Amlexanox: A Novel Therapeutic for Atopic, Metabolic, and Inflammatory Disease.

Amlexanox, a small molecule targeted therapy which has been used in the treatment of atopic conditions was previously but is not currently available in the United States. Amlexanox has also been legally utilized and administered in Japan as a treatment for asthma, a chronic pulmonary disease characterized by inflammation of the lower respiratory tract. Amlexanox's immune modulatory effects have been the subject of studies which have repurposed the drug for potential therapeutic applications in metabolic and inflammatory disease. Because amlexanox inhibits TANK-binding kinase1 (TBK1) and nuclear factor kB kinase epsilon (IKKε), several studies have demonstrated its usefulness through its evidence downregulation of the immune system and attenuation of downstream TBK1 signaling. Novel therapies, such as amlexanox, for inflammatory conditions such as asthma will continue to be of value in clinical management. This report summarizes key applications of the drug based on animal and human studies and explores its potential in treatment of metabolic and inflammatory diseases.

Neural Correlates of Obesity and Inflammation in Children and Adolescents with Congenital Adrenal Hyperplasia.

INTRODUCTION: Patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency exhibit an increased prevalence of obesity from childhood including central adiposity and inflammation. There is also an emerging affected brain phenotype in CAH, with decreased cortico-limbic gray matter volumes and white matter abnormalities. We aimed to study the relationship between brain structure, obesity, and inflammation in children and adolescents with CAH compared to controls. METHODS: 27 CAH (12.6±3.4y, 16 females) and 35 controls (13.0±2.8y, 20 females) had MRI of gray matter regions of interest [prefrontal cortex (PFC), amygdala, hippocampus] and white matter microstructure [fornix, stria terminalis (ST)]. Anthropometric measures and lab analytes were obtained. Relaimpo analyses (relative importance for linear regression; percent variance) identified which brain structures were most different between groups. Subsequent regressions further quantified the magnitude and direction of these relationships. Correlations analyzed relationships between brain structure, obesity, and inflammation in the context of CAH status. RESULTS: PFC (13.3% variance) and its superior frontal (SF) subregion (14%) were most different between CAH and controls for gray matter; ST (16%) for white matter. Patients with CAH had lower caudal middle frontal [ß = -0.56, (-0.96, -0.15)] and superior frontal [ß = -0.58 (-0.92, -0.25)] subregion volumes, increased orientation dispersion index in the fornix [ß = 0.56 (0.01, 1.10)] and ST [ß = 0.85 (0.34, 1.36)], and decreased fractional anisotropy in the fornix [ß = -0.91 (-1.42, -0.42)] and ST [ß = -0.83 (-1.34, -0.33)] (all p's <0.05) indicating axonal disorganization, reduced myelin content, and/or higher microglial density within the affected white matter tracts. For the full cohort, SF was correlated with MCP-1 (r=-0.41), visceral adipose tissue (r=-0.25), and waist-to-height ratio (r=-0.27, all p's <0.05); ST was correlated with MCP-1 (r=0.31) and TNF-α (r= 0.29, all p's <0.05); however, after adjusting for CAH status, almost all correlations were attenuated for significance. CONCLUSIONS: Relationships among key brain structures, body composition and inflammatory markers in pediatric patients with CAH could be largely driven by having CAH, with implications for obesity and neuroinflammation in this high-risk population.

Statewide Longitudinal Trends in Transmitted HIV-1 Drug Resistance in Rhode Island, USA.

BACKGROUND: HIV-1 transmitted drug resistance (TDR) remains a global challenge that can impact care, yet its comprehensive assessment is limited and heterogenous. We longitudinally characterized statewide TDR in Rhode Island. METHODS: Demographic and clinical data from treatment-naïve individuals were linked to protease, reverse transcriptase, and integrase sequences routinely obtained over 2004-2020. TDR extent, trends, impact on first-line regimens, and association with transmission networks were assessed using the Stanford Database, Mann-Kendall statistic, and phylogenetic tools. RESULTS: In 1123 individuals, TDR to any antiretroviral increased from 8% (2004) to 26% (2020), driven by non-nucleotide reverse transcriptase inhibitor (NNRTI; 5%-18%) and, to a lesser extent, nucleotide reverse transcriptase inhibitor (NRTI; 2%-8%) TDR. Dual- and triple-class TDR rates were low, and major integrase strand transfer inhibitor resistance was absent. Predicted intermediate to high resistance was in 77% of those with TDR, with differential suppression patterns. Among all individuals, 34% were in molecular clusters, some only with members with TDR who shared mutations. Among clustered individuals, people with TDR were more likely in small clusters. CONCLUSIONS: In a unique (statewide) assessment over 2004-2020, TDR increased; this was primarily, but not solely, driven by NNRTIs, impacting antiretroviral regimens. Limited TDR to multiclass regimens and pre-exposure prophylaxis are encouraging; however, surveillance and its integration with molecular epidemiology should continue in order to potentially improve care and prevention interventions.