Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4 subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease.

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A 68-year-old man with known history of IgG4-related disease presented with a 1-year history of mucoid discharge OD and progressive proptosis OS. MRI showed diffuse enlargement of the left lacrimal gland along with prolonged infiltrative changes involving the left extraocular muscles, supraorbital nerve, and infraorbital nerve. No identifiable masses were noted in either nasolacrimal drainage system on MRI. Due to clinical evidence of nasolacrimal duct obstruction, a right external dacryocystorhinostomy was performed along with biopsies of the right lacrimal sac and left lacrimal gland. Immunohistochemical stains identified IgG4-positive plasma cells in the biopsy of the right lacrimal sac indicative of secondary acquired nasolacrimal duct obstruction despite the absence of mass forming lesions on exam and nasolacrimal imaging. This report is the first to describe nasolacrimal drainage system IgG4-related ophthalmic disease involvement in an otherwise clinically and radiographically normal appearing tear drainage system.

IMPORTANCEBecause 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. OBJECTIVE To determine the efficacy of mass azithromycin distributions to preschool-aged children as a strategy for trachoma elimination in areas with hypoendemic disease. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS Every 6 months, a single dose of either oral azithromycin (20 mg/kg using heightbased 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. MAIN OUTCOMES AND MEASURES 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. RESULTS 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).