Correlation of SARS-CoV-2 Viral Load and Clinical Evolution of Pediatric Patients in a General Hospital From Buenos Aires, Argentina.

Background: SARS-CoV-2 infection is associated with a wide range of clinical manifestations and severity. Pediatric cases represent <10% of total cases, with a mortality rate below 1%. Data of correlation between SARS-CoV-2 viral load in respiratory samples and severity of disease in pediatric patients is scarce. The cycle threshold (CT) value for the detection of SARS-CoV-2 could be used as an indirect indicator of viral load in analyzed respiratory samples. Objective: The aim of this study was to describe CT values and their correlation with clinical manifestations, epidemiology and laboratory parameters in pediatric patients with confirmed COVID-19. Methods: In this observational, retrospective, analytic and single-center study we included patients under 15 years with confirmed COVID-19 by RT-PCR SARS-CoV-2 admitted to the Isidoro Iriarte Hospital (Argentina) between March 1st 2020 and April 30th 2021. Results: 485 patients were included, the distribution according to disease severity was: 84% (408 patients) presented mild disease, 12% (59 patients) moderate disease and 4% (18 patients) severe disease. Patients with moderate and severe illness had an increased hospitalization rate, prolonged hospitalization, higher frequency of comorbidities and oxygen and antibiotics use. CT values, that could be used as an indirect measure of viral load, was associated with severity of clinical manifestations and age under 12 months. No patient required admission to PICU nor mechanical ventilation. No deaths were registered. Conclusions: In this study, the viral load of SARS-CoV-2 in respiratory samples, determined by the cycle threshold, was significantly correlated with moderate to severe cases and with age.

Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma.

The Ras homologous family of small guanosine triphosphate-binding enzymes (GTPases) is critical for cell migration and proliferation. The novel drug 1A-116 blocks the interaction site of the Ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase with some of its guanine exchange factors (GEFs), such as T-cell lymphoma invasion and metastasis 1 (TIAM1), inhibiting cell motility and proliferation. Knowledge of circadian regulation of targets can improve chemotherapy in glioblastoma. Thus, circadian regulation in the efficacy of 1A-116 was studied in LN229 human glioblastoma cells and tumor-bearing nude mice. METHODS: Wild-type LN229 and BMAL1-deficient (i.e., lacking a functional circadian clock) LN229E1 cells were assessed for rhythms in TIAM1, BMAL1, and period circadian protein homolog 1 (PER1), as well as Tiam1, Bmal1, and Rac1 mRNA levels. The effects of 1A-116 on proliferation, apoptosis, and migration were then assessed upon applying the drug at different circadian times. Finally, 1A-116 was administered to tumor-bearing mice at two different circadian times. RESULTS: In LN229 cells, circadian oscillations were found for BMAL1, PER1, and TIAM1 (mRNA and protein), and for the effects of 1A-116 on proliferation, apoptosis, and migration, which were abolished in LN229E1 cells. Increased survival time was observed in tumor-bearing mice when treated with 1A-116 at the end of the light period (zeitgeber time 12, ZT12) compared either to animals treated at the beginning (ZT3) or with vehicle. CONCLUSIONS: These results unveil the circadian modulation in the efficacy of 1A-116, likely through RAC1 pathway rhythmicity, suggesting that a chronopharmacological approach is a feasible strategy to improve glioblastoma treatment.