma may have been eliminated as a public health problem in this part of Niger.ClinicalTrials.gov Identifier: NCT02048007.

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’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.

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).

Objective To determine the relationship between visual impairment and other disabilities in a developing country. Methods In this cross-sectional ancillary study, all individuals 50 years and older in 18 communities in the Chitwan region of Nepal were administered visual acuity screening and the Washington Group Short Set (WGSS) of questions on disability. The WGSS elicits a 4-level response for six disability domains: vision, hearing, walking/climbing, memory/concentration, washing/dressing, and communication. The association between visual impairment and disability was assessed with age- and sex-adjusted logistic regression models. Results Overall, 4719 of 4726 individuals successfully completed visual acuity and disability screening. Median age of participants was 61 years (interquartile range: 55-69 years), and 2449 (51.9%) were female. Participants with vision worse than 6/60 in the better-seeing eye were significantly more likely to be classified as having a disability in vision (OR 18.4, 95% CI 9.9-33.5), walking (OR 5.3, 95% CI 2.9-9.1), washing (OR 9.4, 95% CI 4.0-21.1), and communication (OR 5.0, 95% CI 1.7-13.0), but not in hearing (OR 0.6, 95% CI 0.006-2.2) or memory (OR 2.2, 95% CI 0.7-5.1). Conclusions Visually impaired participants were more likely to self-report disabilities, though causality could not be ascertained. Public health programs designed to reduce visual impairment could use the WGSS to determine unintended benefits of their interventions.

Previous studies have used subjective assessments to implicate darker skin color as a risk factor for glaucoma. This study used objective measurements to determine whether skin melanin is a risk fa...

PurposeTo determine whether a community health worker (CHW) program increases referrals to local eye care providers and ultimately reduces the incidence of corneal ulcers.DesignCluster-randomized trial performed from 2014 to 2017 in rural South India.MethodsThis was a community-based study that included all inhabitants of 42 rural South Indian communities. CHWs were trained to diagnose corneal abrasions and assist participants in seeking care at a local vision center. Given the nature of the intervention, the trial was not masked. The main outcome measure was incident corneal ulcer, defined as an active infiltrate or evidence of a new opacity, as assessed by means of penlight examination during an annual door-to-door census.ResultsTwenty-one study clusters were randomized to the CHW intervention and 21 to no intervention. Vision centers diagnosed 195 corneal abrasions from the intervention clusters during the 2-year study (rate, 223 per 100,000 person-years; 95% CI, 28-1743) and 62 from the control clusters (rate, 62 per 100,000 person-years; 95% CI, 8-496; incidence rate ratio, 3.57; 95% CI, 2.01-6.35; P < .001). The estimated incidence of corneal ulceration during the study period was 60 per 100,000 person-years (95% CI, 25-141) in the intervention group and 32 per 100,000 person-years (95% CI, 13-80) in the control group (incidence rate ratio, 1.86; 95% CI, 0.5-6.4; P=.32).ConclusionsA CHW program resulted in 3.5 times more referrals to local eye care providers for corneal abrasions, but no difference could be detected in the incidence of corneal ulceration. CHW programs provide a mechanism for increasing referrals to eye hospitals.Trial registrationClinicalTrials.gov ID: NCT02284698.

BackgroundMass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear.MethodsWe investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants' gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months.ResultsOver the entire 48-month period, the mean (±SD) coverage was 86.6±12% in the villages that received placebo and 83.2±16.4% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of nonmacrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa.ConclusionsAmong villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02047981.).

Mid-upper arm circumference (MUAC)

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.

The Cassegrain U-Band Efficient Spectrograph (CUBES) is a high-efficiency spectrograph designed for observations from 305 to 400nm. It will be integrated at a Cassegrain focus of the Very Large Telescope (VLT). The image slicer technology is applied to reformat the field of view reducing the spectrograph entrance slit etendue and minimising the spectrograph volume and weight without slit losses. Two image slicers will provide CUBES with two spectral resolving powers: R≥20,000 for high resolution (HR) and R≥5,000 for low resolution (LR). Both image slicers are composed of two arrays of six spherical mirrors. For the HR mode, a rectangular field of view of 1.5arcsec by 10arcsec is reorganised into a slit of 0.19mm × 88mm; for the LR mode, a field of view of 6arcsec by 10arcsec is reformatted into a slit of 0.77mm × 88mm, with slicer mirrors of width 0.5mm and 2mm, respectively. CUBES is currently in the Preliminary Design Phase (Phase B). This communication presents the Conceptual (Phase A) design and the main performance for the HR and LR image slicers addressing the following technological challenges: compact layout with the minimum number of optical components to optimise throughput, near diffraction limited optical quality, telecentric design with overlapped exit pupils for all slices of the field of view, distribution of the slicer mirrors to reduce shadows and selection of the best substrate for the very short wavelengths at which CUBES will operate.

Childhood wasting and stunting affect large numbers of children globally. Both are important risk factors for illness and death yet, despite the fact that these conditions can share common risk factors and are often seen in the same child, they are commonly portrayed as relatively distinct manifestations of undernutrition. In 2014, the Wasting and Stunting project was launched by the Emergency Nutrition Network. Its aim was to better understand the complex relationship and associations between wasting and stunting and examine whether current separations that were apparent in approaches to policy, financing, and programs were justified or useful. Based on the project's work, this article aims to bring a wasting and stunting lens to how research is designed and financed in order for the nutrition community to better understand, prevent, and treat child undernutrition. Discussion of lessons learnt focuses on the synergy and temporal relationships between children's weight loss and linear growth faltering, the proximal and distal factors that drive diverse forms of undernutrition, and identifying and targeting people most at risk. Supporting progress in all these areas requires research collaborations across interest groups that highlight the value of research that moves beyond a focus on single forms of undernutrition, and ensures that there is equal attention given to wasting as to other forms of malnutrition, wherever it is present. publishedVersion

Author(s): Arzika, Ahmed M; Maliki, Ramatou; Abdou, Amza; Mankara, Alio K; Harouna, Abdoul N; Cook, Catherine; Hinterwirth, Armin; Worden, Lee; Zhong, Lina; Chen, Cindi; Ruder, Kevin; Zhou, Zhaoxia; Lebas, Elodie; O'Brien, Kieran S; Oldenburg, Catherine E; Le, Victoria; Arnold, Benjamin F; Porco, Travis C; Keenan, Jeremy D; Lietman, Thomas M; Doan, Thuy | Abstract: We evaluated the gut resistome of children from communities treated with 10 twice-yearly azithromycin distributions. Although the macrolide resistance remained higher in the azithromycin arm, the selection of non-macrolide resistance observed at earlier time points did not persist. Longitudinal resistance monitoring should be a critical component of mass distribution programs.Clinical trials registrationNCT02047981.

Summary Background Mass drug administration of azithromycin to children in sub-Saharan Africa has been shown to improve survival in high-mortality settings. The period after hospital discharge is a time of elevated risk unaddressed by current interventions and might provide an opportunity for targeting empirical azithromycin administration. We aimed to assess the efficacy of azithromycin administered at hospital discharge on risk of death and rehospitalisation in Kenyan children younger than 5 years. Methods In this double-blind, placebo-controlled randomised trial, children were randomly assigned (1:1) to receive a 5-day course of azithromycin (oral suspension 10 mg/kg on day 1, followed by 5mg/kg per day on days 2–5) or identically appearing and tasting placebo at discharge from four hospitals in western Kenya. Children were eligible if they were aged 1–59 months at hospital discharge, weighed at least 2 kg, and had been admitted to hospital for any medical reason other than trauma, poisoning, or congenital anomaly. The primary outcome was death or rehospitalisation in the subsequent 6-month period in a modified intention-to-treat population, compared by randomisation group with Cox proportional hazards regression and Kaplan-Meier. Azithromycin resistance in Escherichia coli isolates from a random subset of children was compared by randomisation group with generalised estimating equations. This trial is registered with ClinicalTrials.gov, NCT02414399. Findings Between June 28, 2016, and Nov 4, 2019, 1400 children were enrolled in the trial at discharge from hospital, with 703 (50·2%) randomly assigned to azithromycin and 697 (49·8%) to placebo. Among the 1398 children included in the modified intention-to-treat analysis (702 in the azithromycin group and 696 in the placebo group), the incidence of death or rehospitalisation was 20·4 per 100 child-years in the azithromycin group and 22·5 per 100 child-years in the placebo group (adjusted hazard ratio 0·91, 95·5% CI 0·64–1·29, p=0–58). Azithromycin resistance was common in commensal E coli isolates from enrolled children before randomisation (37·7% of 406 isolates) despite only 3·7% of children having received a macrolide antibiotic during the hospitalisation. Azithromycin resistance was slightly higher at 3 months after randomisation in the azithromycin group (26·9%) than in the placebo group (19·1%; adjusted prevalence ratio 1·41, 95% CI 0·95–2·09, p=0·088), with no difference observed at 6 months (1·17, 0·78–1·76, p=0·44). Interpretation We did not observe a significant benefit of a 5-day course of azithromycin delivered to children younger than 5 years at hospital discharge despite the overall high risk of mortality and rehospitalisation. These findings highlight the need for more research into mechanisms and interventions for prevention of morbidity and mortality in the post-discharge period. Funding Eunice Kennedy Shriver National Institute of Child Health & Human Development.

Background/aimsWe aimed to examine risk factors for corneal ulcer in a rural and peri-urban setting in Nepal.MethodsThis population-based matched case–control study was nested in a cluster randomised trial in 24 village development committees in Nepal. Incidence density sampling was used to match incident corneal opacity cases to controls, matching on time of opacity, age, sex and location. Cases and controls were invited to participate in a survey of risk factors for corneal ulcer. Risk factors were evaluated using conditional logistic regression to account for matching.ResultsOf the 540 participants with incident opacities identified in the trial, 433 were willing to participate in this substudy and matched to a control. Compared with controls, cases had lower odds of having any education vs no education (adjusted OR, aOR 0.60, 95% CI 0.39 to 0.94), working in non-manual labour occupations vs manual labour occupations (aOR 0.64, 95% CI 0.42 to 0.95) and preferring medical shops for ocular trauma versus eye care system centres (aOR 0.58, 95% CI 0.37 to 0.92). Cases had higher odds of protective goggle use versus no protection (aOR 3.8, 95% CI 1.3 to 11.0) and having an ocular injury vs none (aOR 7.7, 95% CI 4.3 to 13.6) compared with controls.ConclusionWe found ocular injury, manual labour and lower education to be strongly associated with the development of corneal ulcer. Given the persistent burden of corneal blindness in this area, prevention efforts could target efforts to increase access to care in areas where these factors are common.

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

To determine the diagnostic accuracy of potential screening tests for moderate to advanced glaucoma.Prospective diagnostic test accuracy study.The study enrolled a consecutive series of patients aged ≥50 years who presented to a glaucoma clinic in South India without ever having received automated visual field testing.All participants underwent 8 index tests: OCT of the peripapillary retinal nerve fiber layer, optic disc photography, Moorfield's Motion Displacement Test (MDT), frequency doubling technique perimetry, noncontact tonometry, pneumatonometry, presenting visual acuity, and best-corrected visual acuity. Participants also underwent stereoscopic photographs and Humphrey visual fields, which were used by 2 ophthalmologists to arrive at the reference standard diagnosis of moderate to advanced glaucoma.Sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio.A total of 217 people were enrolled; 321 eyes from 180 participants had all tests performed. Of these, 127 eyes (40%) were classified as having moderate to advanced glaucoma. Among the 8 tests, OCT best optimized sensitivity (84%, 95% confidence interval [CI], 76-90) and specificity (75%, 95% CI, 68-81). Moorfield's Motion Displacement Test was the best perimetric test, with a sensitivity of 91% (95% CI, 85-96) and specificity of 53% (95% CI, 44-61). Pressure and vision tests were not sensitive (e.g., sensitivity of 16%, 95% CI, 9-23 for noncontact tonometry and 23%, 95% CI, 15-31 for best-corrected visual acuity). Moorfield's Motion Displacement Test identified 16 of 127 eyes (13%) with glaucoma that were not captured by OCT, but also had false-positive results in 65 of 194 eyes (34%) without glaucoma that OCT correctly classified as negative.OCT had moderate sensitivity and fair specificity for diagnosing moderate to advanced glaucoma and should be prioritized during an initial assessment for glaucoma.

IntroductionGiven the potential for asymptomatic infection in children with uncomplicated severe acute malnutrition (SAM), the World Health Organization recommends a broad-spectrum antibiotic like amoxicillin. Azithromycin is a promising alternative to amoxicillin as it can be administered as a single dose and has efficacy against several pathogens involved in the burden of infectious disease and mortality in this population. In this pilot study, we aimed to establish the feasibility of a larger randomized controlled trial and to provide preliminary evidence comparing the effect of azithromycin to amoxicillin on weight gain in children with uncomplicated SAM.MethodsThis pilot randomized trial enrolled children 6-59 months old with uncomplicated SAM at 6 healthcare centers in Burkina Faso. Participants were randomized to a single dose of azithromycin or a 7-day course of amoxicillin. All participants received ready-to-use therapeutic food and were followed weekly until nutritional recovery and again at 8 weeks. The primary feasibility outcomes included enrollment potential, refusals, and loss to follow-up. The primary clinical outcome was weight gain (g/kg/day) over the 8-week period. Outcome assessors were masked.ResultsBetween June and October 2020, 312 children were screened, 301 were enrolled with 0 refusals, and 282 (93.6%) completed the 8-week visit. Average weight gain was 2.5 g/kg/day (SD 2.0) in the azithromycin group and 2.6 (SD) 1.7) in the amoxicillin group (Mean Difference - 0.1, 95% CI -0.5 to 0.3, P = 0.63). Fewer adverse events were reported in the azithromycin group (Risk Ratio 0.50, 95% CI 0.31 to 0.82, P = 0.006).ConclusionsNo differences were found in weight gain between groups. Given the ability to administer a single dose and the potential for fewer adverse events, azithromycin may be an alternative to amoxicillin for uncomplicated SAM. With strong enrollment and follow-up, a larger trial in this setting is feasible.

Biannual mass azithromycin distribution to children younger than 5 years has been shown to reduce all-cause mortality in sub-Saharan Africa. Antibiotic-sparing approaches to azithromycin distribution, such as targeting to younger children who are at higher risk of mortality, are being considered by policymakers. We evaluated the absolute number of deaths averted in the Macrolides Oraux pour Réduire le Décès avec un Oeil sur la Résistance study in three age-groups: 1–5 months, 1–11 months, and 1–59 months. The number of deaths averted decreased from 729 (95% CI 492 to 966) in children aged 1–59 months to 297 (95% CI 168 to 427) and 126 (95% CI 43 to 209) in the 1- to 11-month and 1- to 5-month groups, respectively. Limiting antibiotic treatment to a subgroup of higher risk children may result in fewer deaths averted compared with treating all preschool children.

Antibiotics are recommended by the WHO as part of the management of uncomplicated severe acute malnutrition in children. We evaluated whether azithromycin, an antibiotic with antimalarial properties, improved malarial parasitemia outcomes in children with severe acute malnutrition compared with amoxicillin, an antibiotic commonly used for severe acute malnutrition that does not have antimalarial properties. Total of 301 children were randomized (1:1) to a single oral dose of azithromycin or a 7-day course of amoxicillin and followed for 8 weeks. We found no significant evidence that children receiving azithromycin had improved parasitemia outcomes relative to amoxicillin. Although azithromycin may have advantages over amoxicillin in terms of dosing and administration for uncomplicated severe acute malnutrition, it may not yield additional benefit for malaria outcomes.

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.

BackgroundThe Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (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. Additional endpoints in the trial have attempted to elucidate the mechanisms for mortality reduction. In this pre-specified secondary analysis, we assessed the effect of azithromycin compared with placebo on IgG- based measures of infectious disease exposure with a multiplex bead assay that included antigens to malaria parasites (Plasmodium falciparum, P. vivax, P. malariae, P. ovale), bacterial pathogens (Campylobacter spp., enterotoxigenic Escherichia coli, Vibrio cholerae, Salmonella enterica, Streptococcus pyogenes) and protozoans (Cryptosporidium parvum, Giardia duodenales).Methods and FindingsThirty communities in rural Niger were randomized 1:1 to biannual distributions of azithromycin or placebo among children ages 1-59 months. The analysis included 5,642 blood specimens collected from 3,814 children ages 1-59 months, measured at 6, 12, 24, and 36 months of follow-up in a repeated cross-sectional design. Campylobacter spp. seroprevalence averaged over all study visits was lower in azithromycin communities compared to placebo (91% vs 94%, difference = –3%, 95% CI: –5%, –1%; P=0.03), which corresponded to a 29% lower seroconversion rate (1.30 versus 1.84 seroconversions per year, hazard ratio = 0.71, 95% CI: 0.56, 0.89; P=0.004). Antibody-based measures of infection with P. falciparum and group A streptococcus were consistently lower in azithromycin communities, but were not statistically different from placebo, and there were no other differences across pathogens. Strengths of the study included masking of participants, investigators, and analysts, high treatment coverage, large sample size, and objective outcomes. Principal limitations included the timing of blood collection with respect to treatment (approximately 6 months later, which could have missed transient effects in the weeks immediately following treatment), and the durability of IgG response following clearance of infection. Both limitations would lead the trial to under-estimate effects on antibody-based measures of infection.ConclusionsThe reduction in Campylobacter spp. despite these limitations suggests an effect on carriage, findings which align with an independent metagenomic analysis of rectal swabs collected in the same villages and with previously reported reductions in dysentery-associated mortality. Given significant sequelae of Campylobacter infection among preschool aged children, our results support at least one possible mechanism through which biannual mass distribution of azithromycin likely reduced mortality in this study population.

Background Given the high risk of infectious mortality among children with severe acute malnutrition (SAM), the World Health Organization recommends routine administration of a broad-spectrum antibiotic like amoxicillin as part of the management of uncomplicated SAM. However, evidence for the efficacy of amoxicillin to improve nutritional recovery or reduce mortality has been mixed. With a long half-life and evidence of efficacy to reduce mortality in high-risk populations, azithromycin is a potential alternative to amoxicillin in the management of SAM. In this pilot study, we aim to compare the efficacy of azithromycin to amoxicillin to improve nutritional outcomes in children with uncomplicated SAM. Methods This pilot randomized controlled trial will enroll 300 children with uncomplicated SAM from 6 Centre de Santé et de Promotion Sociale in the Boromo health district in Burkina Faso. Eligible children are randomized to receive a single directly observed dose of oral azithromycin or a 7-day course of oral amoxicillin in addition to the standard package of care for uncomplicated SAM. Enrolled children are followed weekly until nutritional recovery, and all children return for a final study visit at 8 weeks after enrollment. Anthropometric indicators, vital status, and clinical outcomes are monitored at each visit and compared by arm. Primary feasibility outcomes include enrollment potential, refusals, loss to follow-up, and completeness of data collection. The primary clinical outcome is weight gain (g/kg/day) over the 8-week study period. Discussion This pilot trial will establish the feasibility of conducting a full-scale randomized controlled trial to evaluate alternative antibiotics in this setting and provide preliminary evidence for the efficacy of azithromycin compared to amoxicillin to improve outcomes for children with SAM. Trial registration This trial was first registered on clinicaltrials.gov on 26 June 2018 (NCT03568643).

Background Biannual azithromycin distribution to children 1–59 months old reduced all-cause mortality by 18% [incidence rate ratio (IRR) 0.82, 95% confidence interval (CI): 0.74, 0.90] in an intention-to-treat analysis of a randomized controlled trial in Niger. Estimation of the effect in compliance-related subgroups can support decision making around implementation of this intervention in programmatic settings. Methods The cluster-randomized, placebo-controlled design of the original trial enabled unbiased estimation of the effect of azithromycin on mortality rates in two subgroups: (i) treated children (complier average causal effect analysis); and (ii) untreated children (spillover effect analysis), using negative binomial regression. Results In Niger, 594 eligible communities were randomized to biannual azithromycin or placebo distribution and were followed from December 2014 to August 2017, with a mean treatment coverage of 90% [standard deviation (SD) 10%] in both arms. Subgroup analyses included 2581 deaths among treated children and 245 deaths among untreated children. Among treated children, the incidence rate ratio comparing mortality in azithromycin communities to placebo communities was 0.80 (95% CI: 0.72, 0.88), with mortality rates (deaths per 1000 person-years at risk) of 16.6 in azithromycin communities and 20.9 in placebo communities. Among untreated children, the incidence rate ratio was 0.91 (95% CI: 0.69, 1.21), with rates of 33.6 in azithromycin communities and 34.4 in placebo communities. Conclusions As expected, this analysis suggested similar efficacy among treated children compared with the intention-to-treat analysis. Though the results were consistent with a small spillover benefit to untreated children, this trial was underpowered to detect spillovers.

Medical shops in Nepal are a main point of treatment for many diseases including ophthalmic conditions. We sought to evaluate pharmaceutical shop worker knowledge of corneal ulcers and abrasions. A pharmaceutical shop worker from each of 117 different pharmacies surrounding Bharatpur, Nepal, was presented four different eye photographs (i.e., corneal ulcer, corneal abrasion, conjunctivitis, and a normal eye) and asked about diagnosis and management. Of 117 participants, 86 (74%) identified conjunctivitis correctly but few were able to identify corneal abrasion (50/117; 43%) or corneal infection (47/117; 40%). When presented with an illustrated diagram of potential medications to dispense, 15 (13%) participants chose a topical medication containing a corticosteroid for the corneal abrasion and 25 (21%) did so for the corneal ulcer. The appropriate use of corticosteroids for external eye infections is an important topic for additional training, given the potential for these medications to worsen corneal abrasions and ulcers.

Nucleic acid amplification tests are increasingly used to detect ocular chlamydia infection in trachoma research and programs. To evaluate the reliability of Chlamydia trachomatis detection by the Abbott RealTime CT/NG assay (Abbott Molecular, Inc., Des Plaines, IL) on the m2000 platform, three conjunctival samples were collected from each of 200 children aged 0-9 years in Ethiopia: two from the right eye and one from the left eye. Four aliquots were processed for each child: two from the first right eye sample, one from the second right eye sample, and one from the left eye sample. Sixty-nine swabs were processed in a U.S. laboratory and 131 in an Ethiopian laboratory. Intra-class correlation coefficients (ICCs) were high when comparing two aliquots from the same swab (ICC ranged from 0.96 to 0.99), two separate swabs from the right eye (0.89-0.91), and one right and one left eye swab (0.87-0.89), indicating reliable chlamydial load assessment across different samples and laboratory settings.

The relationship between malaria and malnutrition is complicated, and existence of one may predispose or exacerbate the other. We evaluated the relationship between malaria parasitemia and nutritional status in children living in communities participating in a cluster-randomized trial of biannual azithromycin compared with placebo for prevention of childhood mortality. Data were collected during the low malaria transmission and low food insecurity season. Parasitemia was not associated with weight-for-height Z-score (24 months: P = 0.11 azithromycin communities, P = 0.75 placebo communities), weight-for-age Z-score (24 months: P = 0.83 azithromycin, P = 0.78 placebo), height-for-age Z-score (24 months: P = 0.30 azithromycin, P = 0.87 placebo), or mid-upper arm circumference (24 months: P = 0.12 azithromycin, P = 0.56 placebo). There was no statistically significant evidence of a difference in the relationship in communities receiving azithromycin or placebo. During the low transmission season, there was no evidence that malaria parasitemia and impaired nutritional status co-occur in children.

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

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.

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.