Possible mechanism of action potential propagation mediated by static electric field: A novel assumption of understanding nerve interaction and ephaptic coupling.

The generation and propagation of physical signals in living biosystems are continuous issues. Traditional Hodgkin-Huxley model based on ionic current conduction could not explain the fast transmission of action potential in myelinated axons and factors influencing action potential velocity. We propose that the ion flow induced by N a v channel generates near field quasi-static electric field at extracellular space, termed as an ephaptic field which is able to excite nearby passive axons. Our simulation indicates that the static electric field produced by sodium ion channels in one node of Ranvier is improbable to stimulate the ion channels in the adjacent neighboring node. However, the ion channel ring in one node of Ranvier could induce the shift of membrane potential (0.01 mV) on the node at nearby axons (100 µm) in a bundle of axon synchronously, suggesting zig-zag propagation of action potential. Together with the superposition effect of ephaptic feedback field generated by the synchronized movement of adjacent parallel axons stimulate the adjacent node of the original axon, strengthen the action potential to travel in a zig-zag pattern. Our model also provides an explanation for the rapid velocity of action potential propagation reported in experimental studies.

Impaired calcium influx underlies skewed T helper cell differentiation in children with IgE-mediated food allergies.

BACKGROUND: Reasons for Th2 skewing in IgE-mediated food allergies remains unclear. Clinical observations suggest impaired T cell activation may drive Th2 responses evidenced by increased atopic manifestations in liver transplant patients on tacrolimus (a calcineurin inhibitor). We aimed to assess differentiation potential, T cell activation and calcium influx of naïve CD4+ T cells in children with IgE-mediated food allergies. METHODS: Peripheral blood mononuclear cells from infants in the Starting Time for Egg Protein (STEP) Trial were analyzed by flow cytometry to assess Th1/Th2/Treg development. Naïve CD4+ T cells from children with and without food allergies were stimulated for 7 days to assess Th1/Th2/Treg transcriptional factors and cytokines. Store operated calcium entry (SOCE) was measured in children with and without food allergies. The effect of tacrolimus on CD4+ T cell differentiation was assessed by treating stimulated naïve CD4+ T cells from healthy volunteers with tacrolimus for 7 days. RESULTS: Egg allergic infants had impaired development of IFNγ+ Th1 cells and FoxP3+ transitional CD4+ T cells compared with non-allergic infants. This parallels reduced T-bet, IFNγ and FoxP3 expression in naïve CD4+ T cells from food allergic children after in vitro culture. SOCE of naïve CD4+ T cells was impaired in food allergic children. Naïve CD4+ T cells treated with tacrolimus had reduced IFNγ, T-bet, and FoxP3, but preserved IL-4 expression. CONCLUSIONS: In children with IgE-mediated food allergies, dysregulation of T helper cell development is associated with impaired SOCE, which underlies an intrinsic impairment in Th1 and Treg differentiation. Along with tacrolimus-induced Th2 skewing, this highlights an important role of SOCE/calcineurin pathway in T helper cell differentiation.

Phase I PIANO trial-PIPAC-oxaliplatin and systemic nivolumab combination for gastric cancer peritoneal metastases: clinical and translational outcomes.

INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy-oxaliplatin (PIPAC-OX) induces direct DNA damage and immunogenic cell death in patients with gastric cancer peritoneal metastases (GCPM). Combining PIPAC-OX with immune checkpoint inhibition remains untested. We conducted a phase I first-in-human trial evaluating the safety and efficacy of PIPAC-OX combined with systemic nivolumab (NCT03172416). METHODS: Patients with GCPM who experienced disease progression on at least first-line systemic therapy were recruited across three centers in Singapore and Belgium. Patients received PIPAC-OX at 90 mg/m2 every 6 weeks and i.v. nivolumab 240 mg every 2 weeks. Translational studies were carried out on GCPM samples acquired during PIPAC-OX procedures. RESULTS: In total, 18 patients with GCPM were prospectively recruited. The PIPAC-OX and nivolumab combination was well tolerated with manageable treatment-related adverse events, although one patient suffered from grade 4 vomiting. At second and third PIPAC-OX, respectively, the median decrease in peritoneal cancer index (PCI) was -5 (interquartile range: -12 to +1) and -7 (interquartile range: -6 to -20) and peritoneal regression grade 1 or 2 was observed in 66.7% (6/9) and 100% (3/3). Translational analyses of 43 GCPM samples revealed enrichment of immune/stromal infiltration and inflammatory signatures in peritoneal tumors after PIPAC-OX and nivolumab. M2 macrophages were reduced in treated peritoneal tumor samples while memory CD4+, CD8+ central memory and naive CD8+ T-cells were increased. CONCLUSIONS: The first-in-human trial combining PIPAC-OX and nivolumab demonstrated safety and tolerability, coupled with enhanced T-cell infiltration within peritoneal tumors. This trial sets the stage for future combinations of systemic immunotherapy with locoregional intraperitoneal treatments.

'Gear up and get ready': Collaborative curriculum for radiographers supporting percutaneous nephrolithotomy in the operating theatre.

INTRODUCTION: Newly qualified radiographers often find working in the operating theatre (OT) challenging and intimidating. These perceptions, which inhibit confidence, may hinder their effectiveness in interprofessional teamwork, which may in turn adversely affect patient outcomes. A collaborative education programme was designed, building upon the foundations of competency-based education (CBE) and simulation-based mastery learning (SBML) to examine its potential in mitigating these perceptions. The objective of this research was to assess participants' experience and level of competency after attending the curated collaborative educational programme. METHODS: The programme was developed based on the Analysis, Design, Development, Implementation, and Evaluation (ADDIE) model and comprises two teaching and learning phases: educational session and simulation. A collaborative approach was undertaken to develop an assessment checklist for the interprofessional simulation. Requirements for the simulation, such as scenario design, information and storyboard, task trainer, logistics, and learners' briefing, debrief, and feedback, were identified and assembled. The radiographers' performance was recorded using a practical skills assessment checklist and a theory assessment. RESULTS: Twelve radiographers participated and showed improvement in their self-rating of learning objectives before and after the programme. The median (interquartile range) score achieved in the theory assessment, out of a possible of 11, was 9.00 (7.75-9.50). The median (interquartile range) score achieved in the simulation component, out of a possible of 16, was 15.00 (14.00-15.00). There was statistically significant difference in self-perceived performance in all learning objective domains. CONCLUSION: The findings from the programme were promising. The use of simulation and an assessment checklist proved to be useful learning tools in preparing newly qualified radiographers for work in the OT. IMPLICATIONS FOR PRACTICE: Assessment checklists are valuable tools that should be considered to facilitate teaching and learning. The use of interprofessional simulation activities can support radiographers in developing knowledge, professional skills, and clinical competency. It should be conducted in a timely manner to facilitate the introduction to role understanding and effective communication.

Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

The NCS code of practice for the quality assurance of treatment planning systems (NCS-35).

A subcommittee of the Netherlands Commission on Radiation Dosimetry (NCS) was initiated in 2018 with the task to update and extend a previous publication (NCS-15) on the quality assurance of treatment planning systems (TPS) (Bruinviset al2005). The field of treatment planning has changed considerably since 2005. Whereas the focus of the previous report was more on the technical aspects of the TPS, the scope of this report is broader with a focus on a department wide implementation of the TPS. New sections about education, automated planning, information technology (IT) and updates are therefore added. Although the scope is photon therapy, large parts of this report will also apply to all other treatment modalities. This paper is a condensed version of these guidelines; the full version of the report in English is freely available from the NCS website (http://radiationdosimetry.org/ncs/publications). The paper starts with the scope of this report in relation to earlier reports on this subject. Next, general aspects of the commissioning process are addressed, like e.g. project management, education, and safety. It then focusses more on technical aspects such as beam commissioning and patient modeling, dose representation, dose calculation and (automated) plan optimisation. The final chapters deal with IT-related subjects and scripting, and the process of updating or upgrading the TPS.

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.