In-Flight Transmission of a SARS-CoV-2 Lineage B.1.617.2 Harbouring the Rare S:E484Q Immune Escape Mutation

We describe a flight-associated infection scenario of seven individuals with a B.1.617.2 (Delta) lineage, harbouring an S:E484Q point mutation. In Sweden, at least 10% of all positive SARS-CoV-2 samples were sequenced in each county; the B.1.717.2 + S:E484Q combination was not detected in Sweden before and was imported within the scenario described in this report. The high transmission rate of the delta lineage combined with the S:E484Q mutation, associated with immune escape in other lineages, makes this specific genetic combination a possible threat to the global fight against the COVID-19 pandemic. Even within the Omicron wave, the B.1.617.2 + S:E484Q variant appeared in community samples in Sweden, as it seems that this combination has an evolutionary gain compared to other B.1.617.2 lineages. The here described genomic combination was not detectable with the common fasta file-based Pango-lineage analysis, hence increasing the probability of the true global prevalence to be higher.     

Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis

Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising new anti-TB drug, and efavirenz (EFV) is a commonly used antiretroviral. Due to EFV''s induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a phase I, single-dose pharmacokinetic study, a nonlinear mixed-effects model characterizing BDQ pharmacokinetics and interaction with multiple-dose EFV was developed. BDQ pharmacokinetics were best described by a 3-compartment disposition model with absorption through a dynamic transit compartment model. Metabolites M2 and M3 were described by 2-compartment models with clearance of BDQ and M2, respectively, as input. Impact of induction was described as an instantaneous change in clearance 1 week after initialization of EFV treatment and estimated for all compounds. The model predicts average steady-state concentrations of BDQ and M2 to be reduced by 52% (relative standard error [RSE], 3.7%) with chronic coadministration. A range of models with alternative structural assumptions regarding onset of induction effect and fraction metabolized resulted in similar estimates of the typical reduction and did not offer a markedly better fit to data. Simulations to investigate alternative regimens mitigating the estimated interaction effect were performed. The results suggest that simple adjustments of the standard regimen during EFV coadministration can prevent reduced exposure to BDQ without increasing exposures to M2. However, exposure to M3 would increase. Evaluation in clinical trials of adjusted regimens is necessary to ensure appropriate dosing for HIV-infected TB patients on an EFV-based regimen.     

Experiences from treatment-predictive KRAS testing; high mutation frequency in rectal cancers from females and concurrent mutations in the same tumor

Background  

KRAS mutations represent key alterations in colorectal cancer development and lead to constitutive EGFR signaling. Since EGFR inhibition represents a therapeutic strategy in advanced colorectal cancer, KRAS mutation analysis has quickly been introduced as a treatment-predictive test.     

Strenuous exercise increases late outgrowth endothelial cells in healthy subjects

Endothelial progenitor cells (EPCs) and late outgrowth endothelial cells (OECs) seem to play an important role in vessel formation. While EPCs seem to exert their function mainly through a paracrine effect, the OECs can develop into mature endothelial cells and form tubular structures. Exercise is known to increase angiogenic factors that can mobilize EPCs; however, the effect on OECs is not known. We investigated the response to a single session of strenuous exercise on OECs, vascular endothelial growth factor (VEGF) and inflammatory cell levels in the healthy. Eleven healthy subjects performed 1 h of spinning exercise. Blood samples were collected at 1, 6, 24 and 48 h post-exercise for cell culture and biochemical analysis. OEC colonies doubled one hour after the spinning session (baseline 4.5 ± 4.3 vs. 9.0 ± 3.7, P < 0.05). Serum VEGF increased from 194 ± 107 pg/ml at baseline to 224 ± 111 pg/ml after 1 h, p = ns and neutrophilic granulocytes increased from 3.73 ± 1.38 at baseline to 9.08 ± 10.5 at 1 h (P < 0.01). The increased levels of OECs, VEGF and neutrophilic granulocytes declined gradually at the following time points. VEGF levels and neutrophilic granulocytes were highly correlated to OEC levels, r = 0.903 (VEGF) and r = 0.85 (neutrophilic granulocytes), respectively. Strenuous physical activity increases OEC colonies and is correlated to serum VEGF and neutrophilic granulocytes levels. An acute exercise-induced inflammatory response might be responsible for the VEGF release and subsequent increase of OECs. The clinical importance of these findings remains to be elucidated.