Raising concerns in the current NHS climate: a qualitative study exploring junior doctors’ attitudes to training and teaching

BACKGROUND: High profile cases continue to demonstrate failures to raise concerns with detrimental effects on patient safety. This research sought to establish what educational support junior doctors needed to effectively raise clinical and professional concerns. // STUDY DESIGN: A qualitative study with 16 participants taking part in three focus groups. The transcripts were thematically analysed. // RESULTS: All the data could be coded into four themes: past experiences of teaching; suggested teaching; reporting mechanisms and educational challenges. Most participants were dissatisfied with the teaching they had received on raising concerns. Current systems were thought to be good for raising patient safety issues but not for concerns about professional behaviour of healthcare staff. // CONCLUSIONS: There is a need for improved education to tackle the way this is taught in postgraduate curricula. Frequent rotations and a lack of meaningful relationships left junior doctors feeling less invested in improving organisational culture. Junior doctors are apprehensive about raising concerns because of personal risk to their career trajectory

Attitudes towards attrition among UK trainees in obstetrics and gynaecology

Physician dissatisfaction in the workplace has consequences for patient safety. Currently in the UK, 1 in 5 doctors who enter specialist training in obstetrics and gynaecology leave the programme before completion. Trainee attrition has implications for workforce planning, organization of health-care services and patient care. The authors conducted a survey of current trainees' and former trainees' views concerning attrition and ‘peri-attrition’ – a term coined to describe the trainee who has seriously considered leaving the specialty. The authors identified six key themes which describe trainees' feelings about attrition in obstetrics and gynaecology: morale and undermining; training processes and paperwork; support and supervision; work–life balance and realities of life; NHS environment; and job satisfaction. This article discusses themes of an under-resourced health service, bullying, lack of work–life balance and poor personal support

Breaking the cycle: reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate

Objective To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in relapsing-remitting MS patients (RRMS) using untargeted plasma metabolomics. Methods Plasma from 27 RRMS patients was collected at baseline and six-weeks after initiating DMF. Patients were separated into discovery (n=15) and validation cohorts (n=12). Ten healthy controls were also recruited. Metabolomic profiling using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was performed on the discovery cohort and healthy controls at Metabolon Inc. (Durham, NC). UPLC-MS was performed on the validation cohort at the National Phenome Centre (London, UK). Plasma neurofilament concentration (pNfL) was assayed using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events. Results In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine increased 6-weeks following treatment (q < 0.05). Methyl succinyl carnitine increased in the validation cohort (q < 0.05). These changes were not observed in the control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing, abdominal symptoms). pNfL concentration was higher in RRMS patients than controls and reduced over 15-months treatment. Conclusion TCA cycle intermediates and metabolites are increased in RRMS patients treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxylic acid receptor-2 to both therapeutic effects and adverse events requires investigation

Lipoprotein markers associated with disability from multiple sclerosis

Altered lipid metabolism is a feature of chronic inflammatory disorders. Increased plasma lipids and lipoproteins have been associated with multiple sclerosis (MS) disease activity. Our objective was to characterise the specific lipids and associated plasma lipoproteins increased in MS and to test for an association with disability. Plasma samples were collected from 27 RRMS patients (median EDSS, 1.5, range 1–7) and 31 healthy controls. Concentrations of lipids within lipoprotein sub-classes were determined from NMR spectra. Plasma cytokines were measured using the MesoScale Discovery V-PLEX kit. Associations were tested using multivariate linear regression. Differences between the patient and volunteer groups were found for lipids within VLDL and HDL lipoprotein sub-fractions (p < 0.05). Multivariate regression demonstrated a high correlation between lipids within VLDL sub-classes and the Expanded Disability Status Scale (EDSS) (p < 0.05). An optimal model for EDSS included free cholesterol carried by VLDL-2, gender and age (R2 = 0.38, p < 0.05). Free cholesterol carried by VLDL-2 was highly correlated with plasma cytokines CCL-17 and IL-7 (R2 = 0.78, p < 0.0001). These results highlight relationships between disability, inflammatory responses and systemic lipid metabolism in RRMS. Altered lipid metabolism with systemic inflammation may contribute to immune activation

Personalised medicine for multiple sclerosis care.

Treatments with a range of efficacy and risk of adverse events have become available for the management of multiple sclerosis (MS). However, now the heterogeneity of clinical expression and responses to treatment pose major challenges to improving patient care. Selecting and managing the drug best balancing benefit and risk demands a new focus on the individual patient. Personalised medicine for MS is based on improving the precision of diagnosis for each patient in order to capture prognosis and provide an evidence-based framework for predicting treatment response and personalising patient monitoring. It involves development of predictive models involving the integration of clinical and biological data with an understanding of the impact of disease on the lives of individual patients. Here, we provide a brief, selective review of challenges to personalisation of the management of MS and suggest an agenda for stakeholder engagement and research to address them

Mononuclear cell transcriptome changes associated with dimethyl fumarate in multiple sclerosis.

Objective To identify short-term changes in gene expression in peripheral blood mononuclear cells (PBMCs) associated with treatment response to dimethyl fumarate (DMF, Tecfidera) in patients with relapsing-remitting MS (RRMS). Methods Blood samples were collected from 24 patients with RRMS (median Expanded Disability Status Scale score, 2.0; range 1–7) at baseline, 6 weeks, and 15 months after the initiation of treatment with DMF (BG-12; Tecfidera). Seven healthy controls were also recruited, and blood samples were collected over the same time intervals. PBMCs were extracted from blood samples and sequenced using next-generation RNA sequencing. Treatment responders were defined using the composite outcome measure “no evidence of disease activity” (NEDA-4). Time-course and cross-sectional differential expression analyses were performed to identify transcriptomic markers of treatment response. Results Treatment responders (NEDA-4 positive, 8/24) over the 15-month period had 478 differentially expressed genes (DEGs) 6 weeks after the start of treatment. These were enriched for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inhibition of nuclear factor κB (NFκB) pathway transcripts. For patients who showed signs of disease activity, there were no DEGs at 6 weeks relative to their (untreated) baseline. Contrasting transcriptomes expressed at 6 weeks with those at 15 months of treatment, 0 and 1,264 DEGs were found in the responder and nonresponder groups, respectively. Transcripts in the nonresponder group (NEDA-4 negative, 18/24) were enriched for T-cell signaling genes. Conclusion Short-term PBMC transcriptome changes reflecting activation of the Nrf2 and inhibition of NFκB pathways distinguish patients who subsequently show a medium-term treatment response with DMF. Relative stabilization of gene expression patterns may accompany treatment-associated suppression of disease activity