Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Can simulation-based education and precision teaching improve paediatric trainees’ behavioural fluency in performing lumbar puncture? A pilot study

Abstract Background Low levels of success in performing lumbar puncture have been observed among paediatric trainees. This study assessed the efficacy of simulation-based education with frequency building and precision teaching for training lumbar puncture to behavioural fluency. Methods The intervention group was assessed at baseline, at the final training trial, in the presence of distraction, and a minimum of one month after the cessation of the intervention in order to ascertain whether behavioural fluency in lumbar puncture was obtained. Subsequently, the performance of this intervention group (10 paediatric senior house officers) was compared to the performance of a comparator group of 10 more senior colleagues (paediatric registrars) who had not received the intervention. Retrospective chart audit was utilised to examine performance in the clinical setting. Results Intervention group participants required a mean of 5 trials to achieve fluency. Performance accuracy was significantly higher in the intervention group than the comparator group. Learning was retained at follow-up and persisted during distraction. Retrospective chart audit revealed no significant difference between the performance of the intervention group and a comparator group, comprised of more senior physicians, in the clinical setting, although the interpretation of these analyses are limited by a low number of lumbar punctures performed in the clinical setting. Conclusions The programme of simulation-based education with frequency building and precision teaching delivered produced behavioural fluency in lumbar puncture among paediatric trainees. Following the intervention, the performance of these participants was equivalent to, or greater than, that of senior paediatricians. This study supports the need for further research exploring the effectiveness of simulation-based education with precision teaching to train procedural skills to fluency, and the consideration of how best to explore the impact of these on patient outcomes

An assessment of the simulated performance of basic clinical procedures by junior doctors during the first year of clinical practice

Abstract Background Upon entering the healthcare system, junior doctors may lack the skills required to care for patients, and feel unprepared for their role, with considerable variation in the level of proficiency in the performance of particular clinical procedures. Objective To compare the performance and proficiency (self-report and observed) of the performance of nine basic clinical procedures. Methods Seventeen interns were observed performing nine clinical procedures in a simulated setting in June 2021 (Assessment 1) and January 2022 (Assessment 2). The observers identified whether each step in the procedure was performed correctly, and provided an overall assessment of proficiency. The participants also rated their own level proficiency. Results At Assessment 1 the number of steps performed correctly ranged from a mean of 41.9–83.5%. At Assessment 2 the number of steps performed correctly ranged from a mean of 41.9–97.8%. The most common median proficiency rating for Assessment 1 was ‘close supervision’, and was ‘indirect supervision’ at Assessment 2. There was a significant and large effect size in the improvement in performance from Assessment 1 to Assessment 2. Low correlations were found between observer and self-reported proficiency in performance of the procedures. Conclusions The large improvement in performance across the two assessments is encouraging. However, there is a need to address the variability in performance on graduation from medical school, and to ensure that any assessment of proficiency is not only reliant on self-report

Stress, coping, and psychological resilience among physicians

Abstract Background Recent research has demonstrated that burnout is widespread among physicians, and impacts their wellbeing, and that of patients. Such data have prompted efforts to teach resilience among physicians, but efforts are hampered by a lack of understanding of how physicians experience resilience and stress. This study aimed to contribute to knowledge regarding how physicians define resilience, the challenges posed by workplace stressors, and strategies which enable physicians to cope with these stressors. Methods A qualitative approach was adopted, with 68 semi-structured interviews conducted with Irish physicians. Data were analysed using deductive content-analysis. Results Five themes emerged from the interviews. The first theme, ‘The Nature of Resilience’ captured participants’ understanding of resilience. Many of the participants considered resilience to be “coping”, rather than “thriving” in instances of adversity. The second theme was ‘Challenges of the Profession’, as participants described workplace stressors which threatened their wellbeing, including long shifts, lack of resources, and heavy workloads. The third theme, ‘Job-related Gratification’, captured aspects of the workplace that support resilience, such as gratification from medical efficacy. ‘Resilience Strategies (Protective Practices)’ summarised coping behaviours that participants considered to be beneficial to their wellbeing, including spending time with family and friends, and the final theme, ‘Resilience Strategies (Attitudes)’, captured attitudes which protected against stress and burnout. Conclusions This study emphasised the need for further research the mechanisms of physician coping in the workplace and how we can capitalise on insights into physicians’ experiences of coping with system-level stressors to develop interventions to improve resilience

The development and preliminary evaluation of a clinician e-learning training platform for a neonatal sepsis risk monitor for use in ICU settings

International audienceBackground: Training clinicians on the use of hospital-based patient monitoring systems (PMS) is vital to mitigate the risk of use errors and of frustration using these devices, especially when used in ICU settings. PMS training is typically delivered through face-to-face training sessions in the hospital. However, it is not always feasible to deliver training in this format to all clinical staff given some constraints (e.g., availability of staff and trainers to attend in-person training sessions and the costs associated with face-to-face training). Objective: The literature indicates that E-learning has the potential to mitigate barriers associated with time restrictions for trainers and trainees and evidence shows it to be more flexible, and convenient for learners in healthcare settings. This study aimed to develop and carry out a preliminary evaluation via a case study of an e -learning training platform designed for a novel neonatal sepsis risk monitor system (Digi-NewB).Methods: A multi-modal qualitative research case study approach was used, including the analysis of three qualitative data sources: (i) audio/video recordings of simulation sessions in which participants were asked to operate the system as intended (e.g., update the clinical observations and monitor the sepsis risk), (ii) interviews with the simulation participants and an attending key opinion leader (KOL), who observed all simulation ses-sions, and (iii) post-simulation survey.Results: After receiving ethical approval for the study, nine neonatal intensive care unit (NICU) nurses completed the online training and participated in the simulation and follow-up interview sessions. The KOL was also interviewed, and seven out of the nine NICU nurses answered the post-simulation survey. The video/audio analysis of the simulations revealed that participants were able to use and interpret the Digi-NewB interface. Interviews with simulation participants and the KOL, and feedback extracted from the survey, revealed that participants were overall satisfied with the training platform and perceived it as an efficient and effective method to deliver medical device training.Conclusions: This study developed an online training platform to train clinicians in the use of a critical care medical device and carried out a preliminary evaluation of the platform via a case study. The e-learning platform was designed to supplement and enhance other training approaches. Further research is required to evaluate the effectiveness of this approach

Exploring barriers and enablers to simulation-based training in emergency departments: an international qualitative study (BEST-ED Study)

Introduction Simulation-based training (SBT) has gained significant traction within emergency medicine. The growing body of evidence describes the benefits that SBT can bring. However, identifying barriers and enablers when establishing successful SBT programmes in busy emergency departments (EDs), and ensuring longevity of such programmes, can be difficult.Objective We aim to identify barriers and enablers to SBT in busy EDs.Methods We explored and analysed the thoughts, experience and opinions of professionals involved in SBT and organisational support. 32 participants across 15 international sites were invited to a semistructured interview process. We included participants from a variety of backgrounds, from clinical staff to management staff. Transcribed interview data was classified and coded based on capability, opportunity and motivation behaviour (COM-B) domains and analysed based on theoretical domains framework. Frequency of the most mentioned thematic domain among participants is reported.Results The interview data revealed several common themes, including the following: knowledge and skills (90%), support and leadership (96%), mental barriers (87.5%), local culture (96.6%), dedicated space (65.2%), time constraints (46.8%), social influence (87.5%), education (90.6%), professional development (68.75%), exams (59.3%) and personal goals (93.75%). Management staff was observed to prioritise resource, staffing and flow, while the clinical cohort tended to focus on specialty and personal development when it came to simulation training in the ED.Conclusion Potential barriers and enablers to SBT and in situ simulation for EDs were identified through interviews conducted in this study. The central themes in terms of barriers and enablers were local culture, leadership, individual needs, resources and optimisation. A tailored approach is vital for establishing a successful SBT and in situ simulation programme