Targeted Mass Azithromycin Distribution for Trachoma: A Community-Randomized Trial (TANA II).

BACKGROUND: Current guidelines recommend annual community-wide mass administration of azithromycin for trachoma. Targeting treatments to those most likely to be infected could reduce the amount of unnecessary antibiotics distributed. METHODS: In a cluster-randomized trial conducted from 1 November 2010 through 8 November 2013, 48 Ethiopian communities previously treated with annual mass azithromycin distributions for trachoma were randomized in equal numbers to (1) annual azithromycin distributions targeted to children aged 0-5 years, (2) annual azithromycin distributions targeted to households with a child aged 0-5 years found to have clinically active trachoma, (3) continued annual mass azithromycin distributions to the entire community, or (4) cessation of treatment. The primary outcome was the community prevalence of ocular chlamydia infection among children aged 0-9 years at month 36. Laboratory personnel were masked to treatment allocation. RESULTS: The prevalence of ocular chlamydia infection among children aged 0-9 years increased from 4.3% (95% confidence interval [CI], .9%-8.6%) at baseline to 8.7% (95% CI, 4.2%-13.9%) at month 36 in the age-targeted arm, and from 2.8% (95% CI, .8%-5.3%) at baseline to 6.3% (95% CI, 2.9%-10.6%) at month 36 in the household-targeted arm. After adjusting for baseline chlamydia prevalence, the 36-month prevalence of ocular chlamydia was 2.4 percentage points greater in the age-targeted group (95% CI, -4.8% to 9.6%; P = .50; prespecified primary analysis). No adverse events were reported. CONCLUSIONS: Targeting azithromycin treatment to preschool children was no different than targeting azithromycin to households with a child with clinically active trachoma. Neither approach reduced ocular chlamydia over the 3-year study. CLINICAL TRIALS REGISTRATION: NCT01202331.

A double-masked, sham-controlled trial of rose bengal photodynamic therapy for the treatment of fungal and acanthameoba keratitis: Rose Bengal Electromagnetic Activation with Green Light for Infection Reduction (REAGIR) Study.

Background: Infectious keratitis secondary to fungus or acanthamoeba often has a poor outcome despite receiving the best available medical therapy. In vitro Rose Bengal Photodynamic therapy (RB-PDT) appears to be effective against fungal and acanthamoeba isolates. 22,23 In one published series RB-PDT reduced the need for therapeutic penetrating keratoplasty in severe bacterial, fungal, and acanthameoba keratitis not responsive to medical therapy. Methods: This international, randomized, sham and placebo controlled 2-arm clinical trial, randomizes patients with smear positive fungal and acanthameoba and smear negative corneal ulcers in a 1:1 fashion to one of two treatment arms: 1) Topical antimicrobial plus sham RB-PDT or 2) Topical antimicrobial plus RB-PDT Discussion: We anticipate that RB-PDT will improve best spectacle corrected visual acuity and also reduce complications such as corneal perforation and the need for therapeutic penetrating keratoplasty. This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Our results will be disseminated via clinicaltrials.gov website, meetings, and journal publications. Our data will also be available upon reasonable request. Trial Registration: NCT, NCT05110001, Registered November 5, 2021. https://www.clinicaltrials.gov/study/NCT05110001.

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.

Descemet Endothelial Thickness Comparison Trial 1 (DETECT 1): outcome masked, placebo-controlled trial comparing two types of corneal transplant surgeries and effect of rho kinase inhibitors on endothelial cell loss protocol.

BACKGROUND: It remains uncertain which endothelial keratoplasty (EK) technique yields the best outcomes while maintaining safety, particularly in eyes with coexisting ocular conditions. Moreover, the impact of endothelial cell loss (ECL) on long-term graft survival requires further investigation. Adjuvant ripasudil, a rho kinase inhibitor, may address the challenge of ECL in corneal transplantation. This paper presents the protocol for the Descemet Endothelial Thickness Comparison Trial 1 (DETECT 1), a multicentre, outcome-masked, randomised, placebo-controlled, four-arm clinical trial. METHODS: A total of 160 eligible patients with endothelial dysfunction will be enrolled from five participating sites in the USA. The patients will be randomly assigned in a 2×2 factorial design to one of the following treatment groups: group 1-ultrathin Descemet stripping endothelial keratoplasty (UT-DSAEK) plus topical ripasudil 0.4%; group 2-UT-DSAEK plus topical placebo; group 3-Descemet membrane endothelial keratoplasty (DMEK) plus topical ripasudil 0.4% and group 4-DMEK plus topical placebo. Primary outcomes include the best spectacle-corrected visual acuity at 12 months and ECL at 12 months. Secondary outcomes include visual acuity at different time points, vision-related quality of life, endothelial cell morphology and cost-effectiveness. RESULTS: The study outcomes will be analysed using mixed effects linear regression models, taking into account the treatment arms and relevant covariates. Adverse events, including rebubble procedures, graft failure and graft rejection, will be documented and analysed using appropriate statistical methods. CONCLUSION: DETECT I aims to provide evidence on the comparative effectiveness of UT-DSAEK and DMEK, as well as the potential benefits of adjuvant topical ripasudil in reducing ECL. The results of this trial will contribute to optimising corneal transplantation techniques and improving long-term graft survival, while also exploring the cost-effectiveness of these interventions. Dissemination of findings through peer-reviewed publications and national/international meetings will facilitate knowledge translation and guide clinical practice in the field of corneal transplantation. ETHICS AND DISSEMINATION: A data and safety monitoring committee (DSMC) has been empaneled by the NEI.All study protocols will be subject to review and approval by WCG IRB as the single IRB of record.This study will comply with the National Institute of Health (NIH) Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Data from the trial will be made available on reasonable request.

Pregnant women's perspectives on screening for adverse childhood experiences and resilience during prenatal care.

OBJECTIVE: To examine the acceptability of routine screening for adverse childhood experiences (ACEs) and resilience during prenatal care. METHOD: This study examined pregnant women's perspectives (N = 119) on ACEs and resilience screening during prenatal care in two medical centers via postscreening telephone surveys. Chi-square tests and Fisher's Exact Tests examined whether responses varied with ACEs (0 [62.2%], 1-2 [21.0%], 3+ [16.8%]) or resilience (high [64.7%] vs. low [35.3%]). RESULTS: The sample (N = 119) was 36.1% non-Hispanic White, 26.1% Hispanic, 8.4% Black, 23.5% Asian/Pacific Islander, and 5.9% Other, with a median age of 31 (IQR: 28-34) and average neighborhood median household income of $100,734 (SD = $37,079). Most women thought prenatal care should include conversations about ACEs (82.2%) and resilience (94.0%) and very strongly believed that good coping skills can help reduce the harmful effects of childhood stress (79.0%). Nearly half (41.2%) used ≥1 mental health resource from the resource handout provided at screening. Some women thought conversations could be improved if they took place with a mental health professional (37.3%), with more provider empathy (40.7%), more education about ACEs and health (55.1%), and if the screening included additional stressors (53.4%). Notably, most women (73.5%) would like their partner to also receive the screening. Women with more ACEs were more likely to want a longer conversation, and those with low versus high resilience were more likely to prefer that a mental health professional conduct the screening. CONCLUSIONS: Results indicate that women value ACEs screening during prenatal care and provide actionable recommendations to improve future screenings and discussions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The Improving Risk Informed HPV Screening (IRIS) Study: Design and Baseline Characteristics.

BACKGROUND: Cervical cancer screening with high-risk human papillomavirus (HrHPV) testing is being introduced. Most HrHPV infections are transient, requiring triage tests to identify individuals at highest risk for progression to cervical cancer. Head-to-head comparisons of available strategies for screening and triage are needed. Endometrial and ovarian cancers could be amenable to similar testing. METHODS: Between 2016 and 2020, discarded cervical cancer screening specimens from women ages 25 to 65 undergoing screening at Kaiser Permanente Northern California were collected. Specimens were aliquoted, stabilized, and stored frozen. Human papillomavirus (HPV), cytology, and histopathology results as well as demographic and cofactor information were obtained from electronic medical records (EMR). Follow-up collection of specimens was conducted for 2 years, and EMR-based data collection was planned for 5 years. RESULTS: Collection of enrollment and follow-up specimens is complete, and EMR-based follow-up data collection is ongoing. At baseline, specimens were collected from 54,957 HPV-positive, 10,215 HPV-negative/Pap-positive, and 12,748 HPV-negative/Pap-negative women. Clinical history prior to baseline was available for 72.6% of individuals, of which 53.9% were undergoing routine screening, 8.6% recently had an abnormal screen, 30.3% had previous colposcopy, and 7.2% had previous treatment. As of February 2021, 55.7% had one or more colposcopies, yielding 5,563 cervical intraepithelial neoplasia grade 2 (CIN2), 2,756 cervical intraepithelial neoplasia grade 3 (CIN3), and 146 cancer histopathology diagnoses. CONCLUSIONS: This robust population-based cohort study represents all stages of cervical cancer screening, management, and posttreatment follow-up. IMPACT: The IRIS study is a unique and highly relevant resource allowing for natural history studies and rigorous evaluation of candidate HrHPV screening and triage markers, while permitting studies of biomarkers associated with other gynecologic cancers.

Extraction and comparison of gene expression patterns from 2D RNA in situ hybridization images.

MOTIVATION: Recent advancements in high-throughput imaging have created new large datasets with tens of thousands of gene expression images. Methods for capturing these spatial and/or temporal expression patterns include in situ hybridization or fluorescent reporter constructs or tags, and results are still frequently assessed by subjective qualitative comparisons. In order to deal with available large datasets, fully automated analysis methods must be developed to properly normalize and model spatial expression patterns. RESULTS: We have developed image segmentation and registration methods to identify and extract spatial gene expression patterns from RNA in situ hybridization experiments of Drosophila embryos. These methods allow us to normalize and extract expression information for 78,621 images from 3724 genes across six time stages. The similarity between gene expression patterns is computed using four scoring metrics: mean squared error, Haar wavelet distance, mutual information and spatial mutual information (SMI). We additionally propose a strategy to calculate the significance of the similarity between two expression images, by generating surrogate datasets with similar spatial expression patterns using a Monte Carlo swap sampler. On data from an early development time stage, we show that SMI provides the most biologically relevant metric of comparison, and that our significance testing generalizes metrics to achieve similar performance. We exemplify the application of spatial metrics on the well-known Drosophila segmentation network. AVAILABILITY: A Java webstart application to register and compare patterns, as well as all source code, are available from: http://tools.genome.duke.edu/generegulation/image_analysis/insitu CONTACT: uwe.ohler@duke.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Adverse Childhood Experiences and Pregnancy Intentions among Pregnant Women Seeking Prenatal Care.

BACKGROUND: This study examined whether adverse childhood experiences (ACEs) are associated with increased risk of having an unwanted or mistimed pregnancy. METHODS: Women in two medical centers within an integrated health system were screened for ACEs during standard prenatal care (N = 745). Multinomial multivariable logistic regression analyses examined the associations of ACEs (count and type) with pregnancy intentions, adjusting for covariates. RESULTS: Overall, 58.3% of pregnant women reported no ACEs, 19.1% reported one ACE, and 22.7% reported two or more ACEs; 76.2% reported wanting to get pregnant, 18.5% reported wanting to get pregnant but not at this time (i.e., mistimed pregnancy), and 5.2% reported not wanting to get pregnant at all (i.e., unwanted pregnancy). Having two or more (vs. 0) ACEs was associated with higher odds of an unwanted pregnancy (odds ratio, 2.60; 95% confidence interval, 1.19-5.68). Further, childhood loss of parent (odds ratio, 2.20; 95% confidence interval, 1.03-4.71) and neglect (odds ratio, 5.67; 95% confidence interval, 1.72-18.72) were each associated with higher odds of an unwanted pregnancy in separate analyses. ACEs count and type were not significantly associated with having a mistimed pregnancy. CONCLUSIONS: Among women screened for ACEs during standard prenatal care, ACEs were associated with increased odds of having an unwanted pregnancy, but not a mistimed pregnancy. Additional research is needed to better understand the mechanisms through which ACEs and other individual, social, and contextual factors impact pregnancy intentions to better support women and provide appropriate resources to help prevent unintended pregnancies.

Development of a large biorepository of cervical specimens for the Improving Risk Informed HPV Screening study (IRIS).

INTRODUCTION: Biomarkers of Human Papillomavirus (HPV) cervical carcinogenesis are critical to address questions of how to triage and manage women who screen positive for high-risk HPV (HrHPV) and identify those at highest cancer risk. METHODS: We describe the development of a large biorepository of cervical specimens for the Improving Risk Informed HPV Screening Study (IRIS) using residual specimens collected in the regional laboratory from women aged 25 and older who had cervical cancer screening or follow-up testing with high-risk human papillomavirus (HrHPV) testing and liquid-based cytology (co-testing) at Kaiser Permanente Northern California (KPNC) from January 2016 to August 2018. Specimen selection, processing for long-term storage, follow-up tracking, consent and demographic and clinical characteristics of the women in the IRIS cohort are described. RESULTS: Selecting from 897,680 women who had at least one co-test during the study period, we collected 199,403 baseline and 216,390 follow-up HrHPV and cytology specimens from a stratified random sample of 81,348 women, of which 3,428 (4.2%) opted out of the study and were excluded. The majority (79.9%) of the baseline specimens were from HrHPV-positive women. The mean age was 36 years, and the cohort is racially/ethnically diverse with 56% of women being Hispanic or non-white. Over two-thirds of the cohort were members of KPNC for two or more years prior to inclusion. Of the 77,920 women included in the cohort, 57,414 (73.7%) had at least one follow-up co-test. CONCLUSION: Use of specimens from the biorepository will elucidate molecular mechanisms underlying HPV carcinogenesis and inform more effective screening and follow-up strategies.

Adverse Childhood Experiences and Early and Continued Breastfeeding: Findings from an Integrated Health Care Delivery System.

Purpose: To examine whether adverse childhood experiences (ACEs) are associated with breastfeeding behaviors. Methods: Women in three Kaiser Permanente Northern California medical centers were screened for ACEs during standard prenatal care (N = 926). Multivariable binary and multinomial logistic regression was used to test whether ACEs (count and type) were associated with early breastfeeding at the 2-week newborn pediatric visit and continued breastfeeding at the 2-month pediatric visit, adjusting for covariates. Results: Overall, 58.2% of women reported 0 ACEs, 19.2% reported 1 ACE, and 22.6% reported 2+ ACEs. Two weeks postpartum, 92.2% reported any breastfeeding (62.9% exclusive, 29.4% mixed breastfeeding/formula). Compared with women with 0 ACEs, those with 2+ ACEs had increased odds of any breastfeeding (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.3-5.6) and exclusive breastfeeding 2 weeks postpartum (OR = 3.0, 95% CI = 1.4-6.3). Among those who breastfed 2 weeks postpartum, 86.4% reported continued breastfeeding (57.5% exclusive, 28.9% mixed breastfeeding/formula) 2 months postpartum. ACE count was not associated with continued breastfeeding 2 months postpartum. Individual ACEs were not related to breastfeeding outcomes, with the exception that living with someone who went to jail or prison was associated with lower odds of continued breastfeeding 2 months postpartum. Conclusions: ACE count was associated with greater early breastfeeding, but not continued breastfeeding, among women screened for ACEs as part of standard prenatal care. Results reiterate the need to educate and assist all women to meet their breastfeeding goals, regardless of ACE score.

Community Hand-Dug Wells for Trachoma: A Cluster-Randomized Trial.

The WHO recommends improving access to water as part of a comprehensive strategy for elimination of trachoma as a public health problem; however, this recommendation is not based on evidence from randomized trials. In a region of Ethiopia with hyperendemic trachoma, seven communities were randomized to a hand-dug well (HDW) and seven communities to no intervention to determine the impact of HDWs on the community prevalence of ocular chlamydia infection (primary prespecified outcome). All communities continued to receive government hygiene and sanitation services and outreach. Participants were not masked, given the nature of the intervention, but laboratory personnel were masked to treatment allocation. Hand-dug wells were successfully built in six of the seven communities; five of these wells were still functional at the conclusion of the trial. At the end of the trial, an average of 74% of households reported traveling < 30 minutes to collect water in the HDW arm, compared with 45% in the control arm, and the daily volume of water used for hygiene was similar (e.g., mean of 0.7 L per person in each arm). The pseudo-median prevalence of ocular chlamydia among 0- to 5-year old children at the 24-month visit was 23% in the HDW group and 13% in the control group (P > 0.99). This small cluster-randomized trial provided no evidence to suggest that simply constructing HDWs, in the absence of other hygiene promotion activities, is effective for reducing transmission of ocular chlamydia.

Effect of Mass Azithromycin Distributions on Childhood Growth in Niger: A Cluster-Randomized Trial.

Importance: Mass azithromycin distributions may decrease childhood mortality, although the causal pathway is unclear. The potential for antibiotics to function as growth promoters may explain some of the mortality benefit. Objective: To investigate whether biannual mass azithromycin distributions are associated with increased childhood growth. Design, Setting, and Participants: This cluster-randomized trial was performed from December 2014 until March 2020 among 30 rural communities in Boboye and Loga departments in Niger, Africa, with populations from 200 to 2000 individuals. Communities were randomized in a 1:1 ratio to biannual mass distributions of azithromycin or placebo for children ages 1 to 59 months. Participants, field-workers, and study personnel were masked to treatment allocation. Height and weight changes from baseline to follow-up at 4 years were compared between groups. Data were analyzed from June through November 2021. Interventions: Participants received azithromycin at 20 mg/kg using height-based approximation or by weight for children unable to stand every 6 months at the participants' households. Placebo contained the vehicle of the azithromycin suspension. Main Outcomes and Measures: Longitudinal anthropometric assessments were performed on a random sample of children before the first treatment and then annually for 5 years. Height and weight were the prespecified primary outcomes. Results: Among 3936 children enrolled from 30 communities, baseline characteristics were similar between 1299 children in the azithromycin group and 2637 children in the placebo group (mean 48.2% [95% CI, 45.5% to 50.8%] girls vs 48.0% [95% CI, 45.7% to 50.3%] girls; mean age, 30.8 months [95% CI, 29.5 to 32.0 months] vs 30.6 months [95% CI, 29.2 to 31.6 months]). Baseline anthropometric assessments were performed among 2230 children, including 985 children in the azithromycin group and 1245 children in the placebo group, of whom follow-up measurements were available for 789 children (80.1%) and 1063 children (85.4%), respectively. At the prespecified 4-year follow-up visit, children in the azithromycin group gained a mean 6.7 cm (95% CI, 6.5 to 6.8 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year and children in the placebo group gained a mean 6.6 cm (95% CI, 6.4 to 6.7 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year. Height at 4 years was not statistically significantly different between groups when adjusted for baseline height (0.08 cm [95% CI, -0.12 to 0.28 cm] greater in the azithromycin group; P = .45), and neither was weight when adjusted for height and baseline weight (0.02 kg [95% CI, -0.10 to 0.06 kg] less in the azithromycin group; P = .64). However, among children in the shortest quartile of baseline height, azithromycin was associated with a 0.4 cm (95% CI, 0.1 to 0.7 cm) increase in height compared with placebo. Conclusions and Relevance: This study did not find evidence of an association between mass azithromycin distributions and childhood growth, although subgroup analysis suggested some benefit for the shortest children. These findings suggest that the mortality benefit of mass azithromycin distributions is unlikely to be due solely to growth promotion. Trial Registration: ClinicalTrials.gov Identifier: NCT02048007.

Comparison of Smartphone Photography, Single-Lens Reflex Photography, and Field-Grading for Trachoma.

Conjunctival examination for trachomatous inflammation-follicular (TF) guides public health decisions for trachoma. Smartphone cameras may allow remote conjunctival grading, but previous studies have found low sensitivity. A random sample of 412 children aged 1-9 years received an in-person conjunctival examination and then had conjunctival photographs taken with 1) a single-lens reflex (SLR) camera and 2) a smartphone coupled to a 3D-printed magnifying attachment. Three masked graders assessed the conjunctival photographs for TF. Latent class analysis was used to determine the sensitivity and specificity of each grading method for TF. Single-lens reflex photo-grading was 95.0% sensitive and 93.6% specific, and smartphone photo-grading was 84.1% sensitive and 97.6% specific. The sensitivity of the smartphone-CellScope device was considerably higher than that of a previous study using the native smartphone camera, without attachment. Magnification of smartphone images with a simple attachment improved the grading sensitivity while maintaining high specificity in a region with hyperendemic trachoma.