Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect

No abstract available

Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients

Purpose: Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity. Methods: We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients during therapy. Results: We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that patients. Conclusions: Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrexate- induced neurotoxic effects

Effects of 'pre-fracking' operations on ambient air quality at a shale gas exploration site in rural North Yorkshire, England

Rural observations of air quality and meteorological parameters (NOx, O3, NMHCs, SO2, PM) were made over a 2.5-year period (2016-2018) before, during and after preparations for hydraulic fracturing (fracking) at a shale gas exploration site near Kirby Misperton, North Yorkshire, England. As one of the first sites to apply for permits to carry out hydraulic fracturing, it has been subject to extensive regulatory and public scrutiny, as well as the focus for a major programme of long-term environmental monitoring. A baseline period of air quality monitoring (starting 2016) established the annual climatology of atmospheric composition against which a 20-week period of intensive activity on the site in preparation for hydraulic fracturing could be compared. During this 'pre-operational phase' of work in late 2017, the most significant effect was an increase in ambient NO (3-fold) and NOx (2-fold), arising from a combination of increased vehicle activity and operation of equipment on site. Although ambient NOx increased, air quality limit values for NO2 were not exceeded, even close to the well-site. Local ozone concentrations during the pre-operational period were slightly lower than the baseline phase due to titration with primary emitted NO. The activity on site did not lead to significant changes in airborne particulate matter or non-methane hydrocarbons. Hydraulic fracturing of the well did not subsequently take place and the on-site equipment was decommissioned and removed. Air quality parameters then returned to the original (baseline) climatological conditions. This work highlights the need to characterise the full annual climatology of air quality parameters against which short-term local activity changes can be compared. Based on this study, changes to ambient NOx appear to be the most significant air quality ahead of hydraulic fracturing. However, in rural locations, concentrations at individual sites are expected to be below ambient air quality limit thresholds

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Prevalence, features and workplace factors associated with burnout among intensivists in Australia and New Zealand

Objectives: To investigate the prevalence and features of self-reported burnout among intensivists working in Australia and New Zealand, and evaluate potentially modifiable workplace stressors associated with increased risk of self-reported burnout. Methods: We performed an electronic survey among registered intensivists in Australia and New Zealand. Burnout and professional quality of life were measured using the Professional Quality of Life Scale version 5 (ProQOL-5). Socio-organisational factors were defined a priori and assessed using a five-point Likert scale. Thematic analysis was conducted on an open-ended question on workplace stressors. Results: 261 of 921 estimated intensivists responded (response rate, 28.3%). Overall, few participants (0.8%) demonstrated high scores (> 75th centile) for burnout, and 70.9% of participants scored in the average range for burnout. Of note, 98.1% of participants scored in the average to high range for compassion satisfaction. No association was found between sex, age, or years of practice with the level of burnout or compassion satisfaction. Seven themes emerged regarding intensivists' most stressful aspects of work: interpersonal interactions and workplace relationships (25.5%), workload and its impact (24.9%), resources and capacity (22.6%), health systems leadership and bureaucracy (16.1%), end-of-life issues and moral distress (8.4%), clinical management (4.9%), and job security and future uncertainty (1.3%). Conclusion: Fewer Australian and New Zealand intensivists experienced burnout than previously reported. Many self-reported work stressors do not relate to clinical work and are due to interpersonal interactions with other colleges and hospital administrators. Such factors are potentially modifiable and could be the focus of future interventions

Optimization of adsorptive removal of α-toluic acid by CaO2 nanoparticles using response surface methodology

The present work addresses the optimization of process parameters for adsorptive removal of α-toluic acid by calcium peroxide (CaO2) nanoparticles using response surface methodology (RSM). CaO2 nanoparticles were synthesized by chemical precipitation method and confirmed by Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analysis which shows the CaO2 nanoparticles size range of 5–15 nm. A series of batch adsorption experiments were performed using CaO2 nanoparticles to remove α-toluic acid from the aqueous solution. Further, an experimental based central composite design (CCD) was developed to study the interactive effect of CaO2 adsorbent dosage, initial concentration of α-toluic acid, and contact time on α-toluic acid removal efficiency (response) and optimization of the process. Analysis of variance (ANOVA) was performed to determine the significance of the individual and the interactive effects of variables on the response. The model predicted response showed a good agreement with the experimental response, and the coefficient of determination, (R2) was 0.92. Among the variables, the interactive effect of adsorbent dosage and the initial α-toluic acid concentration was found to have more influence on the response than the contact time. Numerical optimization of process by RSM showed the optimal adsorbent dosage, initial concentration of α-toluic acid, and contact time as 0.03 g, 7.06 g/L, and 34 min respectively. The predicted removal efficiency was 99.50%. The experiments performed under these conditions showed α-toluic acid removal efficiency up to 98.05%, which confirmed the adequacy of the model prediction