Demographic diversity of US-based participants in GSK-sponsored interventional clinical trials.

BACKGROUND: Demographic diversity among clinical trials is required for representing the real-world populations intended for treatment and disease prevention. Moreover, genetic and environmental differences between ethnic and racial groups necessitate appropriately powered trials for relevant subgroups. We investigate the racial and ethnic demographic diversity of US-based participants in GSK-sponsored interventional trials. We also assess the evaluation of demographic diversity against US Census and epidemiologic data. METHODS: GSK-sponsored interventional phase I-IV clinical trials conducted from 2002 to 2019 across three areas were analyzed: pharmaceutical (includes therapeutic medicines except for vaccines and human immunodeficiency virus (HIV)), vaccine (includes prophylactic and therapeutic vaccines), and ViiV (includes HIV therapies). A total of 1005 global trials encompassing 460,707 global participants were identified, of which 495 had US-based sites with a total of 108,261 (23.5% of global) US participants (pharmaceutical, n = 357 trials; vaccine, n = 45 trials; and ViiV, n = 93 trials). We evaluated how GSK US-based trial recruitment compares with US Census (in line with previously published studies from other groups) and with epidemiologic data. RESULTS: GSK participant data for race and ethnicity combined across areas were generally similar to US Census levels (e.g. GSK versus census: White, 76.5% versus 76.3%; Black or African American, 15.1% versus 13.4%; Asian, 1.8% versus 5.9%; Hispanic or Latino, 14.0% versus 18.5%; Non-Hispanic White, 63.5% versus 60.1%). However, this was not the case for the individual pharmaceutical, vaccine, and ViiV data sets; least represented groups were Asian individuals for pharmaceutical and ViiV trials and American Indian or Alaskan Native individuals for vaccine trials (6.2%, 11.8%, and 11.1% of trials met/exceeded census level representation, respectively). The percentage of trials reaching/exceeding census levels also varied per trial phase for race and ethnicity. Furthermore, disparities in the percentage of trials reaching/exceeding census levels versus epidemiology-based prevalence levels have revealed opportunities to improve industry success metrics; in HIV trials, the proportion of Black or African American individuals (35.1%) exceeded census (13.4%) but not epidemiologic levels (55.3%). CONCLUSION: Further work is required to achieve demographic diversity across clinical trials. We conclude that US Census data are an inappropriate universal benchmark. A shift to epidemiology benchmarking will enable the consideration of global participants into US analyses for highly intrinsic (i.e. influenced by ancestry) diseases and more firm requirements for US-based participants into US analyses for extrinsic (i.e. influenced by location or culture) diseases. Benchmarking in line with epidemiologic data will allow us to set better trial enrollment goals, with the aim of conducting more demographically balanced, diverse, and representative clinical trials and enabling a better understanding of drug safety and efficacy per demographic group.

A Rare Case of Staphylococcus lugdunensis Causing a Pseudoaneurysm of the Aorta.

Staphylococcus lugdunensis (SL) is a well-known skin commensal. It is coagulase-negative bacteria that has often been labeled as a contaminant. While coagulase-negative bacteria are not as virulent as Staphylococcus aureus, there has been an increasing trend for this organism to be associated with complications commonly known to occur with its more aggressive counterpart. We report a case of Staphylococcus lugdunensis causing infective endocarditis and pseudoaneurysm of the aorta.

Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants.

GSK3640254 is a next-generation maturation inhibitor with demonstrated potency across HIV-1 subtypes and a high barrier to emergent resistance. This phase I, 2-part, randomized, open-label study (ClinicalTrials.gov identifier, NCT04263142) in healthy participants assessed the relative bioavailability of a single dose of GSK3640254 200 mg in tablet and capsule formulations (part 1) and the effect of food on the pharmacokinetic profile of the tablet formulation (part 2). Overall, 39 participants were randomized to treatment (part 1, n = 18; part 2, n = 21). All participants in part 1 completed the study; 2 participants in part 2 withdrew before study completion (adverse event, n = 1; physician decision, n = 1). In part 1, plasma exposures of the GSK3640254 tablet formulation were not meaningfully different from those of the capsule formulation when administered in the presence of a moderate-fat meal. In part 2, GSK3640254 plasma exposures increased by ≈3- to 4-fold under high- and moderate-fat conditions, respectively, compared with fasted conditions. No major safety or tolerability findings were observed. The highest incidence of adverse events (24%) was reported under high-fat conditions. Taken together, these data support the use of the tablet formulation coadministered with food in the clinical development of GSK3640254 for treatment of HIV-1.

Structural Compactness in Hen Egg White Lysozyme Induced by Bisphenol†S: A†Spectroscopic and Molecular Dynamics Simulation Approach.

The endocrine disrupting compound Bisphenol and its analogues are widely used in food packaging products and can cause serious health hazards. The protein, Lysozyme (Lyz), showing anti-microbial properties, is used as a "natural" food and dairy preservative. Herein, we explored the interaction between Lyz and Bisphenol S (BPS) by multi-spectroscopic and theoretical approaches. Lyz interacts with BPS through static quenching, where hydrophobic force governed the underlying interaction. Molecular docking results reveal that tryptophan plays a vital role in binding, corroborated well with near UV-CD studies. A decrease in the radius of gyration (from 1.43 nm to 1.35 nm) of Lyz substantiates the compactness of the protein conformation owing to such an interaction. This structural alteration experienced by Lyz may alter its functional properties as a food preservative. Consequently, this can degrade the quality of the food products and thereby lead to severe health issues.

Conned by Conn's: The Manifestation of Conn's Syndrome Post-renal Transplant in a Patient with Polycystic Kidney Disease.

We present the case of a 66-year-old African-American male with end-stage renal disease (ESRD) secondary to polycystic kidney disease (PCKD), with well-controlled hypertension. He was placed on peritoneal dialysis for two years before successfully undergoing a cadaveric renal transplant. There was an immediate graft function with no relevant postoperative complications. On regular follow-ups two months later, the patient now presents with worsening control of hypertension despite an increase in anti-hypertensive medications. Common causes of new-onset hypertension, such as renal artery stenosis, anti-calcineurin therapy, and allograft injury, were excluded. The patient's biochemistry revealed the presence of hypokalemia, which was absent in previous reports. In light of this, plasma aldosterone and renin levels were sent and were found to be elevated: aldosterone: 50.4 ng/dL, renin: 0.4 ng/dL, aldosterone-renin Ratio (ARR): 126. In retrospect, a routine CT (computed tomography) scan performed in 2017 revealed an adrenal adenoma of 17 x 13 mm, which was diagnosed as an incidental finding at that time. A repeat CT scan was performed and showed no change in the size of the adenoma. In view of the new symptoms, the patient was started on spironolactone with little to no improvement in blood pressure and potassium levels. We present a case of Conn's syndrome in a patient with PCKD manifesting only after a renal transplant.

Effect of Silica Nanoparticles on the Amyloid Fibrillation of Lysozyme.

Protein fibrils are regarded as undesired products as these are associated with numerous neuro- and non-neurodegenerative disorders. Increasing evidence suggests that the mechanism of fibrillation involves the formation of various oligomeric intermediates, which are known to be more toxic than mature fibrils. Here, we report the impact of synthesized silica nanoparticles (SiNPs) of diameters ∼52 nm on the aggregation behavior of hen egg white lysozyme (HEWL) under heat and acidic conditions. Congo red as well as ThT binding assays and AFM imaging studies indicate that SiNPs trigger the amyloid formation of HEWL in a dose-dependent manner. ThT kinetic studies and FTIR studies suggest that the fibrillation kinetics does not involve the formation of toxic oligomeric intermediates at higher concentrations of SiNPs. By measuring fluorescence lifetime values of the bound ThT, SiNP-induced fibrillation of HEWL can easily be realized. CD spectroscopic studies indicate that native HEWL becomes unfolded upon incubation under the experimental conditions and is rapidly converted into the ß-sheet-rich fibrillar aggregates in the presence of SiNPs with increasing concentrations. It has been further revealed that fibrillar aggregates formed at higher concentrations of SiNPs preferably adopt an antiparallel ß-sheet configuration. The enhanced fibrillation in the presence of SiNPs is likely because of preferential adsorption of the non-amyloidogenic regions of HEWL, resulting in the exposure of the aggregation-prone regions of HEWL toward the solvent. The study will provide deeper insights into the evolution of oligomer-free fibrillation that can be useful to demonstrate the underlying mechanism of amyloid fibrillation.