Faculty Bibliography

Critical-sized bone defects remain a significant clinical challenge, and dipyridamole (DIPY)-coated 3D-tricalcium phosphate (β-TCP) scaffolds have shown promising osteogenic efficacy in preclinical models. However, the literature on the systematic physicochemical characterization of this scaffold system, including optimization of DIPY loading parameters, release kinetics, and surface properties, is lacking. This study addresses these gaps by characterizing DIPY-loaded 3D-printed β-TCP scaffolds across solid and porous architectures, three coating concentrations (10, 100, and 1000 µM), and three coating volumes (250, 500, and 1000 µL). Under static PBS conditions, drug release over 21 days was quantifiable only at 1000 µM, and release-kinetics modeling (zero-order, Higuchi, and Korsmeyer-Peppas) was therefore restricted to this highest concentration. At 1000 µM, both scaffold types showed biphasic release profiles, with standard empirical models reasonably approximating the overall kinetics, while not fully capturing the biphasic behavior over the entire duration. Porous scaffolds showed significant volume-dependent release (p = 0.002, η

BACKGROUND:Pathogenic variants in AGO2, encoding a central component of the RNA-induced silencing complex (RISC), cause the neurodevelopmental disorder Lessel-Kreienkamp syndrome (LESKRES). The variant spectrum and associated molecular mechanisms underlying phenotypic variability and disease severity remain incompletely understood. METHODS:We investigated 45 newly identified individuals carrying 33 distinct AGO2 variants, 30 of which were previously unreported. Phenotypic data from these and previously reported cases (n = 70) were integrated to delineate the LESKRES-associated clinical spectrum and genotype-phenotype correlations. Functional studies included shRNA-based silencing, co-immunoprecipitation, subcellular localization, and sequencing of AGO2-bound miRNAs. RESULTS:All individuals presented with a neurodevelopmental disorder of variable severity. Delayed speech and language development (97%), intellectual disability (97%), and motor delay (93%) were the most consistent features, frequently accompanied by muscular hypotonia, autistic traits, attention deficit hyperactivity disorder, visual impairment and structural brain anomalies. Systemic manifestations, including skeletal, craniofacial, cardiac, and male urogenital anomalies were common, underscoring AGO2's multisystemic role. Moreover, we report occurrence of gonadal mosaicism and reveal the presence of interfamilial and variant-specific clinical heterogeneity. Variants clustered in defined regions of AGO2, including the L1 loop, helix-7, and multiple loops of the PIWI domain, highlight structural hotspots critical for RISC activity. Not all pathogenic variants impaired shRNA-mediated silencing; this was restricted to p.(Arg714Trp) and p.(Asn729His). Biochemical analyses revealed that p.(Asp619Asn) impaired GW182 binding and P-body assembly. Variants p.(Arg506Gln), p.(Glu531Gln) p.(Gly604Arg) and p.(Asp619Asn), reduced C-terminal phosphorylation, implicating defective AGO2 recycling. AGO2-miRNA co-immunoprecipitation and sequencing demonstrated variant-specific perturbations in miRNA association, strand selectivity, and isomiR generation. Variants near the hinge of the helix-7 region, especially p.(Phe182del), induced extensive changes in miRNA association and 3'-end modification, suggesting impaired anchoring within the miRNA-binding pocket. CONCLUSIONS:Our findings substantially broaden the clinical and molecular landscape of LESKRES, establishing AGO2 as a pivotal regulator of neurodevelopment whose structural integrity is essential for precise miRNA-mediated gene regulation. Pathogenic variants disrupt distinct interconnected processes: P-body association, phosphorylation-dependent turnover, and miRNA interactions, culminating in dysregulated post-transcriptional gene silencing. These mechanistic insights link specific structural perturbations in AGO2 to graded clinical outcomes and underscore the critical role of AGO2 conformational dynamics in human neurodevelopment.

INTRODUCTION/BACKGROUND:Adolescents and young adults living with HIV (AYLHIV) experience poor outcomes across the care continuum, and most reside in sub-Saharan Africa. The African Cohort Study (AFRICOS) provides an opportunity to examine HIV outcomes in this population across Kenya, Nigeria, Tanzania, and Uganda. METHODS:We conducted a cross-sectional analysis of AYLHIV aged 15-29 years, enrolled in AFRICOS 2013-2023, and on antiretroviral therapy (ART) ≥ six months. Primary outcomes were HIV viremia and 30-day ART non-adherence. Factors included HIV acquisition route, ART duration, ART class, and site. We used multivariate robust Poisson regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). Site directors were surveyed to assess youth-friendly services. RESULTS:Among 656 participants, the median age was 20.0 years (IQR 17.5-23.3); 41.6% were male, 61.6% had perinatally-acquired HIV, and median duration since HIV diagnosis was nine years. At enrollment, 83.8% had viral suppression (<200 copies/mL) and 80.2% were ART adherent. ART regimen and clinic site were associated with viral suppression: youth on integrase vs. protease inhibitor-based regimens (adjusted relative risk (aRR) 0.38, CI 0.23-0.63, p<0.001), and in Uganda (aRR 0.42, CI 0.20-0.90, p=0.026) or Kisumu, Kenya (aRR 0.40, CI 0.22-0.76, p=0.005) had lower likelihood of non-suppression. Compared to Nigeria, participants from other sites were less likely to report non-adherence (unadjusted RR 0.31-0.44). Youth-friendly service provision varied. CONCLUSIONS:Viral suppression and ART adherence were high among AYLHIV in AFRICOS. Clinic site and ART regimen were associated with outcomes, highlighting the importance of health system factors.

PURPOSE/UNASSIGNED:To report a unique case of hydroxychloroquine-associated retinal toxicity presenting with cystoid macular edema (CME) and retinal vasculopathy and to discuss its potential pathophysiology. METHODS/UNASSIGNED:A single case was reviewed. CASE REPORT/UNASSIGNED:A 65-year-old woman with a history of hydroxychloroquine use for approximately 5.5 years presented with bilateral CME and parafoveal ellipsoid zone disruption with outer retinal loss on optical coherence tomography. Multimodal imaging demonstrated central bull's-eye maculopathy and peripheral pigmentary changes on fundus autofluorescence and peripheral vascular leakage on fluorescein angiography. The uveitis workup, anti-retinal antibody testing, and genetic testing were negative. As retinal findings were normal at the first hydroxychloroquine screening, the patient was diagnosed with advanced hydroxychloroquine toxicity. CONCLUSIONS/UNASSIGNED:This case expands the phenotypic spectrum of hydroxychloroquine retinal toxicity to include CME associated with retinal vasculopathy. Annual retinal examination should begin promptly in patients receiving hydroxychloroquine at doses exceeding 5 mg/kg/day.