Outcomes in Patients with Vogt-Koyanagi-Harada Disease from the First-line Antimetabolites for Steroid-sparing Treatment Uveitis Trial.

PURPOSE: To compare the effectiveness of methotrexate (MTX) and mycophenolate mofetil (MMF) in achieving corticosteroid-sparing control of uveitis in patients with Vogt-Koyanagi-Harada (VKH) disease. METHODS: A subanalysis of patients with VKH from the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial, a randomized, observer-masked, comparative effectiveness trial, with comparisons by treatment (MTX versus MMF) and disease stage (acute versus chronic). Individuals with noninfectious uveitis were placed on a standardized corticosteroid taper and block randomized 1:1 to either 25mg weekly oral MTX or 1.5g twice daily oral MMF. The primary outcome was treatment success defined by corticosteroid-sparing control of uveitis at 6 months. Additional outcomes included change in best spectacle-corrected visual acuity (BSCVA), retinal central subfield thickness (CST), and resolution of serous retinal detachment (SRD). RESULTS: Ninety-three out of 216 enrolled patients had VKH; 49 patients were randomized to MTX and 44 to MMF, of which 85 patients (46 on MTX, 39 on MMF) contributed to the primary outcome. There was no significant difference in treatment success by antimetabolite (80.4% for MTX compared to 64.1% for MMF; P=.12) or in BSCVA improvement (P=.78). Methotrexate was superior to MMF in reducing CST (P=.003) and resolving SRD (P=.02). There was no significant difference in treatment success by disease stage (P=.25), but patients with acute VKH had greater improvement in BSCVA (P<.001) and reduction of CST (P=.02) than chronic VKH patients. CONCLUSIONS: MTX and MMF have comparable outcomes as corticosteroid-sparing immunosuppressive therapies for VKH. Visual acuity improvement was greater in acute vs chronic VKH. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00182929.

Coxsackievirus A24 causing acute conjunctivitis in a 2023 outbreak in Vietnam.

OBJECTIVES: To determine the associated pathogen during the 2023 conjunctivitis outbreak in Vietnam METHODS: RNA-sequencing was used to identify pathogens before and during the outbreak. RESULTS: 24 patients with infectious conjunctivitis between March and October 2023 from Hai Yen Vision Institute in Vietnam were swabbed. Coxsackievirus A24v was the most common pathogen identified. Phylogenetic analysis of these strains demonstrates similarities to the Coxsackievirus identified in the 2022 India outbreak. Human adenovirus D was also circulating. Ocular findings of tearing, purulence, and itching were common in this outbreak. CONCLUSIONS: Multiple viruses can co-circulate during conjunctivitis outbreaks. Hemorrhagic conjunctivitis, commonly associated with coxsackievirus conjunctivitis, was not a common clinical sign in this outbreak. Repeat genetic surveillance, with the notable inclusion of RNA virus detection strategies, is important for outbreak detection.

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

BACKGROUND: Randomized controlled trials found that twice-yearly mass azithromycin administration (MDA) reduces childhood mortality, presumably by reducing infection burden. World Health Organization (WHO) issued conditional guidelines for mass azithromycin administration in high-mortality settings in sub-Saharan Africa given concerns for antibiotic resistance. While prolonged twice-yearly MDA has been shown to increase antibiotic resistance in small randomized controlled trials, the objective of this study was to determine if macrolide and non-macrolide resistance in the gut increases with the duration of azithromycin MDA in a larger setting. METHODS AND FINDINGS: The Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95% CI 1.5 to 3.51, Punadj < 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability. CONCLUSIONS: In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored. TRIAL REGISTRATION: NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.

Assessment of spillover of antimicrobial resistance to untreated children 7 to 12 years old after mass drug administration of azithromycin for child survival in Niger: a secondary analysis of the MORDOR cluster-randomized trial.

BACKGROUND: The risk of antibiotic resistance is complicated by the potential for spillover effects from one treated population to another. Azithromycin mass drug administration programs report higher rates of antibiotic resistance among treatment arms in targeted groups. This study aims to understand the risk of spillover of antibiotic resistance to non-target groups in these programs. METHODS: Data was used from a cluster-randomized trial comparing the effect of biannual azithromycin and placebo distribution to children 1-59 months on child mortality. Nasopharyngeal samples from untreated children 7-12 years old were tested for genetic determinants of macrolide resistance (primary outcome) and resistance to other antibiotic classes (secondary outcomes). Linear regression was used to compare the community-level mean difference in prevalence by arm at the 24-month timepoint adjusting for baseline prevalence. RESULTS: 1,103 children 7-12 years old in 30 communities were included in the analysis (15 azithromycin, 15 placebo). Adjusted mean differences in prevalence of resistance determinants for macrolides, beta-lactams and tetracyclines were 3.4% (95% CI -4.1% to 10.8%, P-value 0.37), -1.2% (95% CI -7.9% to 5.5%, P-value 0.72), and -3.3% (95% CI -9.5% to 2.8%, P-value 0.61), respectively. CONCLUSIONS: We were unable to demonstrate a statistically significant increase in macrolide resistance determinants in untreated groups in an azithromycin mass drug administration program. While the result might be consistent with a small spillover effect, this study was not powered to detect such a small difference. Larger studies are warranted to better understand the potential for spillover effects within these programs.

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

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

Use of Large Language Models to Assess the Likelihood of Epidemics From the Content of Tweets: Infodemiology Study.

BACKGROUND: Previous work suggests that Google searches could be useful in identifying conjunctivitis epidemics. Content-based assessment of social media content may provide additional value in serving as early indicators of conjunctivitis and other systemic infectious diseases. OBJECTIVE: We investigated whether large language models, specifically GPT-3.5 and GPT-4 (OpenAI), can provide probabilistic assessments of whether social media posts about conjunctivitis could indicate a regional outbreak. METHODS: A total of 12,194 conjunctivitis-related tweets were obtained using a targeted Boolean search in multiple languages from India, Guam (United States), Martinique (France), the Philippines, American Samoa (United States), Fiji, Costa Rica, Haiti, and the Bahamas, covering the time frame from January 1, 2012, to March 13, 2023. By providing these tweets via prompts to GPT-3.5 and GPT-4, we obtained probabilistic assessments that were validated by 2 human raters. We then calculated Pearson correlations of these time series with tweet volume and the occurrence of known outbreaks in these 9 locations, with time series bootstrap used to compute CIs. RESULTS: Probabilistic assessments derived from GPT-3.5 showed correlations of 0.60 (95% CI 0.47-0.70) and 0.53 (95% CI 0.40-0.65) with the 2 human raters, with higher results for GPT-4. The weekly averages of GPT-3.5 probabilities showed substantial correlations with weekly tweet volume for 44% (4/9) of the countries, with correlations ranging from 0.10 (95% CI 0.0-0.29) to 0.53 (95% CI 0.39-0.89), with larger correlations for GPT-4. More modest correlations were found for correlation with known epidemics, with substantial correlation only in American Samoa (0.40, 95% CI 0.16-0.81). CONCLUSIONS: These findings suggest that GPT prompting can efficiently assess the content of social media posts and indicate possible disease outbreaks to a degree of accuracy comparable to that of humans. Furthermore, we found that automated content analysis of tweets is related to tweet volume for conjunctivitis-related posts in some locations and to the occurrence of actual epidemics. Future work may improve the sensitivity and specificity of these methods for disease outbreak detection.

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

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

Mass Azithromycin Distribution to Prevent Child Mortality in Burkina Faso: The CHAT Randomized Clinical Trial.

Importance: Repeated mass distribution of azithromycin has been shown to reduce childhood mortality by 14% in sub-Saharan Africa. However, the estimated effect varied by location, suggesting that the intervention may not be effective in different geographical areas, time periods, or conditions. Objective: To evaluate the efficacy of twice-yearly azithromycin to reduce mortality in children in the presence of seasonal malaria chemoprevention. Design, Setting, and Participants: This cluster randomized placebo-controlled trial evaluating the efficacy of single-dose azithromycin for prevention of all-cause childhood mortality included 341 communities in the Nouna district in rural northwestern Burkina Faso. Participants were children aged 1 to 59 months living in the study communities. Interventions: Communities were randomized in a 1:1 ratio to receive oral azithromycin or placebo distribution. Children aged 1 to 59 months were offered single-dose treatment twice yearly for 3 years (6 distributions) from August 2019 to February 2023. Main Outcomes and Measures: The primary outcome was all-cause childhood mortality, measured during a twice-yearly enumerative census. Results: A total of 34 399 children (mean [SD] age, 25.2 [18] months) in the azithromycin group and 33 847 children (mean [SD] age, 25.6 [18] months) in the placebo group were included. A mean (SD) of 90.1% (16.0%) of the censused children received the scheduled study drug in the azithromycin group and 89.8% (17.1%) received the scheduled study drug in the placebo group. In the azithromycin group, 498 deaths were recorded over 60 592 person-years (8.2 deaths/1000 person-years). In the placebo group, 588 deaths were recorded over 58 547 person-years (10.0 deaths/1000 person-years). The incidence rate ratio for mortality was 0.82 (95% CI, 0.67-1.02; P = .07) in the azithromycin group compared with the placebo group. The incidence rate ratio was 0.99 (95% CI, 0.72-1.36) in those aged 1 to 11 months, 0.92 (95% CI, 0.67-1.27) in those aged 12 to 23 months, and 0.73 (95% CI, 0.57-0.94) in those aged 24 to 59 months. Conclusions and Relevance: Mortality in children (aged 1-59 months) was lower with biannual mass azithromycin distribution in a setting in which seasonal malaria chemoprevention was also being distributed, but the difference was not statistically significant. The study may have been underpowered to detect a clinically relevant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03676764.

Azithromycin during Routine Well-Infant Visits to Prevent Death.

BACKGROUND: Mass distribution of azithromycin to children 1 to 59 months of age has been shown to reduce childhood all-cause mortality in some sub-Saharan African regions, with the largest reduction seen among infants younger than 12 months of age. Whether the administration of azithromycin at routine health care visits for infants would be effective in preventing death is unclear. METHODS: We conducted a randomized, placebo-controlled trial of a single dose of azithromycin (20 mg per kilogram of body weight) as compared with placebo, administered during infancy (5 to 12 weeks of age). The primary end point was death before 6 months of age. Infants were recruited at routine vaccination or other well-child visits in clinics and through community outreach in three regions of Burkina Faso. Vital status was assessed at 6 months of age. RESULTS: Of the 32,877 infants enrolled from September 2019 through October 2022, a total of 16,416 infants were randomly assigned to azithromycin and 16,461 to placebo. Eighty-two infants in the azithromycin group and 75 infants in the placebo group died before 6 months of age (hazard ratio, 1.09; 95% confidence interval [CI], 0.80 to 1.49; P = 0.58); the absolute difference in mortality was 0.04 percentage points (95% CI, -0.10 to 0.21). There was no evidence of an effect of azithromycin on mortality in any of the prespecified subgroups, including subgroups defined according to age, sex, and baseline weight, and no evidence of a difference between the two trial groups in the incidence of adverse events. CONCLUSIONS: In this trial conducted in Burkina Faso, we found that administration of azithromycin to infants through the existing health care system did not prevent death. (Funded by the Bill and Melinda Gates Foundation; CHAT ClinicalTrials.gov number, NCT03676764.).

Gut Microbiome Diversity and Antimicrobial Resistance After a Single Dose of Oral Azithromycin in Children: A Randomized Placebo-Controlled Trial.

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

Association between Quality of Life and Visual Acuity in a Randomized Clinical Trial of Patients with Uveitis Taking Antimetabolites.

PURPOSE: To evaluate how changes in visual acuity are associated with changes in quality of life (QoL) among patients with non-infectious uveitis taking antimetabolites. METHODS: This secondary analysis of the multicenter First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial involves 216 participants randomized to methotrexate or mycophenolate mofetil. Vision-related (NEI-VFQ and IND-VFQ) and health-related (PCS and MCS SF-36v2) QoL and visual acuity were measured at baseline and 6-month primary endpoint. RESULTS: Visual acuity was significantly associated and correlated with all QoL measures (Spearman correlation coefficients = 0.5, 0.5, 0.3, and 0.4 for NEI-VFQ, IND-VFQ, SF-36v2 MCS and PCS, respectively). All observed changes in QoL met or exceeded the minimal clinically important difference definition on each scale. Treatment group was not significantly associated with any QoL measure. CONCLUSION: By adding insight beyond visual acuity, QoL provides a more comprehensive picture of the patient experience during uveitis treatment.Abbreviations and Acronyms: QoL = quality of life; VR-QoL = vision-related quality of life; HR-QoL = health-related quality of life; FAST = First-line Antimetabolites as Corticosteroid Sparing Treatment; NEI-VFQ = National Eye Institute Visual Functioning Questionnaire; IND-VFQ = Indian Visual Functioning Questionnaire; SF-36v2 = Medical Outcomes Study 36-Item Short Form Survey; PCS = physical component score; MCS = mental component score; 95% CI = 95% confidence interval; MCID = minimal clinically important difference.

Practice Patterns in the Initial Management of Herpes Zoster Ophthalmicus in the United States.

PURPOSE: The aims of this study were to examine the trends in the initial management of herpes zoster ophthalmicus (HZO) in the United States from 2010 to 2018 and compare them with the treatment preferences of corneal specialists. METHODS: A retrospective, observational deidentified cohort study was conducted on individuals enrolled in the OptumLabs Data Warehouse who had a new diagnosis of HZO from 1/1/2010 to 12/31/2018. An online survey ascertaining HZO management perspectives was distributed to The Cornea Society listserv. The main outcome assessed was proportion of cases with systemic antiviral prescriptions, eye care provider involvement, and follow-up visits after the initial HZO diagnosis. RESULTS: Approximately 50% of patients received systemic antivirals the day of initial HZO diagnosis or within 7 days (45.6% and 53.7%, respectively). Most initial diagnoses were made by ophthalmologists (45.0%), followed by optometrists (19.2%). Referral rate to ophthalmology within a year of initial diagnosis was 38.6%. 48.7% cases had at least 1 follow-up visit with any type of provider within 30 days. Our survey of corneal specialists found 97% would prescribe systemic antivirals to those with ocular involvement, but 66% would prescribe antivirals to those without ocular or eyelid involvement. Seventy percent supported all patients having follow-up with an eye care provider within a month. CONCLUSIONS: HZO antiviral therapies seem to be underprescribed in the United States, referral rates to ophthalmology are low, and follow-up is suboptimal, which are not aligned with recommendations from corneal specialists. More research is needed to establish standardized guidelines for treatment, referral, and follow-up with ophthalmology for HZO.

Correction: Recommended reporting items for epidemic forecasting and prediction research: The EPIFORGE 2020 guidelines.

[This corrects the article DOI: 10.1371/journal.pmed.1003793.].

Pathogen Surveillance for Acute Infectious Conjunctivitis.

Importance: Acute infectious conjunctivitis is a common ocular condition with major public health consequences. Objective: To assess regional variations and microbial etiologies of acute infectious conjunctivitis to guide treatment. Design, Setting, and Participants: In this cross-sectional study, patients with presumed acute infectious conjunctivitis were enrolled in the study at 5 sites (Honolulu, Hawaii; Los Angeles, San Francisco, and San Diego, California; and Petah-Tikva, Israel) from March 2021 to March 2023. Patients with allergic or toxic conjunctivitis were excluded. Main Outcomes and Measures: Pathogens were identified by unbiased RNA deep sequencing. Results: In all, 52 patients (mean [range] age, 48 [7-80] years; 31 females [60%]) were enrolled at 5 sites (6 patients from Honolulu, 9 from San Diego, 11 from Los Angeles, 13 from San Francisco, and 13 from Petah-Tikva). RNA deep sequencing detected human adenovirus species D in one-quarter of patients (13 of 52). A wide range of pathogens, including human coronavirus 229E, SARS-CoV-2, and herpes simplex virus type 1, was also identified, as well as several bacteria and fungi. Moreover, 62% (32 of 52) of patients presented with purulent discharge, while only 8% (4 of 52) of patients had confirmed bacterial pathogens. Conclusion and Relevance: In this cross-sectional study, pathogens associated with acute infectious conjunctivitis varied between all 5 sites in the US and Israel. Purulent discharge was a common presenting sign in this study, with a low specificity for bacteria-associated conjunctivitis, suggesting that further diagnostic workup may be necessary to inform antibiotic stewardship. Additional research on cost-effectiveness of using RNA deep sequencing is needed to ascertain whether it is better to monitor patients clinically until resolution of disease.

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

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

Anthropometric Differences in Community- Versus Clinic-Recruited Infants Participating in a Trial of Azithromycin for Prevention of Childhood Mortality in Burkina Faso.

Clinic-based recruitment for preventative interventions for child health may select for healthier populations compared with community-based outreach. Nutritional status during infancy as measured by anthropometry is predictive of mortality, growth faltering later in life, and poor cognitive development outcomes. We evaluated baseline differences in infant nutritional status among children recruited directly in their community versus clinic recruitment among infants participating in a trial of azithromycin compared with placebo for prevention of mortality in three districts of Burkina Faso. Infants between 5 and 12 weeks of age were recruited in their community of residence via vaccine outreach teams or in primary health-care clinics during vaccine clinics. Weight, height, and mid upper arm circumference were measured. We used linear and logistic regression models to compare anthropometric outcomes among community and clinic recruited infants, adjusting for age at enrollment, gender, and season. Among 32,877 infants enrolled in the trial, 21,273 (64.7%) were recruited via community outreach. Mean weight-for-age z-score (WAZ) was -0.60 ± 1.2 (SD), weight-for-length z-score (WLZ) was -0.16 ± 1.5, and length-for-age z-score was-0.53 ± 1.3. Infants enrolled in the community had lower WAZ (mean difference, -0.12; 95% CI, -0.20 to -0.04) and WLZ (mean difference, -0.21; 95% CI, -0.32 to -0.09). Community-recruited infants were more often underweight (WAZ < -2; odds ratio [OR], 1.25; 95% CI, 1.09-1.43) and wasted (WLZ < -2; OR, 1.54; 95% CI, 1.31-1.79). There was no evidence of a difference in height-based measures. Community and clinic recruitment likely reach different populations of children.

Rates of SARS-CoV-2 transmission between and into California state prisons.

Correctional institutions are a crucial hotspot amplifying SARS-CoV-2 spread and disease disparity in the U.S. In the California state prison system, multiple massive outbreaks have been caused by transmission between prisons. Correctional staff are a likely vector for transmission into the prison system from surrounding communities. We used publicly available data to estimate the magnitude of flows to and between California state prisons, estimating rates of transmission from communities to prison staff and residents, among and between residents and staff within facilities, and between staff and residents of distinct facilities in the state's 34 prisons through March 22, 2021. We use a mechanistic model, the Hawkes process, reflecting the dynamics of SARS-CoV-2 transmission, for joint estimation of transmission rates. Using nested models for hypothesis testing, we compared the results to simplified models (i) without transmission between prisons, and (ii) with no distinction between prison staff and residents. We estimated that transmission between different facilities' staff is a significant cause of disease spread, and that staff are a vector of transmission between resident populations and outside communities. While increased screening and vaccination of correctional staff may help reduce introductions, large-scale decarceration remains crucially needed as more limited measures are not likely to prevent large-scale disease spread.

A pilot, masked, randomized controlled trial to evaluate local gentamicin versus saline in open tibial fractures (pGO-Tibia).

Background: Open tibial fractures have a high risk of infection that can lead to severe morbidity. Antibiotics administered locally at the site of the open wound are a potentially effective preventive measure, but there are limited data evaluating aminoglycoside antibiotics. The objective of this study was to assess the feasibility of a clinical trial to test the efficacy of local gentamicin in reducing the risk of fracture-related infection after open tibial fracture. Methods: This study is a single-center, pilot, masked, randomized controlled trial conducted at the Muhimbili Orthopaedic Institute. Participants were randomized intraoperatively after wound closure to receive gentamicin solution or normal saline solution injected at the fracture site. Follow-ups were completed at 2 weeks, 6 weeks, 3 months, 6 months, 9 months, and 1 year postoperatively. The primary feasibility outcomes were the rate of enrollment and retention. The primary clinical outcome was the occurrence of fracture-related infection. Results: Of 199 patients screened, 100 eligible patients were successfully enrolled and randomized over 9 months (11.1 patients/month). Complete data were recorded at baseline and follow-up for >95% of cases. The rate of follow-up at 6 weeks, 3 months, 6 months, 9 months, and 1 year were 70%, 68%, 69%, 61%, and 80%, respectively. There was no difference in adverse events or any of the measured primary and secondary outcomes. Conclusion: This pilot study is among the first to evaluate locally administered gentamicin in open tibial fractures. Results indicate a rigorous clinical trial with acceptable rates of enrollment and follow-up to address this topic is possible in this setting.

GO-Tibia: a masked, randomized control trial evaluating gentamicin versus saline in open tibia fractures.

BACKGROUND: The rate of open tibia fractures is rapidly increasing across the globe due to a recent rise in road traffic accidents, predominantly in low- and low-middle-income countries. These injuries are orthopedic emergencies associated with infection rates as high as 40% despite the use of systemic antibiotics and surgical debridement. The use of local antibiotics has shown some promise in reducing the burden of infection in these injuries due to increasing local tissue availability; however, no trial has yet been appropriately powered to evaluate for definitive evidence and the majority of current studies have taken place in a high-resource countries where resources and the bio-burden may be different. METHODS: This is a prospective randomized, masked, placebo-controlled superiority trial designed to evaluate the efficacy of locally administered gentamicin versus placebo in the prevention of fracture-related infection in adults (age > 18 years) with primarily closeable Gustillo-Anderson class I, II, and IIIA open tibia fractures. Eight hundred ninety patients will be randomized to receive an injection of either gentamicin (treatment group) or saline (control group) at the site of their primarily closed open fracture. The primary outcome will be the occurrence of a fracture-related infection occurring during the course of the 12-month follow-up. DISCUSSION: This study will definitively assess the effectiveness of local gentamicin for the prevention of fracture-related infections in adults with open tibia fractures in Tanzania. The results of this study have the potential to demonstrate a low-cost, widely available intervention for the reduction of infection in open tibia fractures. TRIAL REGISTRATION: Clinicaltrials.gov NCT05157126. Registered on December 14, 2021.

A complex systems model of breast cancer etiology: The Paradigm II Model.

BACKGROUND: Complex systems models of breast cancer have previously focused on prediction of prognosis and clinical events for individual women. There is a need for understanding breast cancer at the population level for public health decision-making, for identifying gaps in epidemiologic knowledge and for the education of the public as to the complexity of this most common of cancers. METHODS AND FINDINGS: We developed an agent-based model of breast cancer for the women of the state of California using data from the U.S. Census, the California Health Interview Survey, the California Cancer Registry, the National Health and Nutrition Examination Survey and the literature. The model was implemented in the Julia programming language and R computing environment. The Paradigm II model development followed a transdisciplinary process with expertise from multiple relevant disciplinary experts from genetics to epidemiology and sociology with the goal of exploring both upstream determinants at the population level and pathophysiologic etiologic factors at the biologic level. The resulting model reproduces in a reasonable manner the overall age-specific incidence curve for the years 2008-2012 and incidence and relative risks due to specific risk factors such as BRCA1, polygenic risk, alcohol consumption, hormone therapy, breastfeeding, oral contraceptive use and scenarios for environmental toxin exposures. CONCLUSIONS: The Paradigm II model illustrates the role of multiple etiologic factors in breast cancer from domains of biology, behavior and the environment. The value of the model is in providing a virtual laboratory to evaluate a wide range of potential interventions into the social, environmental and behavioral determinants of breast cancer at the population level.