Background

Worldwide, an estimated 38.0 million people lived with the human immunodeficiency virus in 2019, and 3.4 million young people aged 15~24 years were living with HIV. Sub-Saharan Africa carries a significant HIV burden with West and Central Africa most affected with HIV. Among the young people living with HIV in West and Central Africa, an estimated 810,000 were aged 15~24 years. This study aimed to assess predictors that influence the uptake of HIV testing among youth aged 15~24 years in The Gambia.

Methods

The 2013 Gambia Demographic and Health Survey data for youth aged 15~24 years was used. The Andersen behavioral model of health service use guided this study. A cross-sectional study design was used on 6194 subjects, among which 4730 were female. The analysis employed Chi-squared tests and hierarchical logistic regression.

Results

Less than one-quarter of the youth 1404 (22.6%) had ever been tested for HIV. Young people aged 20~24 years (adjusted odds ratio (aOR): 1.98), who were females (aOR: 1.13), married youth (aOR: 3.89), with a primary (aOR: 1.23), secondary or higher education (aOR: 1.46), and who were from the Jola/Karoninka ethnic group (aOR: 1.81), had higher odds of having been tested for HIV. Those with adequate HIV knowledge and those who were sexually active and had aged at first sex ≥15 years (aOR: 3.99) and those <15 years (aOR: 3.96) were more likely to have been tested for HIV compared to those who never had sex.

Conclusion

This study underscores the low level of model testing on HIV testing among youth (15~24 years) in The Gambia. Using Anderson's Model of Health Service Utilization, the predisposing factors (socio-demographic and HIV knowledge) and the need-for-care factors (sexual risk behaviors) predict healthcare utilization services (HIV testing) in our study; however, only socio-demographic model explained most of the variance in HIV testing. The low effect of model testing could be related to the limited number of major variables selected for HIV knowledge and sexual risk behavior models. Thus, consideration for more variables is required for future studies.

4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate (3b) is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, we describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivatives, which have led to the identification of 3b, and expand these studies to elucidate the principal structural and stereochemical features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of 3ak, a novel inhibitor of human NAAA that shows an improved physicochemical and drug-like profile relative to 3b. This favourable profile, along with the structural diversity of the carbamic acid chain of 3b, identify this compound as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.

The human kinome plays a crucial role in several pathways. Its dysregulation has been linked to diverse central nervous system (CNS)-related disorders with a drastic impact on the aging population. Among them, tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Lobar degeneration (FTLD-tau), are neurodegenerative disorders pathologically defined by the presence of hyperphosphorylated tau-positive intracellular inclusions known as neurofibrillary tangles (NFTs). Compelling evidence has reported the great potential of the simultaneous modulation of multiple protein kinases (PKs) involved in abnormal tau phosphorylation through a concerted pharmacological approach to achieve a superior therapeutic effect relative to classic "one target, one drug" approaches. Here, we report on the identification and characterization of ARN25068 (4), a low nanomolar and well-balanced dual GSK-3β and FYN inhibitor, which also shows inhibitory activity against DYRK1A, an emerging target in AD and tauopathies. Computational and X-Ray studies highlight compound 4's typical H-bonding pattern of ATP-competitive inhibitors at the binding sites of all three PKs. In a tau phosphorylation assay on Tau0N4R-TM-tGFP U2OS cell line, 4 reduces the extent of tau phosphorylation, promoting tau-stabilized microtubule bundles. In conclusion, this compound emerges as a promising prototype for further SAR explorations to develop potent and well-balanced triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau hyperphosphorylation.

We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed anticancer efficacy in vivo. Here, we describe a second class of CDC42 inhibitors with favorable drug-like properties. Out of the 25 compounds here reported, compound 15 (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development.

CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here, we use computer-aided drug design to discover a chemical entity (ARN22089) that has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in 3D vascularized microtumor models (VMT) in vitro. Additionally, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. ARN22089 selectively blocks CDC42 effector interactions without affecting the binding between closely related GTPases and their downstream effectors. Taken together, we identify a class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.