Recent Submissions

  • Standard care vs. TRIVEntricular pacing in Heart Failure (STRIVE HF): a prospective multicentre randomized controlled trial of triventricular pacing vs. conventional biventricular pacing in patients with heart failure and intermediate QRS left bundle branch block

    Nicolson, Will
    Aims: To determine whether triventricular (TriV) pacing is feasible and improves CRT response compared to conventional biventricular (BiV) pacing in patients with left bundle branch block (LBBB) and intermediate QRS prolongation (120-150 ms). Methods and results: Between October 2015 and November 2019, 99 patients were recruited from 11 UK centres. Ninety-five patients were randomized 1:1 to receive TriV or BiV pacing systems. The primary endpoint was feasibility of TriV pacing. Secondary endpoints assessed symptomatic and remodelling response to CRT. Baseline characteristics were balanced between groups. In the TriV group, 43/46 (93.5%) patients underwent successful implantation vs. 47/49 (95.9%) in the BiV group. Feasibility of maintaining CRT at 6 months was similar in the TriV vs. BiV group (90.0% vs. 97.7%, P = 0.191). All-cause mortality was similar between TriV vs. BiV groups (4.3% vs. 8.2%, P = 0.678). There were no significant differences in echocardiographic LV volumes or clinical composite scores from baseline to 6-month follow-up between groups. Conclusion: Implantation of two LV leads to deliver and maintain TriV pacing at 6 months is feasible without significant complications in the majority of patients. There was no evidence that TriV pacing improves CRT response or provides additional clinical benefit to patients with LBBB and intermediate QRS prolongation and cannot be recommended in this patient group. Clinical trial registration number: NCT02529410.
  • Microbiomes in physiology: Insights into 21st century global medical challenges

    Suzuki, Toru
    New findings: What is the topic of this review? This review summarises the role of the gut microbiome in physiology and how it can be targeted as an effective strategy against two of the most important global medical challenges of our time namely, metabolic diseases and antibacterial resistance. What advances does it highlight? We outline the critical roles of the microbiome in regulating host physiology and discuss how microbiome analysis is useful for disease stratification to enable informed clinical decisions and develop interventions such as faecal microbiota transplantation (FMT), prebiotics, and probiotics. We also discuss the limitations of microbiome modulation, including the potential for probiotics to enhance antimicrobial resistance gene reservoirs, and that currently a "healthy microbiome" that can be used as a biobank for transplantation is yet to be defined. Abstract: The human gut microbiome plays a key factor in the development of metabolic diseases and antimicrobial resistance which are among the greatest global medical challenges of the 21st century. The symposium aimed to highlight state-of-the-art evidence for the role of the gut microbiome in physiology, from childhood to adulthood, and the impact this has on global disease outcomes, ageing and antimicrobial resistance. Although the gut microbiome is established early in life, over time the microbiome and their components including metabolites can become perturbed due to changes such as dietary habits, use of antibiotics and age. As gut microbial metabolites, including short chain fatty acids (SCFAs), secondary bile acids and trimethylamine-N-Oxide (TMAO), can interact with host receptors including G protein coupled receptors (GPCRs), and can alter host metabolic fluxes, they can significantly affect physiological homeostasis leading to metabolic diseases. These metabolites can be used to stratify disease phenotypes such as irritable bowel syndrome (IBS) and adverse events after heart failure and provide informed decisions on clinical management and treatment. While strategies such as probiotics, prebiotics, and faecal microbiota transplantation (FMT) have been proposed as interventions to treat and prevent metabolic diseases and antimicrobial resistance, caution must be exercised; first due to the potential of probiotics to enhance antimicrobial resistance gene reservoirs and second, a "healthy gut microbiome" that can be used as a biobank for transplantation is yet to be defined. We highlight that sampling other parts of the GI tract may produce more representative data than the faecal microbiome alone. This article is protected by copyright. All rights reserved.
  • NUT carcinoma arising from the parotid gland: a case report and review of the literature

    Da Forno, Philip
    NUT carcinoma is an aggressive carcinoma with an overall poor survival outcome. The mediastinum and head and neck area, especially the sinonasal region, are among the common sites of disease. Histopathological diagnosis of NUT carcinoma is often very challenging due to its overlapping features with other poorly differentiated carcinomas. We report a case of NUT carcinoma arising from the parotid gland of a young female patient. Primary NUT carcinoma of salivary gland is very rare, with only 15 such cases reported in the literature to date. Our case highlights the diagnostic challenges associated with such lesions.
  • Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

    Vasudevan, Pradeep
    Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
  • Coronary artery bypass grafting in patients with high risk of bleeding

    Mariscalco, Giovanni
    Background: Postoperative bleeding after cardiac surgery is associated with increased morbidity and mortality. We tested the hypothesis that patients with a preoperatively estimated high risk of severe perioperative bleeding may have impaired early outcome after on-pump versus off-pump coronary artery bypass grafting (CABG). Method: Data from 7,352 consecutive patients who underwent isolated CABG from January 2015 to May 2017 were included in the multicentre European Coronary Artery Bypass Grafting registry. The postoperative bleeding risk was estimated using the WILL-BLEED risk score. Of all included patients, 3,548 had an increased risk of severe perioperative bleeding (defined as a WILL-BLEED score ≥4) and were the subjects of this analysis. We compared the early outcomes between patients who underwent on-pump or off-pump CABG using a multivariate mixed model for risk-adjusted analysis. Results: Off-pump surgery was performed in 721 patients (20.3%). On-pump patients received more packed red blood cell units (on-pump: 1.41 [95% confidence interval {CI} 0.99-1.86]; off-pump: 0.86 [95% CI 0.64-1.08]; p<0.001), had a longer stay in the intensive care unit (on-pump: 4.4 [95% CI 3.6-8.1] days; off-pump: 3.2 [95% CI 2.0-4.4] days; p=0.049), and a higher rate of postoperative atrial fibrillation (on-pump: 46.5% [95% CI 34.9-58.1]; off-pump: 31.3% [95% CI 21.7-40.9]; p=0.025). Furthermore, on-pump patients showed a trend towards a higher rate of postoperative stroke (on-pump: 2.4% [95% CI 0.9-4.1]; off-pump: 1.1 [95% CI 0.2-2.7]; p=0.094). Conclusion: Our data suggest that in patients with an increased risk of bleeding, the use of cardiopulmonary bypass is associated with higher morbidity. These patients may benefit from off-pump surgery if complete revascularisation can be ensured.
  • Variation in human herpesvirus 6B telomeric integration, excision, and transmission between tissues and individuals

    Romaine, Simon; Samani, Nilesh
    Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether, we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.
  • Nonadherence in hypertension: how to develop and implement chemical adherence testing

    Lane, Dan; Patel, Prashanth; Gupta, Pankaj
    Nonadherence to antihypertensive medication is common, especially in those with apparent treatment-resistant hypertension (true treatment-resistant hypertension requires exclusion of nonadherence), and its routine detection is supported by clinical guidelines. Chemical adherence testing is a reliable and valid method to detect adherence, yet methods are unstandardized and are not ubiquitous. This article describes the principles of chemical adherence testing for hypertensive patients and provides a set of recommendations for centers wishing to develop the test. We recommend testing should be done in either of two instances: (1) in those who have resistant hypertension or (2) in those on 2 antihypertensives who have a less than 10 mm Hg drop in systolic blood pressure on addition of the second antihypertensive medication. Furthermore, we recommend that verbal consent is secured before undertaking the test, and the results should be discussed with the patient. Based on medications prescribed in United Kingdom, European Union, and United States, we list top 20 to 24 drugs that cover >95% of hypertension prescriptions which may be included in the testing panel. Information required to identify these medications on mass spectrometry platforms is likewise provided. We discuss issues related to ethics, sample collection, transport, stability, urine versus blood samples, qualitative versus quantitative testing, pharmacokinetics, instrumentation, validation, quality assurance, and gaps in knowledge. We consider how to best present, interpret, and discuss chemical adherence test results with the patient. In summary, this guidance should help clinicians and their laboratories in the development of chemical adherence testing of prescribed antihypertensive drugs.
  • Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study

    McMillan, Andrew; Miall, Fiona
    Background: Obinutuzumab with polatuzumab vedotin or lenalidomide showed tolerability and activity in phase 1b/2 trials that recruited patients with relapsed or refractory follicular lymphoma. We aimed to examine whether the novel polatuzumab vedotin-obinutuzumab-lenalidomide (Pola-G-Len) combination might enhance antitumour response in patients with relapsed or refractory follicular lymphoma. Methods: This multicentre, single-arm phase 1b/2 study tested Pola-G-Len in patients with relapsed or refractory follicular lymphoma, and polatuzumab vedotin in combination with rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Here we report the results from the cohort of patients with follicular lymphoma. The trial was done in 18 cancer centres across three countries (Spain, UK, and USA). Patients (≥18 years old) with CD20-positive relapsed or refractory follicular lymphoma (excluding grade 3b) and Eastern Cooperative Oncology Group performance status of 2 or less who had previously received anti-CD20-containing chemotherapy were eligible for inclusion. During the dose-escalation phase, patients received six 28-day cycles of induction treatment with intravenous obinutuzumab 1000 mg (all cohorts), and intravenous polatuzumab vedotin and oral lenalidomide (Celgene, Summit, NJ, USA) in the following doses: 1·4 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 1); 1·8 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 2); 1·4 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 3); 1·8 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 4); 1·4 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 5); and 1·8 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 6). Polatuzumab vedotin was administered on day 1, lenalidomide on days 1-21, and obinutuzumab on days 1, 8, and 15 of cycle one and day 1 of cycles two to six of each 28-day cycle. During phase 2 (dose expansion phase), patients received six cycles of induction with Pola-G-Len at the recommended phase 2 dose established during dose-escalation. Patients who had a response or stable disease at the end of induction were eligible to enter the maintenance phase, in which they received obinutuzumab for 24 months at 1000 mg on day 1 of every other 28-day cycle for a total of 12 doses, and lenalidomide for 12 months at 10 mg on days 1-21 of each 28-day cycle for a maximum of 12 cycles. The primary activity endpoint was complete response at the end of induction. Adverse events were monitored throughout the study. The primary safety objective was to determine the maximum tolerated dose of Pola-G-Len. Analyses were in the safety population, which included all patients that received at least one dose of any of the component drugs (ie, all patients who entered the induction phases in both the escalation and expansion phases), and activity-evaluable population, which included all patients who received at least one dose of any of the component drugs at the recommended phase 2 dose (ie, all patients who received the recommended phase 2 dose in the dose escalation investigation and all patients who entered induction in the dose expansion investigation). This ongoing trial is registered at, NCT02600897. Findings: Between March 24, 2016, and August 23, 2018, 56 patients (33 [59%] men and 23 [41%] women; 49 [88%] non-Hispanic or Latino) were enrolled. Two of four patients in cohort 2 reported dose-limiting toxicity events during dose escalation (one patient had grade 4 amylase and lipase elevation and one patient had grade 4 neutropenia and grade 3 thrombocytopenia), and there were no dose-limiting toxicities observed in cohorts 3 or 5; therefore, the recommended phase 2 dose for the dose-expansion was 1·4 mg/kg polatuzumab vedotin plus 20 mg lenalidomide. 46 (82%) patients were included in the activity-evaluable population. After a median follow up of 26·7 months (IQR 22·2-31·3) the objective response rate was 76% (90% CI 64-86) and complete response rate was 63% (90 CI 50-75). After a median follow-up of 27·0 months (IQR 18·7-34·0), the most common grade 3-4 adverse events were neutropenia (31 [55%] of 56 patients) and thrombocytopenia (14 [25%] patients). 61 serious adverse events were reported in 35 (63%) patients; the most common of which were febrile neutropenia (five [9%] patients; a sixth patient had febrile neutropenia, but this was not considered serious by the investigator), pneumonia (four [7%] patients), and pyrexia (four [7%] patients). One fatal adverse event (grade 5 septic shock) occurred in a patient who had discontinued study treatment due to disease progression and had initiated a new anti-lymphoma tyrosine kinase inhibitor treatment. This was not considered related to study treatment by the investigator. Interpretation: Pola-G-Len showed high complete response rates, although it did not reached the prespecified threshold for activity, in patients who were heavily pretreated with refractory follicular lymphoma. Our findings compare favourably with available therapies and support future investigation of Pola-G-Len in a larger patient population. Funding: Genentech/F Hoffmann-La Roche.
  • Primary skeletal muscle cells from chronic kidney disease patients retain hallmarks of cachexia in vitro

    Graham-Brown, Matthew; Major, Rupert; Ashford, Robert; Smith, Alice; Watson, Emma L
    Background: Skeletal muscle wasting and dysfunction are common characteristics noted in people who suffer from chronic kidney disease (CKD). The mechanisms by which this occurs are complex, and although progress has been made, the key underpinning mechanisms are not yet fully elucidated. With work to date primarily conducted in nephrectomy-based animal models, translational capacity to our patient population has been challenging. This could be overcome if rationale developing work could be conducted in human based models with greater translational capacity. This could be achieved using cells derived from patient biopsies, if they retain phenotypic traits noted in vivo. Methods: Here, we performed a systematic characterization of CKD derived muscle cells (CKD; n = 10; age: 54.40 ± 15.53 years; eGFR: 22.25 ± 13.22 ml/min/1.73 m2 ) in comparison with matched controls (CON; n = 10; age: 58.66 ± 14.74 years; eGFR: 85.81 ± 8.09 ml/min/1.73 m2 ). Harvested human derived muscle cells (HDMCs) were taken through proliferative and differentiation phases and investigated in the context of myogenic progression, inflammation, protein synthesis, and protein breakdown. Follow up investigations exposed HDMC myotubes from each donor type to 0, 0.4, and 100 nM of IGF-1 in order to investigate any differences in anabolic resistance. Results: Harvested human derived muscle cells isolated from CKD patients displayed higher rates of protein degradation (P = 0.044) alongside elevated expression of both TRIM63 (2.28-fold higher, P = 0.054) and fbox32 (6.4-fold higher, P < 0.001) in comparison with CONs. No differences were noted in rates of protein synthesis under basal conditions (P > 0.05); however, CKD derived cells displayed a significant degree of anabolic resistance in response to IGF-1 stimulation (both doses) in comparison with matched CONs (0.4 nm: P < 0.001; 100 nM: P < 0.001). Conclusions: In summary, we report for the first time that HDMCs isolated from people suffering from CKD display key hallmarks of the well documented in vivo phenotype. Not only do these findings provide further mechanistic insight into CKD specific cachexia, but they also demonstrate this is a reliable and suitable model in which to perform targeted experiments to begin to develop novel therapeutic strategies targeting the CKD associated decline in skeletal muscle mass and function.
  • Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant

    Searle, Claire; Vasudevan, Pradeep
    Smith-Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.(Glu1799Lys) variant. Limited phenotypic data impacts the quality of information delivered to families and the robustness of interpretation of novel MTOR missense variation. This study aims to improve our understanding of the SKS phenotype through the investigation of 16 further patients with the MTOR c.5395G>A p.(Glu1799Lys) variant. Through the careful phenotypic evaluation of these 16 patients and integration with data from 14 previously reported patients, we have defined major (100% patients) and frequent (>15%) SKS clinical characteristics and, using these data, proposed guidance for evidence-based management. In addition, in the absence of functional studies, we suggest that the combination of the SKS major clinical features of megalencephaly (where the head circumference is at least 3SD) and an intellectual disability with a de novo MTOR missense variant (absent from population databases) should be considered diagnostic for SKS.
  • Phosphaturic mesenchymal tumors: radiological aspects and suggested imaging pathway

    Hussein, Mohsin; Rennie, Winston
    Phosphaturic mesenchymal tumors (PMTs) are rare mesenchymal neoplasms of soft tissue or bone origin that can give rise to a challenge in diagnostic imaging. These tumors are frequently associated with tumor-induced osteomalacia, also called oncogenic osteomalacia, which is a rare paraneoplastic syndrome characterized by ectopic secretion of fibroblast growth factor 23, a hormone that regulates serum phosphate level. PMTs show polymorphic features on both radiological findings and histological examination, causing problems in diagnosis owing to their similarity with other mesenchymal tumors. Thus, this paper aims to describe radiological aspects of PMTs and suggest an imaging pathway for accurate diagnosis throughout the evidence from the literature review.
  • Severe symptomatic hypercalcemia in a patient with familial hypocalciuric hypercalcemia

    Kurian, Roshini
    One of the less common causes of hypercalcemia is familial hypocalciuric hypercalcemia (FHH). It is an autosomal-dominant genetic condition, which presents asymptomatically in most patients while some may have mild symptoms. The serum calcium levels are mildly elevated with mild elevation in parathyroid hormone, which rarely requires management with pharmacologic agents. We present an unusual case report of a 76-year-old woman, confirmed to have FHH type 1 mutation, presented with symptomatic hypercalcemia probably set off by metabolic stresses of her age and needing intensive treatment with intravenous bisphosphonates, calcitonin and cinacalcet.
  • Persistent hesitancy for SARS-CoV-2 vaccines among healthcare workers in the United Kingdom: analysis of longitudinal data from the UK-REACH cohort study

    Martin, Christopher; Carr, Sue; Nazareth, Joshua; Tobin, Martin; Pan, Daniel; Pareek, Manish
    No abstract available.
  • Hydroxyurea - a cost effective treatment in developing countries for Atypical Chronic Myeloid Leukemia (aCML): case report of two patients

    Iqbal, Muhammad
    Introduction: Atypical chronic myeloid leukaemia (aCML) is a rare chronic myeloproliferative disorder with a poor prognosis. Case report: This case report presents two cases of male geriatric patients, both referred from primary care in rural areas and received at an urban clinic in a tertiary care hospital on separate instances. The first patient complained of low-grade fever (on/off), generalized body aches, rapid weight loss and shortness of breath for the last 2 months. The second patient arrived pale looking with symptoms of generalized body aches, dizziness and anorexia. Both patients were diagnosed to have aCML according to the World Health organization criteria. Management & outcome: Both the patients were from a low economic bracket and were treated with Hydroxyurea a relatively economic medicine successfully. The follow-up lasted for 12 months in both cases. No progression to acute myeloid leukaemia (AML) or relapse was observed. Discussion: This case report shows the promising results of Hydroxyurea in treating aCML and can be a cost effective alternate to other expensive treatments (allogeneic hematopoietic stem cell transplantation) and expensive medicines in lower and middle-income countries especially for resource-limited patients. These two cases show promising evidence for further studies to evaluate and conduct pharmaco-economic evaluations as well as clinical trials to compare hydroxyurea with other available alternative treatments for an affordable therapeutic option towards prevention of relapse and disease free survival after aCML.
  • Guidelines on the diagnosis and management of Waldenström macroglobulinaemia-A British Society for Haematology guideline

    Krishna, Rajesh
    Scope: The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with Waldenström macroglobulinaemia. In individual patients, circumstances may dictate an alternative approach. Methodology: This guideline was compiled according to the British Society for Haematology (BSH) process at Recommendations are based on a review of the literature using Medline, Pubmed, Embase, Central, Web of Science searches from beginning of 2013 (since the publication of the previous guidelines) up to November 2021. The following search terms were used: Waldenström('s) macroglobulin(a)emia OR lymphoplasmacytic lymphoma, IgM(-related) neuropathy OR cold h(a)emagglutinin disease OR cold agglutinin disease OR cryoglobulin(a)emia AND (for group a only) cytogenetic OR molecular OR mutation OR MYD88 OR CXCR4, management OR treatment OR transfusion OR supportive care OR plasma exchange OR plasmapheresis OR chemotherapy OR bendamustine OR bortezomib OR ibrutinib OR fludarabine OR dexamethasone OR cyclophosphamide OR rituximab OR everolimus, bone marrow transplantation OR stem cell transplantation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haemato-Oncology Task Force, the BSH Guidelines Committee and the Haemato-Oncology sounding board of BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by UK Charity WMUK; these organisations do not necessarily approve or endorse the contents.
  • Rapidly progressive iga nephropathy: clinicopathological characteristics and outcomes assessed according to the revised definition of the KDIGO 2021 guideline

    Barratt, Jonathan
    Background: Rapidly progressive IgA nephropathy (RPIgAN) is a severe clinical phenotype of IgAN, associated with a poor outcome. The recently published KDIGO 2021 Guideline for the Management of Glomerular Diseases has proposed a new definition for RPIgAN, which is based simply on a ≥ 50% decline in eGFR ≤ 3 months. Methods: In 1,677 IgAN patients followed at a single centre in China, we evaluated the utility of this new definition to identify the highest risk IgAN patients who might be suitable for combination immunosuppressive therapy. Results: The proportion of a ≥ 50% decline in eGFR ≤ 3 months was 5.2%. The majority of these patients had reversible causes, only 2.3% (39/1,677) meeting the KDIGO 2021 criteria for RPIgAN. These patients had a significantly higher risk for ESKD than non-RPIgAN patients (log rank P < 0.001). RPIgAN was an independent risk factor for ESKD (hazard ratio [HR] 3.99; 95% confidence interval [CI] 2.25 - 7.09; P < 0.001). A minority of the RPIgAN patients (25.6%) had ≥ 50% crescents. There was no significant difference in the risk for ESKD between patients in the RPIgAN group with ≥ 50% crescents and ˂ 50% crescents (log rank P = 0.27). Patients with RPIgAN and ≥ 50% crescents had a higher risk for ESKD than patients with non-RPIgAN and ≥ 50% crescents (log rank P = 0.04). Conclusions: These data support the validity of the KDIGO 2021 definition but require independent validation in other non-Chinese cohorts.
  • Artificial intelligence for stepwise diagnosis and monitoring of COVID-19

    Ang, Keng-Leong
    Background: Main challenges for COVID-19 include the lack of a rapid diagnostic test, a suitable tool to monitor and predict a patient's clinical course and an efficient way for data sharing among multicenters. We thus developed a novel artificial intelligence system based on deep learning (DL) and federated learning (FL) for the diagnosis, monitoring, and prediction of a patient's clinical course. Methods: CT imaging derived from 6 different multicenter cohorts were used for stepwise diagnostic algorithm to diagnose COVID-19, with or without clinical data. Patients with more than 3 consecutive CT images were trained for the monitoring algorithm. FL has been applied for decentralized refinement of independently built DL models. Results: A total of 1,552,988 CT slices from 4804 patients were used. The model can diagnose COVID-19 based on CT alone with the AUC being 0.98 (95% CI 0.97-0.99), and outperforms the radiologist's assessment. We have also successfully tested the incorporation of the DL diagnostic model with the FL framework. Its auto-segmentation analyses co-related well with those by radiologists and achieved a high Dice's coefficient of 0.77. It can produce a predictive curve of a patient's clinical course if serial CT assessments are available. Interpretation: The system has high consistency in diagnosing COVID-19 based on CT, with or without clinical data. Alternatively, it can be implemented on a FL platform, which would potentially encourage the data sharing in the future. It also can produce an objective predictive curve of a patient's clinical course for visualization. Key points: • CoviDet could diagnose COVID-19 based on chest CT with high consistency; this outperformed the radiologist's assessment. Its auto-segmentation analyses co-related well with those by radiologists and could potentially monitor and predict a patient's clinical course if serial CT assessments are available. It can be integrated into the federated learning framework. • CoviDet can be used as an adjunct to aid clinicians with the CT diagnosis of COVID-19 and can potentially be used for disease monitoring; federated learning can potentially open opportunities for global collaboration.
  • Rationale and study design of the MINERVA study: Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction-UK multicentre collaboration

    Ng, G Andre; Mistry, Amar; Newton, Michelle; Nicolson, Will
    Introduction: The purpose of this study is to assess the ability of two new ECG markers (Regional Repolarisation Instability Index (R2I2) and Peak Electrical Restitution Slope) to predict sudden cardiac death (SCD) or ventricular arrhythmia (VA) events in patients with ischaemic cardiomyopathy undergoing implantation of an implantable cardioverter defibrillator for primary prevention indication. Methods and analysis: Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction is a prospective, open label, single blinded, multicentre observational study to establish the efficacy of two ECG biomarkers in predicting VA risk. 440 participants with ischaemic cardiomyopathy undergoing routine first time implantable cardioverter-defibrillator (ICD) implantation for primary prevention indication are currently being recruited. An electrophysiological (EP) study is performed using a non-invasive programmed electrical stimulation protocol via the implanted device. All participants will undergo the EP study hence no randomisation is required. Participants will be followed up over a minimum of 18 months and up to 3 years. The first patient was recruited in August 2016 and the study will be completed at the final participant follow-up visit. The primary endpoint is ventricular fibrillation or sustained ventricular tachycardia >200 beats/min as recorded by the ICD. The secondary endpoint is SCD. Analysis of the ECG data obtained during the EP study will be performed by the core lab where blinding of patient health status and endpoints will be maintained. Ethics and dissemination: Ethical approval has been granted by Research Ethics Committees Northern Ireland (reference no. 16/NI/0069). The results will inform the design of a definitive Randomised Controlled Trial (RCT). Dissemination will include peer reviewed journal articles reporting the qualitative and quantitative results, as well as presentations at conferences and lay summaries.
  • Timing of high dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1,384 patients

    Martinez-Calle, Nicolás; Ahearne, Matthew; Miall, Fiona; Fox, Christopher
    Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n=749) or at the end (n=635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT; 5.7% vs 5.8%, p=0.98, 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n=1,253). In patients with high CNS international prognostic index (n=600), 3-year CNS relapse rate was 9.1% with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk versus i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
  • A focus group study of self-management in patients with glomerular disease

    Barratt, Jonathan
    Introduction: Patients with glomerular disease experience symptoms that impair their physical and mental health while managing their treatments, diet, appointments and monitoring general and specific indicators of health and their illness. We sought to describe the perspectives of patients and their care partners on self-management in glomerular disease. Methods: We conducted 16 focus groups involving adult patients with glomerular disease (n = 101) and their care partners (n = 34) in Australia, Hong Kong, the United Kingdom, and United States. Transcripts were analyzed thematically. Results: We identified the following 4 themes: empowered in autonomy (gaining confidence through understanding, taking ownership of disease and treatment, learning a positive health approach); overwhelmed by compounding treatment burdens (financially undermined and depleted, demoralized by side effects and harms, frustrated by fragmented and inflexible care, fear of possible drug harms); striving for stability and normalcy (making personal sacrifices, maximizing life participation, attentiveness to bodily signs, avoiding precarious health states, integrating medicines into routines); and necessity of health-sustaining relationships (buoyed by social support, fulfilling meaningful responsibilities, sharing and normalizing experiences, seeking a trusting and respectful alliance). Conclusion: Patients with glomerular disease and their care partners value their capacity for autonomy and disease ownership, stability of their health, and relationships that support self-management. Strategies directed at strengthening these factors may increase self-efficacy and improve the care and outcomes for patients with glomerular disease.

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