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Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry.
No full textTo define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)HLA-DRA sublining fibroblasts, IL1B pro-inflammatory monocytes, ITGAXTBX21 autoimmune-associated B cells and PDCD1 peripheral helper T (T) cells and follicular helper T (T) cells. We defined distinct subsets of CD8 T cells characterized by GZMK, GZMB, and GNLY phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1HLA-DRA fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis
Gentamicin as an alternative to ceftriaxone in the treatment of gonorrhoea: the G-TOG non-inferiority RCT.
No full textBACKGROUND
Gonorrhoea is a common sexually transmitted infection that can cause pain and discomfort, affect fertility in women and lead to epididymo-orchitis in men. Current treatment is with ceftriaxone, but there is increasing evidence of antimicrobial resistance reducing its effectiveness. Gentamicin is a potential alternative treatment requiring further evaluation.
OBJECTIVES
To assess the clinical effectiveness and cost-effectiveness of gentamicin as an alternative treatment to ceftriaxone in the treatment of gonorrhoea.
DESIGN
A multicentre, parallel-group, blinded, non-inferiority randomised controlled trial.
SETTING
Fourteen sexual health clinics in England.
PARTICIPANTS
Adults aged 16-70 years with a diagnosis of uncomplicated, untreated genital, pharyngeal or rectal gonorrhoea based on a positive Gram-stained smear on microscopy or a positive nucleic acid amplification test (NAAT).
RANDOMISATION AND BLINDING
Participants were randomised using a secure web-based system, stratified by clinic. Participants, investigators and research staff assessing participants were blinded to treatment allocation.
INTERVENTIONS
Allocation was to either 240 mg of gentamicin (intervention) or 500 mg of ceftriaxone (standard treatment), both administered as a single intramuscular injection. All participants also received 1 g of oral azithromycin.
MAIN OUTCOME MEASURE
The primary outcome measure was clearance of at all infected sites, confirmed by a negative Aptima Combo 2® (Hologic Inc., Marlborough, MA, USA) NAAT, at 2 weeks post treatment.
RESULTS
We randomised 720 participants, of whom 81% were men. There were 358 participants in the gentamicin group and 362 in the ceftriaxone group; 292 (82%) and 306 (85%) participants, respectively, were included in the primary analysis. Non-inferiority of gentamicin to ceftriaxone could not be demonstrated [adjusted risk difference for microbiological clearance -6.4%, 95% confidence interval (CI) -10.4% to -2.4%]. Clearance of genital infection was similar in the two groups, at 94% in the gentamicin group and 98% in the ceftriaxone group, but clearance of pharyngeal infection and rectal infection was lower in the gentamicin group (80% vs. 96% and 90% vs. 98%, respectively). Reported pain at the injection site was higher for gentamicin than for ceftriaxone. The side-effect profiles were comparable between the groups. Only one serious adverse event was reported and this was deemed not to be related to the trial medication. The economic analysis found that treatment with gentamicin is not cost neutral compared with standard care, with average patient treatment costs higher for those allocated to gentamicin (£13.90, 95% CI £2.47 to £37.34) than to ceftriaxone (£6.72, 95% CI £1.36 to £17.84).
LIMITATIONS
Loss to follow-up was 17% but was similar in both treatment arms. Twelve per cent of participants had a negative NAAT for gonorrhoea at their baseline visit but this was balanced between treatment groups and unlikely to have biased the trial results.
CONCLUSIONS
The trial was unable to demonstrate non-inferiority of gentamicin compared with ceftriaxone in the clearance of gonorrhoea at all infected sites. Clearance at pharyngeal and rectal sites was lower for participants allocated to gentamicin than for those allocated to ceftriaxone, but was similar for genital sites in both groups. Gentamicin was associated with more severe injection site pain. However, both gentamicin and ceftriaxone appeared to be well tolerated.
FUTURE WORK
Exploration of the genetic determinants of antibiotic resistance in will help to identify accurate markers of decreased susceptibility. Greater understanding of the immune response to infection can assist gonococcal vaccine development.
TRIAL REGISTRATION
Current Controlled Trials ISRCTN51783227.
FUNDING
This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 20. See the NIHR Journals Library website for further project information
Cross-sectional observation study to investigate the impact of risk-based stratification on care pathways for patients with chronic kidney disease: protocol paper.
No full textINTRODUCTION
Chronic kidney disease (CKD) management in the UK is usually primary care based, with National Institute for Health and Care Excellence (NICE) guidelines defining criteria for referral to secondary care nephrology services. Estimated glomerular filtration rate (eGFR) is commonly used to guide timing of referrals and preparation of patients approaching renal replacement therapy. However, eGFR lacks sensitivity for progression to end-stage renal failure; as a consequence, the international guideline group, Kidney Disease: Improving Global Outcomes has recommended the use of a risk calculator. The validated Kidney Failure Risk Equation may enable increased precision for the management of patients with CKD; however, there is little evidence to date for the implication of its use in routine clinical practice. This study will aim to determine the impact of the Kidney Failure Risk Equation on the redesignation of patients with CKD in the UK for referral to secondary care, compared with NICE CKD guidance.
METHOD AND ANALYSIS
This is a cross-sectional population-based observational study using The Health Improvement Network database to identify the impact of risk-based designation for referral into secondary care for patients with CKD in the UK. Adult patients registered in primary care and active in the database within the period 1 January 2016 to 31 March 2017 with confirmed CKD will be analysed. The proportion of patients who meet defined risk thresholds will be cross-referenced with the current NICE guideline recommendations for referral into secondary care along with an evaluation of urinary albumin-creatinine ratio monitoring.
ETHICS AND DISSEMINATION
Approval was granted by The Health Improvement Network Scientific Review Committee (Reference number: 18THIN061). Study outcomes will inform national and international guidelines including the next version of the NICE CKD guideline. Dissemination of findings will also be through publication in a peer-reviewed journal, presentation at conferences and inclusion in the core resources of the Think Kidneys programme
Memory, attention and fluency deficits in COPD may be a specific form of cognitive impairment.
No full textThere is increasing evidence demonstrating an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment. We present a narrative review of published studies on the subject and a cross-sectional study investigating domain-specific cognitive impairment in people with COPD compared to people with known Alzheimer's dementia, and controls without known COPD or cognitive impairment. The aim of the study was to compare prevalence and pattern of cognitive impairment between the three groups using the Addenbrooke's Cognitive Examination (ACE)-III tool. A total of 89 participants were recruited (44 with COPD, 17 with Alzheimer's and 28 controls). Patients with COPD had significantly lower total ACE-III scores than controls (p<0.001). When comparing the COPD group to the known Alzheimer's dementia group, overall ACE-III scores were significantly lower in the Alzheimer's dementia group than the COPD group (p=0.019). The domain-specific scores for attention (p<0.004), memory (p<0.004) and fluency (p<0.001) were significantly lower in the Alzheimer's dementia group than the COPD group. Our result suggest that the COPD group were significantly more likely to have cognitive impairment than the healthy control group. This was supported by the results of a narrative review of the published literature. Our results show that the pattern of impairment in the COPD group is different to the pattern of impairment shown in the known Alzheimer's dementia group, with significant differences in the cognitive domains affected. These results are in keeping with the findings of other previously published studies included in the narrative review
Ability of Platelet-Derived Extracellular Vesicles to Promote Neutrophil-Endothelial Cell Interactions.
No full textWe tested the ability of platelet-derived extracellular vesicles (PEV) to promote adhesion of flowing neutrophils to endothelial cells (EC). PEV were collected from platelets stimulated with collagen-related peptide, and differential centrifugation was used to collect larger vesicles enriched for platelet membrane microvesicles (PMV) or smaller vesicles enriched for platelet exosomes (Pexo). Vesicle binding and resultant activation of neutrophils and EC were assessed by flow cytometry. Flow-based adhesion assays assessed binding of neutrophils directly to deposited vesicles or to EC, after neutrophils or EC had been treated with vesicles. PEV bound efficiently to neutrophils or EC, with resultant upregulation of activation markers. Binding was Ca-dependent and dominantly mediated by CD62P for neutrophils or by integrins for EC. Deposited PEV supported mainly transient attachments of flowing neutrophils through CD62P and some stable adhesion through CXC-chemokines. Neutrophil adhesion to EC was promoted when either cell was pre-treated with PEV, although the effect was less prominent when EC were pre-activated with tumor necrosis factor-α. The pro-adhesive effects on neutrophils could largely be attributed to the larger PMV rather than Pexo. Thus, surface-bound PEV can capture flowing neutrophils, while PEV also activate neutrophils and EC to promote interactions. PEV may potentiate inflammatory responses after tissue injury
A rare case of unilateral hemifacial spasm and facial palsy associated with an abnormal anatomical variant of the posterior basilar circulation.
No full textTortuous vertebral arteries are a rare anatomical variant. Mild tortuosity is usually asymptomatic whereas severe tortuosity may present with ischaemic symptoms or compressive symptoms (focal neurological deficit). While a resulting hemifacial spasm has been previously described, sparse literature exists for its association with facial palsy. We present a rare case of facial spasm along with facial palsy in a 67-year-old woman who was found to have an anatomical variant in the posterior basilar circulation with an ectatic basilar artery and significantly displaced posterior vertebral artery impinging on the facial nerve
Patient experience and reflective learning (PEARL): a mixed methods protocol for staff insight development in acute and intensive care medicine in the UK.
No full textINTRODUCTION
Patient and staff experiences are strongly influenced by attitudes and behaviours, and provide important insights into care quality. Patient and staff feedback could be used more effectively to enhance behaviours and improve care through systematic integration with techniques for reflective learning. We aim to develop a reflective learning framework and toolkit for healthcare staff to improve patient, family and staff experience.
METHODS & ANALYSIS
Local project teams including staff and patients from the acute medical units (AMUs) and intensive care units (ICUs) of three National Health Service trusts will implement two experience surveys derived from existing instruments: a continuous patient and relative survey and an annual staff survey. Survey data will be supplemented by ethnographic interviews and observations in the workplace to evaluate barriers to and facilitators of reflective learning. Using facilitated iterative co-design, local project teams will supplement survey data with their experiences of healthcare to identify events, actions, activities and interventions which promote personal insight and empathy through reflective learning. Outputs will be collated by the central project team to develop a reflective learning framework and toolkit which will be fed back to the local groups for review, refinement and piloting. The development process will be mapped to a conceptual theory of reflective learning which combines psychological and pedagogical theories of learning, alongside theories of behaviour change based on capability, opportunity and motivation influencing behaviour. The output will be a locally-adaptable workplace-based toolkit providing guidance on using reflective learning to incorporate patient and staff experience in routine clinical activities.
ETHICS & DISSEMINATION
The PEARL project has received ethics approval from the London Brent Research Ethics Committee (REC Ref 16/LO/224). We propose a national cluster randomised step-wedge trial of the toolkit developed for large-scale evaluation of impact on patient outcomes
Nivolumab PD-1 inhibitor immunotherapy associated with vulvar, perineal and perianal lichen sclerosus.
No full textGeriatric medicine and old age psychiatry joint training pre-feasibility pilot study: an innovative approach to collaborative postgraduate training.
No full textBACKGROUND
Physical and psychological health problems are prevalent in older adults and rarely exist in isolation. Treating these problems in isolation is resourceful and can be potentially harmful to patients due to delays in diagnosis and treatment and incomplete holistic care plans. Historically, trainees in geriatric medicine and old age psychiatry within the United Kingdom have completed very different training programmes.
METHODS
We undertook a pre-feasibility pilot study of collaborative postgraduate training between trainees in geriatric medicine and old age psychiatry within the West Midlands training region, United Kingdom. Trainees in each specialty were paired with each other and advised to arrange appropriate training opportunities for their counterpart; these included shadowing each other in their workplace and arranging opportunities to attend training opportunities with their consultants. Pre- and post-pilot surveys were completed by all trainees and reflections from trainees were collated.
RESULTS
Five trainee pairs were formed and arranged shadowing and training opportunities between October 2017 and May 2018. This included a combination of inpatient, outpatient, and community work. For both specialties, trainees' confidence in topics relating to their counterparts' specialty increased between the pre- and post-pilot surveys. Recurrent themes included within reflections included the benefits of collaborative training.
CONCLUSIONS
Our pilot has demonstrated that it is feasible to implement a programme of joint training into postgraduate medical training, and that this can have a positive impact upon the confidence of both specialties. An extended pilot is planned for the training year 2018-2019