ABSTRACT
Therapeutic applications of synthetic mRNA were proposed more than 30 years ago, and are currently the basis of one of the vaccine platforms used at a massive scale as part of the public health strategy to get COVID-19 under control. To date, there are no published studies on the biodistribution, cellular uptake, endosomal escape, translation rates, functional half-life and inactivation kinetics of synthetic mRNA, rates and duration of vaccine-induced antigen expression in different cell types. Furthermore, despite the assumption that there is no possibility of genomic integration of therapeutic synthetic mRNA, only one recent study has examined interactions between vaccine mRNA and the genome of transfected cells, and reported that an endogenous retrotransposon, LINE-1 is unsilenced following mRNA entry to the cell, leading to reverse transcription of full length vaccine mRNA sequences, and nuclear entry. This finding should be a major safety concern, given the possibility of synthetic mRNA-driven epigenetic and genomic modifications arising. We propose that in susceptible individuals, cytosolic clearance of nucleotide modified synthetic (nms-mRNAs) is impeded. Sustained presence of nms-mRNA in the cytoplasm deregulates and activates endogenous transposable elements (TEs), causing some of the mRNA copies to be reverse transcribed. The cytosolic accumulation of the nms-mRNA and the reverse transcribed cDNA molecules activates RNA and DNA sensory pathways. Their concurrent activation initiates a synchronized innate response against non-self nucleic acids, prompting type-I interferon and pro-inflammatory cytokine production which, if unregulated, leads to autoinflammatory and autoimmune conditions, while activated TEs increase the risk of insertional mutagenesis of the reverse transcribed molecules, which can disrupt coding regions, enhance the risk of mutations in tumour suppressor genes, and lead to sustained DNA damage. Susceptible individuals would then expectedly have an increased risk of DNA damage, chronic autoinflammation, autoimmunity and cancer. In light of the current mass administration of nms-mRNA vaccines, it is essential and urgent to fully understand the intracellular cascades initiated by cellular uptake of synthetic mRNA and the consequences of these molecular events.
ABSTRACT
Objectives: The COVID-19 pandemic created an urgent need for protecting patients and clinicians through replacement of face-to-face (F2F) clinics. We aimed to characterise if there were benefits in terms of patient travel time and costs, and environmental savings including carbon emissions. Design: Retrospective cross-sectional study of individual and environmental savings through F2F replacement virtual appointments, during a COVID-19 lockdown. Subjects: 426 Adult neurosurgical patients who underwent a virtual consultation at University Hospital of Wales between 01 April 2020 and 31 May 2020. Methods: All planned adult neurosurgical outpatients' appointments in Wales in the above period were reviewed. A successful replacement 'virtual' appointment was defined as one in which onward clinical management occurred, either by phone, video, or letter. Estimated savings in total mileage, travel time, and petrol costs were derived using a web mapping software and UK government databases. Carbon emissions were approximated based on UK's most popular car. Results: 81 Clinics were conducted. 552 patients originally had F2F appointments scheduled. 77.2% (426) were successfully completed virtually, 12.1% were rearranged and 10.7% were insufficient due to technical issues, need for clinical examination or missed appointment. Successful consultations translated into the following savings: total road mileage (22,651 miles), petrol costs (£3715;mean £8.72/patient), travel time (630 h;median 75 min/patient) and carbon emissions (3.1 tonnes CO2 equivalent). On a 0-10 scale (0= poor, 10= excellent), 81% of patients rated their virtual consultation experience between 7 and 10. 72% of patients would recommend the service to others, and 37% would like virtual consults in the future. Conclusions: Virtual consultations offer several benefits for patients (saving travel time, mileage, and fuel costs) and the environment (reducing emissions and potentially, healthcarerelated traffic and accidents). While they do not replace F2F appointments entirely, they allow greater patient choice and may have a significant role in a future hybrid outpatients model.
ABSTRACT
Objectives: Recent reforms to postgraduate medical education, the 'Shape of Training (SoT)' and 'Excellence by Design: standard for postgraduate curricula' mandate a re-evaluation of the way in which surgical education is delivered, particularly in the teaching of surgical techniques. More so, as we continue to train with the restrictions imposed by the COVID pandemic, emphasis must be placed on maximising every training opportunity. Design: In this article, we demonstrate the utility of an instructional design method to enhance the teaching of neurosurgical procedures. Specifically, we utilise the instructional design method of teaching first described by Robert Gagne in the 1960s. Subjects: The framework we provide can be used to equip all neurosurgical trainees with the necessary capabilities to achieve the high-level outcomes expected from the new curriculum. Methods: We design a lesson plan using Gagne's nine events of instruction, in this case using burr hole evacuation of chronic subdural haematomas as an example. The ordered nature of Gagne's nine-step model allows a complete picture to be formed and structures teaching for a comparable learning experience. Conclusions: One particular strength of this teaching method is placing the learned skill in the wider context of patient care includes perioperative management. By empowering trainees to consider all aspects of the underlying reasoning for a procedure, well-rounded clinicians can be developed who are comfortable in the real-world application of procedural skills. The creative lesson plan optimises the learning process and ensures that the objectives are comprehensively fulfilled. The structured approach fortifies a good basis for understanding the operation and ensures that progression to independence is a safe approach.