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Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.
No full textPsoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis
Strategies adopted by men to deal with uncertainty and anxiety when following an active surveillance/monitoring protocol for localised prostate cancer and implications for care: a longitudinal qualitative study embedded within the ProtecT trial.
No full textOBJECTIVES
Active surveillance (AS) enables men with low risk, localised prostate cancer (PCa) to avoid radical treatment unless progression occurs; lack of reliable AS protocols to determine progression leaves uncertainties for men and clinicians. This study investigated men's strategies for coping with the uncertainties of active monitoring (AM, a surveillance strategy within the Prostate testing for cancer and Treatment, ProtecT trial) over the longer term and implications for optimising supportive care.
DESIGN
Longitudinal serial in-depth qualitative interviews every 2-3 years for a median 7 (range 6-14) years following diagnosis.
SETTING
Four centres within the UK Protect trial.
PARTICIPANTS
Purposive sample of 20 men with localised PCa: median age at diagnosis 64 years (range 52-68); 15 (75%) had low-risk PCa; 12 randomly allocated to, 8 choosing AM. Eleven men continued with AM throughout the study period (median 7 years). Nine received radical treatment after a median 4 years (range 0.8-13.8 years).
INTERVENTION
AM: 3-monthly serum prostate-specific antigen (PSA)-level assessment (year 1), 6-12 monthly thereafter; increase in PSA ≥50% during previous 12 months or patient/clinician concern triggered review.
MAIN OUTCOMES
Thematic analysis of 73 interviews identified strategies to accommodate uncertainty and anxiety of living with untreated cancer; implications for patient care.
RESULTS
Men sought clarity, control or reassurance, with contextual factors mediating individual responses. Trust in the clinical team was critical for men in balancing anxiety and facilitating successful management change/continued monitoring. Only men from ProtecT were included; men outside ProtecT may have different experiences.
CONCLUSION
Men looked to clinicians for clarity, control and reassurance. Where provided, men felt comfortable continuing AM or having radical treatments when indicated. Clinicians build patient trust by clearly describing uncertainties, allowing patients control wherever possible and being aware of how context influences individual responses. Insights indicate need for supportive services to build trust and patient engagement over the long term.
TRIAL REGISTRATION NUMBER
ISRCTN20141297; Pre-results
Guidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI Extension.
No full textThe SPIRIT 2013 (The Standard Protocol Items: Recommendations for Interventional Trials) statement aims to improve the completeness of clinical trial protocol reporting, by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there is a growing recognition that interventions involving artificial intelligence need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes.The SPIRIT-AI extension is a new reporting guideline for clinical trials protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI. Both guidelines were developed using a staged consensus process, involving a literature review and expert consultation to generate 26 candidate items, which were consulted on by an international multi-stakeholder group in a 2-stage Delphi survey (103 stakeholders), agreed on in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants).The SPIRIT-AI extension includes 15 new items, which were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations around the handling of input and output data, the human-AI interaction and analysis of error cases.SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer-reviewers, as well as the general readership, to understand, interpret and critically appraise the design and risk of bias for a planned clinical trial
Monitoring indirect impact of COVID-19 pandemic on services for cardiovascular diseases in the UK.
No full textOBJECTIVE
To monitor hospital activity for presentation, diagnosis and treatment of cardiovascular diseases during the COVID-19) pandemic to inform on indirect effects.
METHODS
Retrospective serial cross-sectional study in nine UK hospitals using hospital activity data from 28 October 2019 (pre-COVID-19) to 10 May 2020 (pre-easing of lockdown) and for the same weeks during 2018-2019. We analysed aggregate data for selected cardiovascular diseases before and during the epidemic. We produced an online visualisation tool to enable near real-time monitoring of trends.
RESULTS
Across nine hospitals, total admissions and emergency department (ED) attendances decreased after lockdown (23 March 2020) by 57.9% (57.1%-58.6%) and 52.9% (52.2%-53.5%), respectively, compared with the previous year. Activity for cardiac, cerebrovascular and other vascular conditions started to decline 1-2 weeks before lockdown and fell by 31%-88% after lockdown, with the greatest reductions observed for coronary artery bypass grafts, carotid endarterectomy, aortic aneurysm repair and peripheral arterial disease procedures. Compared with before the first UK COVID-19 (31 January 2020), activity declined across diseases and specialties between the first case and lockdown (total ED attendances relative reduction (RR) 0.94, 0.93-0.95; total hospital admissions RR 0.96, 0.95-0.97) and after lockdown (attendances RR 0.63, 0.62-0.64; admissions RR 0.59, 0.57-0.60). There was limited recovery towards usual levels of some activities from mid-April 2020.
CONCLUSIONS
Substantial reductions in total and cardiovascular activities are likely to contribute to a major burden of indirect effects of the pandemic, suggesting they should be monitored and mitigated urgently
Platelet function testing in patients with post-operative tonsillectomy bleeding may be a useful early identifier of inherited platelet function disorders.
No full textBACKGROUND
Post-tonsillectomy bleeding is the most frequent complication of tonsillectomy. Inherited platelet function disorders have an estimated prevalence of 1 per cent. Any association between post-tonsillectomy bleeds and undiagnosed inherited platelet function disorders has not been investigated before.
OBJECTIVES
To assess the prevalence of inherited platelet function disorders in a cohort of post-tonsillectomy bleed patients.
METHODS
An observational cohort study was conducted using hospital digital records. Platelet function analyser 100 ('PFA-100') closure time was tested on post-tonsillectomy bleed patients who presented to hospital.
RESULTS
Between 2013 and 2017, 9 of 91 post-tonsillectomy bleed patients who underwent platelet function analyser 100 testing (9.89 per cent) had positive results. Five patients (5.49 per cent) had undiagnosed inherited platelet function disorders. Four patients had false positive results secondary to a non-steroidal anti-inflammatory drug effect (specificity of 95.3 per cent) proven by repeat testing six weeks later, off medication. The false negative rate was 0 per cent.
CONCLUSION
The prevalence of inherited platelet function disorders in our post-tonsillectomy bleed cohort is five-fold higher than in the general population. Platelet function analyser 100 testing when patients present with a post-tonsillectomy bleed allows management of their inherited platelet function disorder
The MUK eight protocol: a randomised phase II trial of cyclophosphamide and dexamethasone in combination with ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor.
No full textBACKGROUND
Multiple myeloma is a plasma cell tumour with approximately 5500 new cases in the UK each year. Ixazomib is a next generation inhibitor of the 20S proteasome and is thought to be an effective treatment for those who have relapsed from bortezomib. The combination of cyclophosphamide and dexamethasone (CD) is a recognised treatment option for patients with relapsed refractory multiple myeloma (RRMM) who have relapsed after treatment with bortezomib and lenalidomide, whilst also often being combined with newer proteasome inhibitors. The most apparent combination for ixazomib is therefore with CD.
METHODS
MUK eight is a randomised, controlled, open, parallel group, multi-centre phase II trial that will recruit patients with RRMM who have relapsed after treatment with thalidomide, lenalidomide, and a proteasome inhibitor. The primary objective of the trial is to evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improved clinical activity compared to CD in terms of progression-free survival (PFS). Secondary objectives include comparing toxicity profiles and the activity and cost-effectiveness of both treatments. Since opening, the trial has been amended to allow all participants who experience disease progression (as per the IMWG criteria) on the CD arm to subsequently switch to receive ICD treatment, once progression has been confirmed with two clinical members of the Trial Management Group (TMG). This 'switch' phase of the study is exploratory and will assess second progression-free survival measured from randomisation to second disease progression (PFS2) and progression-free survival from the point of switching to second disease progression (PFS Switch) in participants who switch from CD to ICD treatment.
DISCUSSION
Development of ixazomib offers the opportunity to further investigate the value of proteasome inhibition through oral administration in the treatment of RRMM. Previous studies investigating the safety and efficacy of ICD in patients with RRMM demonstrate a toxicity profile consistent with ixazomib in combination with lenalidomide and dexamethasone, whilst the combination showed possible activity in RRMM patients. Further investigation of the anti-tumour effect of this drug in RRMM patients is therefore warranted, especially since no trials comparing CD with ICD have been completed at present.
TRIAL REGISTRATION
ISRCTN number: ISRCTN58227268 . Registered on 26 August 2015
Occlusion of the Right Ventricular Wall Branch of a Recessive Right Coronary Artery Resulting in Ventricular Fibrillation and Anterior ST-Segment Elevation-A Case Report.
No full textRight ventricular (RV) infarction is as an extremely rare cause of isolated anterior ST-segment elevation. Occlusion of the RV branch in a recessive right coronary artery (RCA) causing isolated RV infarction and only anterior ST-elevation is extremely rare. To date, the handful of such cases reports do not describe any arrhythmia associated with this presentation. Although ventricular fibrillation (VF) has been well-documented with interruption of flow in the conus branch of the RCA, here we describe VF occurring in a patient with occlusion of the RV branch of a recessive RCA presenting with isolated anterior ST-segment elevation. A 51-year-old man presented with acute chest pain and isolated anterior ST-segment elevation on electrocardiogram (ECG). The patient developed ventricular fibrillation prior to coronary angiography requiring cardiopulmonary resuscitation. Coronary angiography revealed an unobstructed left coronary system and a recessive right coronary artery with ostial occlusion of the RV branch which was treated with a drug eluting balloon, resulting in resolution of the chest pain and ECG changes. Isolated RV infarction due to RV branch occlusion can cause ECG changes mimic anterior left ventricular infarction. This presentation may be complicated by VF, even in the setting of a recessive RCA
Sarcopenia in cirrhosis: A practical overview.
No full textPatients with liver cirrhosis and, in particular, those with liver failure are at high risk of reduced muscle mass and strength/function, otherwise known as sarcopenia. Sarcopenia is a complex, multifactorial (poor nutritional intake, protein catabolism, physical inactivity) chronic condition, which increases the risk of liver-related morbidity and mortality. Early recognition and tailored management incorporating high protein diets and combination aerobic/resistance exercise can ameliorate the complications associated with sarcopenia in cirrhosis. This review provides an overview of the epidemiology, pathogenesis, assessment tools and management of sarcopenia in cirrhosis
Ramadan and Diabetes: A Narrative Review and Practice Update.
No full textFasting in the Islamic month of Ramadan is obligatory for all sane, healthy adult Muslims. The length of the day varies significantly in temperate regions-typically lasting ≥ 18 h during peak summer in the UK. The synodic nature of the Islamic calendar means that Ramadan migrates across all four seasons over an approximately 33-year cycle. Despite valid exemptions, there is an intense desire to fast during this month, even among those who are considered to be at high risk, including many individuals with diabetes mellitus. In this review we explore the current scientific and clinical evidence on fasting in patients with diabetes mellitus, focussing on type 2 diabetes mellitus and type 1 diabetes mellitus, with brief reviews on pregnancy, pancreatic diabetes, bariatric surgery, the elderly population and current practice guidelines. We also make recommendations on the management of diabetes patients during the month of Ramadan. Many patients admit to a do-it-yourself approach to diabetes mellitus management during Ramadan, largely due to an under-appreciation of the risks and implications of the rigors of fasting on their health. Part of the issue may also lie with a healthcare professional's perceived inability to grasp the religious sensitivities of Muslims in relation to disease management. Thus, the pre-Ramadan assessment is crucial to ensure a safe Ramadan experience. Diabetes patients can be risk-stratified from low, medium to high or very high risk during the pre-Ramadan assessment and counselled accordingly. Those who are assessed to be at high to very high risk are advised not to fast. The current COVID-19 pandemic upgrades those in the high-risk category to very high risk; hence a significant number of diabetes patients may fall under the penumbra of the 'not to fast' advisory. We recognize that fasting is a personal choice and if a person chooses to fast despite advice to the contrary, he/she should be adequately supported and monitored closely during Ramadan and for a brief period thereafter. Current advancements in insulin delivery and glucose monitoring technologies are useful adjuncts to strategies for supporting type 1 diabetes patients considered to be high risk as well as 'high-risk' type 2 patients manage their diabetes during Ramadan. Although there is a lack of formal trial data, there is sufficient evidence across the different classes of therapeutic hypoglycaemic agents in terms of safety and efficacy to enable informed decision-making and provide a breadth of therapeutic options for the patient and the healthcare professional, even if the professional advice is to abstain. Thus, Ramadan provides an excellent opportunity for patient engagement to discuss important aspects of management, to improve control in the short term during Ramadan and to help the observants understand that the metabolic gains achieved during Ramadan are also sustainable in the other months of the year by maintaining a dietary and behavioural discipline. The application of this understanding can potentially prevent long-term complications.
Electronic Supplementary Material
The online version of this article (10.1007/s13300-020-00886-y) contains supplementary material, which is available to authorized users
Home parenteral nutrition in neuroendocrine tumour intestinal failure: improved quality of life and longevity.
No full textBACKGROUND
Neuroendocrine tumours (NETs) are neoplastic yet behave differently to typical cancers. Despite often being slow growing, they can lead to significant gastrointestinal complications including intestinal failure (IF). The use of home parenteral nutrition (HPN) in neoplastic conditions is rising, primarily for palliation and bridging through treatments for cancer, but remains a challenging decision with a paucity of high-grade evidence-based guidance.
METHODS
A retrospective analysis of patients with NET on HPN was performed. Data collected included the cause of IF, complications encountered with HPN and changes in nutritional assessments.
RESULTS
Eight patients were identified, all with metastatic NET. Median weight improved following HPN commencement and line sepsis was the sole complication. All patients had stabilisation and optimisation of nutritional and hydration status.
CONCLUSIONS
HPN is commenced to improve or maintain patients' nutritional status during often lifelong treatment. The principle aim in providing HPN was to improve survival and quality of life. While NETs are cancers, our case series demonstrates the potential of HPN to actively support longer term survival in the subgroup of patients who develop IF