RESUMO
The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and related sub-lineages. Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants at two levels: (i) we tracked over 400,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using antibody pools. (ii) we mapped the antibody response at the individual level using blood from strigently curated vaccine and convalescent cohorts. In pooled antibody samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases we observed increased antibody breadth to variants that were yet to be in circulation. Resolution of viral neutralisation at the cohort level supported equivalent coverage across prior and emerging variants with emerging isolates BQ.1.1, XBB.1 and BR.2.1 the most evasive. Further, these emerging variants were resistant to Evusheld, whilst neutralization resistance to Sotrovimab was restricted to BQ.1.1 and further supported by lack of Spike glycoprotein binding to this variant. An outgrowth advantage through better utilization of TMPRSS2 was observed across BQ lineages and not those derived from BA.2.75. We conclude at this current point in time that variants derived from BQ lineages can evade antibodies at levels equivalent to their most evasive BA.2.75 counterparts but sustain an entry phenotype that would promote an additional outgrowth advantage.
RESUMO
The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18-60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35% - 60%) and the plasma concentrations increased (170% - 400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.
RESUMO
A popular first principles simulation code, the Vienna Ab initio Simulation Package (VASP), and a crystal structure prediction (CSP) package, the Universal Structure Predictor: Evolutionary Xtallography (USPEX) have been integrated into the GDIS visualization software. The aim of this integration is to provide users with a unique and simple interface through which most of the steps of a typical crystal optimization or prediction work. This involved, for the latter, not only setting up a CSP calculation with complete support for the latest version of USPEX, but also displaying the many structure results by linking each structure geometry and its energy via interactive graphics. For the optimization part, any structure displayed by GDIS can now be the starting point for VASP calculations, with support for its most commonly used parameters. Atomic and electronic structures can be displayed as well as dynamic properties such as total energy, force, volume, and pressure for each ionic step. It is not only possible to start calculations from the GDIS visualization software, using an in-place task manager, but a running calculation can also be followed, allowing a greater control of the simulation process. The GDIS software is available under the GNU public license in its second version.
RESUMO
This study aimed to evaluate functional effects of Bobath therapy in children with cerebral palsy (CP). Fifteen children with a diagnosis of CP were recruited (9 males, 6 females; mean age 7 years 4 months, SD 2 years 8 months; age range 2 to 12 years). Types of motor disorder were as follows: spastic quadriplegia (n=9); spastic diplegia (n=4); athetoid quadriplegia (n=1), and ataxia (n=1). Participants were distributed across the following Gross Motor Function Classification levels: level I, n=1; level II, n=4; level III, n=5; level IV, n=4; and level V, n=1. Children awaiting orthopaedic intervention were excluded. A repeated measures design was used with participants tested with the Gross Motor Function Measure (GMFM) and Pediatric Evaluation of Disability Inventory (PEDI) at 6-weekly intervals (baseline, before and after Bobath therapy, and follow-up). As the data were of ordinal type, non-parametric statistics were used, i.e. Wilcoxon's test. Participants showed a significant improvement in scores in the following areas following Bobath therapy compared with the periods before and after Bobath therapy: GMFM total score (p=0.009); GMFM goal total (p=0.001); PEDI self care skills (p=0.036); and PEDI caregiver assistance total score (p=0.012). This demonstrates that in this population, gains were made in motor function and self care following a course of Bobath therapy.