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Ram Gupta,1 Anita R Chaudhary,2 Binita N Shah,1 Avinash V Jadhav,3 Shitalkumar P Zambad,1 Ramesh Chandra Gupta,4 Shailesh Deshpande,4 Vijay Chauthaiwale,4 Chaitanya Dutt4 1Department of Pharmacology, 2Cellular and Molecular Biology, 3Preclinical Safety Evaluation, 4Discovery, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India Background and aim: Mucosal healing in inflammatory bowel disease (IBD) can be achieved by improvement of intestinal barrier protection. Activation of hypoxia-inducible factor (HIF) has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis. Methods: The efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn's disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis. Results: TRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome. Conclusion: Our findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor ameliorates IBD in disease models. These findings highlight the potential of TRC160334 for its clinical application in the treatment of IBD. Keywords: IBD, hypoxia-inducible factor, HIF activation

Objectives: There is a lack of high-quality data informing the optimal antithrombotic drug strategy following bioprosthetic heart valve replacement or valve repair. Disparity in recommendations from international guidelines reflects this. This study aimed to document current patterns of antithrombotic prescribing after heart valve surgery in the UK., Methods: All UK consultant cardiac surgeons were e-mailed a custom-designed survey. The use of oral anticoagulant (OAC) and/or antiplatelet drugs following bioprosthetic aortic valve replacement or mitral valve replacement, or mitral valve repair (MVrep), for patients in sinus rhythm, without additional indications for antithrombotic medication, was assessed. Additionally, we evaluated anticoagulant choice following MVrep in patients with atrial fibrillation., Results: We identified 260 UK consultant cardiac surgeons from 36 units, of whom 103 (40%) responded, with 33 units (92%) having at least 1 respondent. The greatest consensus was for patients undergoing bioprosthetic aortic valve replacement, in which 76% of surgeons favour initial antiplatelet therapy and 53% prescribe lifelong treatment. Only 8% recommend initial OAC. After bioprosthetic mitral valve replacement, 48% of surgeons use an initial OAC strategy (versus 42% antiplatelet), with 66% subsequently prescribing lifelong antiplatelet therapy. After MVrep, recommendations were lifelong antiplatelet agent alone (34%) or following 3 months OAC (20%), no antithrombotic agent (20%), or 3 months OAC (16%). After MVrep for patients with established atrial fibrillation, surgeons recommend warfarin (38%), a direct oral anticoagulant (37%) or have no preference between the 2 (25%)., Conclusions: There is considerable variation in the use of antithrombotic drugs after heart valve surgery in the UK and a lack of high-quality evidence to guide practice, underscoring the need for randomized studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Work-related musculoskeletal pain (WRMSP) is increasingly recognised in cardiac ultrasound practice. WRMSP can impact workforce health, productivity and sustainability. We sought to investigate the prevalence, characteristics and clinical impact of WRMSP., Methods: Prospective electronic survey of 157 echocardiographers in 10 institutions. Data acquired on demographics, experience, working environment/pattern, WRMSP location, severity and pattern, the impact on professional, personal life and career., Results: 129/157 (82%) echocardiographers completed the survey, of whom 109 (85%) reported WRMSP and 55 (43%) reported work taking longer due to WRMSP. 40/129 (31%) required time off work. 78/109 (60%) reported sleep disturbance with 26/78 (33%) of moderate or severe severity. 56/129 (45%) required medical evaluation of their WRMSP and 25/129 (19%) received a formal diagnosis of musculoskeletal injury. Those with 11+ years of experience were significantly more likely to receive a formal diagnosis of WRMSP (p = 0.002) and require medication (p = 0.006) compared to those with 10 years or less experience., Conclusion: WRMSP is very common amongst echocardiographers, with a fifth having a related musculoskeletal injury. WRMSP has considerable on impact on personal, social and work-related activities. Strategies to reduce the burden of WRMSP are urgently required to ensure sustainability of the workforce and patient access to imaging., (© 2024. The Author(s).)

Von Hippel-Lindau protein (VHL) is essential to hypoxic regulation of cellular processes. VHL promotes proteolytic clearance of hypoxia-inducible transcription factors (HIFs) that have been modified by oxygen-dependent HIF-prolyl hydroxylases. A homozygous loss-of-function VHL R200W mutation causes Chuvash erythrocytosis, a congenital disorder caused by augmented hypoxia-sensing. Homozygous VHL R200W results in accumulation of HIFs that increase transcription of the erythropoietin gene and raise hematocrit. Phlebotomies reduce hematocrit and hyperviscosity symptoms. However, the major cause of morbidity and mortality in Chuvash erythrocytosis is thrombosis. Phlebotomies cause iron deficiency, which may further elevate HIF activity and transferrin, the HIF-regulated plasma iron transporter recently implicated in thrombogenesis. We hypothesized that transferrin is elevated in Chuvash erythrocytosis, and that iron deficiency contributes to its elevation and to thrombosis. We studied 155 patients and 154 matched controls at steady state and followed them for development of thrombosis. Baseline transferrin was elevated, and ferritin reduced in patients. VHL R200W homozygosity and lower ferritin correlated with higher erythropoietin and transferrin. During 11 years of follow-up, risk of thrombosis increased 8.9-fold in patients versus controls. Erythropoietin elevation, but not hematocrit or ferritin, correlated with thrombosis risk. Unexpectedly, transferrin elevation associated with reduced rather than increased thrombosis risk. The A allele of the promoter EPO single nucleotide polymorphisms (SNP), rs1617640, associated with elevated erythropoietin and increased thrombosis risk, whereas the A allele of the intronic TF SNP, rs3811647, associated with higher transferrin and protection from thrombosis in patients. Our findings suggest an unexpected causal relationship between increased transferrin and protection from thrombosis in Chuvash erythrocytosis., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Objective: To assess gender, ethnicity, and deprivation-based differences in provision of aortic valve replacement (AVR) in England for adults with aortic stenosis (AS)., Methods: We retrospectively identified adults with AS from the English Hospital Episode Statistics (HES) between April 2016 and March 2019 and those who subsequently had an AVR. We separately used HES-linked Clinical Practice Research Datalink (CPRD) to identify people with AVR and evaluate the timeliness of their procedure (CPRD-AVR cohort). ORs for AVR in people with an AS diagnosis were estimated using multivariable logistic regression adjusted for age, region and comorbidity. AVR was considered timely if performed electively and without evidence of cardiac decompensation before AVR., Results: 183 591 adults with AS were identified in HES; of these, 31 436 underwent AVR. The CPRD-AVR cohort comprised 10 069 adults. Women had lower odds of receiving AVR compared with men (OR 0.65; 95% CI 0.63 to 0.66); as did people of black (OR 0.70; 95% CI 0.60 to 0.82) or South Asian (OR 0.75; 95% CI 0.69 to 0.82) compared with people of white ethnicities. People in the most deprived areas were less likely to receive AVR than the least deprived areas (OR 0.8; 95% CI 0.75 to 0.86). Timely AVR occurred in 65% of those of white ethnicities compared with 55% of both those of black and South Asian ethnicities. 77% of the least deprived had a timely procedure compared with 58% of the most deprived; there was no gender difference., Conclusions: In this large, national dataset, female gender, black or South Asian ethnicities and high deprivation were associated with significantly reduced odds of receiving AVR in England. A lower proportion of people of minority ethnicities or high deprivation had a timely procedure. Public health initiatives may be required to increase clinician and public awareness of unconscious biases towards minority and vulnerable populations to ensure timely AVR for everyone., Competing Interests: Competing interests: CTR and SPO'C were employed by CorEvitas (Specialty EMR Data division), which was funded by Medtronic to conduct this research. SB is an employee of Medtronic. DJB is a consultant and proctor for Medtronic. CEA has received honoraria from Medtronic. The remaining authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Conflict of interest: None declared.

Transcriptional changes in compensatory erythropoiesis in sickle cell anemia (SCA) and their disease modulation are unclear. We detected 1226 differentially expressed genes in hemoglobin SS reticulocytes compared to non-anemic hemoglobin AA controls. Assessing developmental expression changes in hemoglobin AA erythroblasts for these genes suggests heightened terminal differentiation in early erythroblasts in SCA that diminishes toward the polychromatic to orthochromatic stage transition. Comparison of reticulocyte gene expression changes in SCA with that in Chuvash erythrocytosis, a non-anemic disorder of increased erythropoiesis due to constitutive activation of hypoxia inducible factors, identified 453 SCA-specific changes attributable to compensatory erythropoiesis. Peripheral blood mononuclear cells (PBMCs) in SCA contain elevated proportions of erythroid progenitors due to heightened erythropoiesis. Deconvolution analysis in PBMCs from 131 SCA patients detected 54 genes whose erythroid expression correlated with erythropoiesis efficiency, which were enriched with SCA-specific changes (OR = 2.9, P = 0.00063) and annotation keyword "ubiquitin-dependent protein catabolic process", "protein ubiquitination", and "protein polyubiquitination" (OR = 4.2, P = 7.5 × 10 -5 ). An erythroid expression quantitative trait locus of one of these genes, LNX2 encoding an E3 ubiquitin ligase, associated with severe pain episodes in 774 SCA patients (OR = 1.7, P = 3.9 × 10 -5 ). Thus, erythroid gene transcription responds to unique conditions within SCA erythroblasts and these changes potentially correspond to vaso-occlusive manifestations., (© 2023. Springer Nature Limited.)

The National Institute for Health and Care Excellence (NICE) guidelines are evidence-based recommendations for health and care in England. In late 2021, NICE published its first ever guidance on the investigation and management of adults with heart valve disease. This followed on from recent updates to the international societal practice guidelines on heart valve disease produced by the American College of Cardiology and American Heart Association (in 2020) and the European Society of Cardiology and European Association for Cardiothoracic Surgery (in 2021). The purpose of the NICE guidance has significant differences from societal guidelines, as NICE guidance is designed for implementation within the UK's taxpayer-funded National Health Service and thus must account not just for clinical effectiveness of treatments but cost-effectiveness also. This explains some of the differences between recent recommendations from these bodies, most notably in the treatment of patients with symptomatic severe aortic stenosis, in which NICE clearly explains that cost implications influenced their final guidance (which differs from the recently published European and North American guidelines). The aims of this review article are to provide an overview of the scope and recommendations of the NICE guideline and to compare and contrast the guidelines, highlighting reasons for differences between the guidance from professional societies and NICE and discussing the relative strengths and weaknesses of the NICE guideline., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hemolysis contributes to the anemia of sickle cell disease (SCD). Hemolysis and anemia are distinct but inter-related pathophysiological processes that underlie end-organ dysfunction in this condition. We hypothesized that real-world medical tests would reveal distinct contributions of hemolysis and anemia to certain cardiopulmonary changes in adults with SCD., Methods: We assessed laboratory and clinical tests of cardiopulmonary function obtained during routine delivery of care in 442 adult SCD patients. We characterized hemolysis by the first principal component (PC1) of reticulocyte percent, lactate dehydrogenase (LDH), aspartate amino transferase (AST) and total bilirubin- the hemolytic component. The relationships of hemoglobin concentration and hemolysis to organ dysfunction were analyzed by multiple regression and path analysis to identify independent associations., Results: Degree of hemolysis and degree of anemia both associated independently with elevated values for left atrial diameter (LAD) and left ventricular end-diastolic diameter (LVED), and with lower percent predicted forced expiratory volume in first second (FEV1). Degree of hemolysis, but not anemia, associated independently with low values for oxygen saturation, forced vital capacity (FVC), and total lung capacity (TLC)]. Path analysis reinforced the trend by multiple regression for association of both degree of hemolysis and anemia with elevated TRV but not with lower diastolic blood pressure., Discussion: Analysis of real-world clinical tests suggest that, although they are inter-related, the degrees of hemolysis and of anemia make independent contributions to cardiopulmonary dysfunction and that treatments that specifically target both aspects of sickle cell disease may be of maximal benefit., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Haptoglobin (HP) is an acute-phase protein and the main scavenger of cell-free hemoglobin. When HP is depleted, as observed in hemolytic conditions such as sickle cell disease (SCD), cell-free hemoglobin can lead to acute organ damage. The impact of the HP 1-1, 2-1, and 2-2 isoforms on HP and cell-free hemoglobin concentrations and SCD-related complications is unclear. In a longitudinal cohort of patients with SCD, the HP 1 allele was associated with higher HP and lower cell-free hemoglobin concentrations at a routine clinic visit as well as during hospitalization for a vaso-occlusive episode or acute chest syndrome. With a median follow-up of 6.8 years, acute chest syndrome occurred in 42% (n = 163) and multiorgan failure in 14% (n = 53) of 391 patients with SCD with a minimum follow-up of 6 months. The HP 1 allele was independently associated with lower risk of developing multiorgan failure during acute chest syndrome (additive model hazard ratio, 0.5; P < .001). Future studies assessing the regulation of HP concentrations and ability to bind cell-free hemoglobin according to the HP genotype may help to identify patients with SCD at high risk for multiorgan failure and to guide interventions, such as rapid initiation of exchange transfusion or HP replacement therapy., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Aims: Little is known about the association between the type of admission ward and quality of care and outcomes for non-ST-segment elevation myocardial infarction (NSTEMI)., Methods and Results: We analysed data from 337 155 NSTEMI admissions between 2010 and 2017 in the UK Myocardial Ischaemia National Audit Project (MINAP) database. The cohort was dichotomised according to receipt of care either on a medical (n = 142,876) or cardiac ward, inclusive of acute cardiac wards and cardiac care unit (n = 194,279) on admission to hospital. Patients admitted to a cardiac ward were younger (median age 70 y vs. 75 y, P &lt; 0.001), and less likely to be female (33% vs. 40%, P &lt; 0.001). Independent factors associated with admission to a cardiac ward included ischaemic ECG changes (OR: 1.20, 95% CI: 1.18-1.23) and prior percutaneous coronary intervention (PCI) (OR: 1.19, 95% CI: 1.16-1.22). Patients admitted to a cardiac ward were more likely to receive optimal pharmacotherapy with statin (85% vs. 81%, P &lt; 0.001) and dual antiplatelet therapy (DAPT) (91% vs. 88%, P &lt; 0.001) on discharge, undergo invasive coronary angiography (78% vs. 59%, P &lt; 0.001), and receive revascularisation in the form of PCI (52% vs. 36%, P &lt; 0.001). Following multivariable logistic regression, the odds of inhospital all-cause mortality (OR: 0.75, 95% CI: 0.70-0.81) and major adverse cardiovascular events (MACE) (OR: 0.84, 95% CI: 0.78-0.91) were lower in patients admitted to a cardiac ward., Conclusion: Patients with NSTEMI admitted to a cardiac ward on admission were more likely to receive guideline directed management and had better clinical outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with the acute coronary syndrome with or without ST-segment elevation. Little is known about its performance at predicting in-hospital mortality for ethnic minority patients., Methods and Results: We identified 326 160 admissions with non-ST-segment elevation myocardial infarction (NSTEMI) in the Myocardial Infarction National Audit Project (MINAP), 2010-17, including White (n = 299 184) and ethnic minorities (excluding White minorities) (n = 26 976). We calculated the GRACE score for in-hospital mortality and assessed ethnic group baseline characteristics by low, intermediate and high risk. The performance of the GRACE risk score was estimated by discrimination [area under the receiver operating characteristic curve (AUC)] and calibration (calibration plots). Ethnic minorities presented younger and had increased prevalence of cardiometabolic risk factors in all GRACE risk groups. The GRACE risk score for White [AUC 0.87, 95% confidence interval (CI) 0.86-0.87] and ethnic minority (AUC 0.87, 95% CI 0.86-0.88) patients had good discrimination. However, whilst the GRACE risk model was well calibrated in White patients (expected to observed (E : O) in-hospital death rate ratio 0.99; slope 1.00), it overestimated risk in ethnic minority patients (E : O ratio 1.29; slope: 0.94)., Conclusion: The GRACE risk score provided good discrimination overall for in-hospital mortality, but was not well calibrated and overestimated risk for ethnic minorities with NSTEMI., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The purpose of this document is to update the existing joint British Societies recommendations on multidisciplinary meetings (MDMs) published in 2015 to reflect changes in practice. We aim to provide guidance on the structure and function of MDMs which should be taking place in every cardiac surgical centre. Out of scope are MDMs that do not require the routine presence of a cardiac surgeon such as electrophysiology MDMs and those which are not provided in every centre, such as complex aortic surgery., Competing Interests: Competing interests: APB: unrestricted educational grant from Boston Scientific, speaker fees from Boston Scientific, Abbott Vascular, Medtronic, Miracor and Shockwave. AB: research support from Abbott Vascular, speaker fees from Microport, AstraZeneca, Sinomed, Medtronic, Terumo, Pi-cardia. GC: payment for expert testimony, Cambridgeshire Coroner, Trustee, The Aortic Dissection Charitable Trust. PMacC: speaker fees and expert testimony, Edwards Life Sciences. SR: fee for chairing advisory board and speaker fee paid to Manchester University Hospitals, Novartis; reimbursement of travel expenses as speaker (no fee), Abbott. Trustee, Heart Valve Voice., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Objective: Handheld ultrasound devices (HUD) has diagnostic value in the assessment of patients with suspected left ventricular (LV) dysfunction. This meta-analysis evaluates the diagnostic ability of HUD compared with transthoracic echocardiography (TTE) and assesses the importance of operator experience., Methods: MEDLINE and EMBASE databases were searched in October 2020. Diagnostic studies using HUD and TTE imaging to determine LV dysfunction were included. Pooled sensitivities and specificities, and summary receiver operating characteristic curves were used to determine the diagnostic ability of HUD and evaluate the impact of operator experience on test accuracy., Results: Thirty-three studies with 6062 participants were included in the meta-analysis. Experienced operators could predict reduced LV ejection fraction (LVEF), wall motion abnormality (WMA), LV dilatation and LV hypertrophy with pooled sensitivities of 88%, 85%, 89% and 85%, respectively, and pooled specificities of 96%, 95%, 98% and 91%, respectively. Non-experienced operators are able to detect cardiac abnormalities with reasonable sensitivity and specificity. There was a significant difference in the diagnostic accuracy between experienced and inexperienced users in LV dilatation, LVEF (moderate/severe) and WMA. The diagnostic OR for LVEF (moderate/severe), LV dilatation and WMA in an experienced hand was 276 (95% CI 58 to 1320), 225 (95% CI 87 to 578) and 90 (95% CI 31 to 265), respectively, compared with 41 (95% CI 18 to 94), 45 (95% CI 16 to 123) and 28 (95% CI 20 to 41), respectively, for inexperienced users., Conclusion: This meta-analysis is the first to establish HUD as a powerful modality for predicting LV size and function. Experienced operators are able to accurately diagnose cardiac disease using HUD. A cautious, supervised approach should be implemented when imaging is performed by inexperienced users. This study provides a strong rationale for considering HUD as an auxiliary tool to physical examination in secondary care, to aid clinical decision making when considering referral for TTE., Trial Registration Number: CRD42020182429., Competing Interests: Competing interests: PG is an advisor for Pie Medical Imaging and Medis Medical Imaging. JW lists commercial relationships with AstraZeneca, Bayer and Novartis., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: A cluster of aortic bioprosthetic valve failures, most of which were Trifecta bioprostheses, was observed in Southampton General Hospital, Southampton, United Kingdom. This study was performed to assess whether the cluster represents a significant failure of this valve model or whether there is a selection bias that can explain the failure of these valves., Methods: This retrospective study evaluated all bioprosthetic aortic valve replacement operations performed between 2011 and 2016 inclusive in our center. The study compared the performance of the Trifecta valve (Abbott, Abbott Park, IL) with that of Perimount (Edwards Lifesciences, Irvine, CA), Perimount Magna Ease, and Mitroflow (LivaNova, London, United Kingdom) bioprostheses. In addition, the study analyzed patient-related and valve-related risk factors for early failure in the failed valves., Results: A total of 2807 bioprosthetic aortic valve replacements were performed. Of these, 836 were Trifecta valves, 1031 were Perimount, 449 were Perimount Magna Ease, and 351 were Mitroflow valves. A total of 24 Trifecta valves had premature structural failure, a number significantly higher than seen with Perimount or Perimount Magna Ease (no failure, P < .001 and P < .005, respectively) valves and the Mitroflow valve (1 failure, P < .05). There was no difference in the incidence of endocarditis or death. At the time of valve failure, 17 (71%) of the failed Trifecta valves had moderate or severe regurgitation, and the average peak gradient was 61 ± 29 mm Hg. The median failed prosthetic size was 23 mm. One failed valve had severe patient-prosthesis mismatch. The mean time to failure was 4.5 ± 1.7 years., Conclusions: The Trifecta bioprosthesis has an increased incidence of early structural valve failure, which is significantly higher than that of Perimount, Perimount Magna Ease, or Mitroflow. No patient-related or valve-related cause for the failure could be identified., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict-of-interest disclosure: The authors declare no relevant competing financial interests.

Haemolysis and vaso-occlusion underlie multi-organ system complications in sickle cell disease (SCD). We assessed real-world biomarkers in University of Illinois adult SCD patients, categorised as severe (HbSS/Sβ 0 -thalassaemia; n = 342) or mild (HbSC/Sβ + -thalassaemia; n = 100) genotypes and stratified according to treatment. African-American controls from the National Health and Nutrition Examination Survey (NHANES) were matched with each genotype category. Most measures of haemolysis, anaemia, inflammation and function of kidneys, liver and lungs differed markedly in untreated severe genotype patients compared to NHANES controls. These same biomarkers were significantly closer to the NHANES control range in untreated mild versus severe genotype patients, but they were not improved in severe genotype patients receiving treatment with hydroxycarbamide or blood transfusions, except that haemoglobin and HbF were higher with hydroxycarbamide. Systolic blood pressures did not differ among the SCD and NHANES groups, but diastolic pressures were higher in mild genotype patients. Ferritin in severe genotype patients on chronic transfusions was 50-fold higher than NHANES controls. The cross-sectional real-world biomarkers of patients on hydroxycarbamide or transfusions were not markedly improved compared to untreated patients. This may be due partly to poor compliance or more severe disease. Our findings highlight the need for more effective treatments., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

FOXM1 transcription factor is an oncogene and a master regulator of chemoresistance in multiple cancers. Pharmacological inhibition of FOXM1 is a promising approach but has proven to be challenging. We performed a network-centric transcriptomic analysis to identify a novel compound STL427944 that selectively suppresses FOXM1 by inducing the relocalization of nuclear FOXM1 protein to the cytoplasm and promoting its subsequent degradation by autophagosomes. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic treatments (platinum-based agents, 5-fluorouracil, and taxanes). RNA-seq analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 toward the FOXM1 pathway. Collectively, the novel autophagy-dependent mode of FOXM1 suppression by STL427944 validates a unique pathway to overcome tumor chemoresistance and improve the efficacy of treatment with conventional cancer drugs., (© 2021. The Author(s).)

Sickle cell disease (SCD) and apolipoprotein L1 (APOL1) G1/G2 variants increase chronic kidney disease (CKD) risk in African Americans by poorly understood mechanisms. We applied bioinformatics to identify new candidate genes associated with SCD-related CKD. An interaction network demonstrated APOA1 connecting haemoglobin subunit β (HBB) and APOL1 with 36 other candidate genes. Gene expression revealed upregulation of engulfment and cell motility 1 (ELMO1) and downregulation of APOA1 in the kidney cortex of SCD versus non-SCD mice. Analysis of candidate genes identified ELMO1 rs10951509 to be associated with albuminuria and APOA1 rs11216132 with haemoglobinuria in patients with SCD. A bioinformatic approach highlights ELMO1 and APOA1 as potentially associated with SCD nephropathy., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

The guideline provides a practical step-by-step guide in order to facilitate high-quality echocardiographic studies of patients with aortic stenosis. In addition, it addresses commonly encountered yet challenging clinical scenarios and covers the use of advanced echocardiographic techniques, including TOE and Dobutamine stress echocardiography in the assessment of aortic stenosis.

Tropheryma whipplei is a bacterium that causes a rare infection called Whipple's disease and can cause devastating effects if left untreated. It is important to recognize that patients with this infection may present with atypical symptoms and are often apyrexial with normal inflammatory markers. Moreover, routine blood cultures often do not isolate these bacteria in conventional growth media. Therefore, it requires a high level of clinical suspicion to make this diagnosis. Here, we present two cases of Tropheryma whipplei aortic valve endocarditis, with atypical presentation and similar unusual but striking echocardiographic images., (© 2021 Wiley Periodicals LLC.)

Objectives: We aimed to assess the frequency and nature of financial conflicts of interest among both the guideline committee authors and the authors of research studies used to support the European Society of Cardiology (ESC) guidelines., Design: We evaluated the competing interests of the doctors that write five of the key ESC clinical practice guidelines (CPG): valvular heart disease (VHD), atrial fibrillation (AF), pericardial diseases (PD), heart failure (HF) and myocardial revascularisation (IHD). In addition, we examined the funding sources of studies cited in the recommendations that were related to pharmaceutical agents. If a study was sponsored by industry, the disclosures of all authors were reviewed to assess whether there was a financial conflict of interest with the study funder., Results: In total, there were 603 recommendations (PD 112, VHD 111, HF 169, IHD 97 and AF 114) across the five guidelines, of which, 271 (45% (PD 26, VHD 23, HF 72, IHD 84 and AF 66)) related to pharmaceutical agents. At least 80% of guideline committee authors, except for the PD guidelines, had a relevant financial conflict of interest, with the most frequent being a direct personal payment (68-82%). Industry support for studies varied across the guidelines from 5% (PD) to 65% (IHD). If a study was funded by industry, authors were frequently (55-90%) conflicted with the industry sponsor., Conclusions: The majority of the doctors that write clinical guidelines have a relevant financial conflict of interest. In addition, industry sponsorship of studies is frequent, and authors are often conflicted with the study funder. We propose that physicians that write clinical guidelines should be free of such financial conflicts of interest to maintain scientific integrity and independence in the clinical guidelines., (© Royal College of Physicians 2021. All rights reserved.)

Genetic modifiers of anemia in Plasmodium falciparum infection and sickle cell disease (SCD) are not fully known. Both conditions are associated with oxidative stress, hemolysis and anemia. The CYB5R3 gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. CYB5R3 c.350C > G encoding CYB5R3 T117S , the most frequent recognized African-specific polymorphism, does not have known functional significance, but its high allele frequency (23% in African Americans) suggests a selection advantage. Glucose-6-phosphate dehydrogenase (G6PD) is essential for protection from oxidants; its African-polymorphic X-linked A+ and A- alleles, and other variants with reduced activity, coincide with endemic malaria distribution, suggesting protection from lethal infection. We examined the association of CYB5R3 c.350C > G with severe anemia (hemoglobin <5 g/dL) in the context of G6PD A+ and A- status among 165 Zambian children with malaria. CYB5R3 c.350C > G offered protection against severe malarial anemia in children without G6PD deficiency (G6PD wild type or A+/A- heterozygotes) (odds ratio 0.29, P = .022) but not in G6PD A+ or A- hemizygotes/homozygotes. We also examined the relationship of CYB5R3 c.350C > G with hemoglobin concentration among 267 children and 321 adults and adolescents with SCD in the US and UK and found higher hemoglobin in SCD patients without G6PD deficiency (β = 0.29, P = .022 children; β = 0.33, P = .004 adults). Functional studies in SCD erythrocytes revealed mildly lower activity of native CYB5R3 T117S compared to wildtype CYB5R3 and higher NADH/NAD+ ratios. In conclusion, CYB5R3 c.350C > G appears to ameliorate anemia severity in malaria and SCD patients without G6PD deficiency, possibly accounting for CYB5R3 c.350C > G selection and its high prevalence., (© 2020 Wiley Periodicals LLC.)

Background: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM., Methods and Findings: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify., Conclusions: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: PH works for Medicines for Malaria Venture (MMV), which has a Research Collaboration Agreement in place with Imperial College. LCO declares grant funding from the World Health Organization, the Bill and Melinda Gates Foundation, and Medicines for Malaria Venture.

The established processes for ensuring safe outpatient surveillance of patients with known heart valve disease (HVD), echocardiography for patients referred with new murmurs and timely delivery of surgical or transcatheter treatment for patients with severe disease have all been significantly impacted by the novel coronavirus pandemic. This has created a large backlog of work and upstaging of disease with consequent increases in risk and cost of treatment and potential for worse long-term outcomes. As countries emerge from lockdown but with COVID-19 endemic in society, precautions remain that restrict 'normal' practice. In this article, we propose a methodology for restructuring services for patients with HVD and provide recommendations pertaining to frequency of follow-up and use of echocardiography at present. It will be almost impossible to practice exactly as we did prior to the pandemic; thus, it is essential to prioritise patients with the greatest clinical need, such as those with symptomatic severe HVD. Local procedural waiting times will need to be considered, in addition to usual clinical characteristics in determining whether patients requiring intervention would be better suited having surgical or transcatheter treatment. We present guidance on the identification of stable patients with HVD that could have follow-up deferred safely and suggest certain patients that could be discharged from follow-up if waiting lists are triaged with appropriate clinical input. Finally, we propose that novel models of working enforced by the pandemic-such as increased use of virtual clinics-should be further developed and evaluated., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Sickle cell disease (SCD) patients are at a four- to 100-fold increased risk for thrombosis compared with the general population, although the mechanisms and risk factors are not clear. We investigated the incidence and predictors for thrombosis in a retrospective, longitudinal cohort of 1193 pediatric and adult SCD patients treated at our institution between January 2008 and December 2017. SCD diagnosis and thrombotic complications were identified using International Classification of Diseases coding and verified through medical chart review. Clinical and laboratory data were extracted from the medical records. With a median follow-up of 6.4 years, 208 (17.4%) SCD patients experienced 352 thrombotic events (64 strokes, 288 venous thromboembolisms [VTE]). Risk factors for stroke included older age and HbSS/Sβ0-genotype and a lower hemoglobin (Hb) F% in the subset of HbSS/Sβ0-genotype patients (P < .05). VTE risk was independently associated with lower estimated glomerular filtration rate, hydroxyurea (HU) use, HbSS/Sβ0 genotype, and higher white blood cell (WBC) counts and Hb (P ≤ .03). Two thrombomodulin gene variants previously associated with thrombosis in the general African American population, THBD rs2567617 (minor allele frequency [MAF] 0.25; odds ratio [OR], 1.5; P = .049) and THBD rs1998081 (MAF, 0.24; OR, 1.5; P = .059), were associated with thrombosis in this cohort. In summary, thrombotic complications are common, and several traditional and SCD-specific risk factors are associated with thrombotic risk. Future studies integrating clinical, laboratory, and genetic risk factors may improve our understanding of thrombosis and guide intervention practices in SCD.

Background: Atrial Fibrillation is the most common arrhythmia worldwide with a global age adjusted prevalence of 0.5% in 2010. Anticoagulation treatment using warfarin or direct oral anticoagulants is effective in reducing the risk of AF-related stroke by approximately two-thirds and can provide a 10% reduction in overall mortality. There has been increased interest in detecting AF due to its increased incidence and the possibility to prevent AF-related strokes. Inexpensive consumer devices which measure the ECG may have the potential to accurately detect AF but do not generally incorporate diagnostic algorithms. Machine learning algorithms have the potential to improve patient outcomes particularly where diagnoses are made from large volumes or complex patterns of data such as in AF., Methods: We designed a novel AF detection algorithm using a de-correlated Lorenz plot of 60 consecutive RR intervals. In order to reduce the volume of data, the resulting images were compressed using a wavelet transformation (JPEG200 algorithm) and the compressed images were used as input data to a Support Vector Machine (SVM) classifier. We used the Massachusetts Institute of Technology (MIT)-Beth Israel Hospital (BIH) Atrial Fibrillation database and the MIT-BIH Arrhythmia database as training data and verified the algorithm performance using RR intervals collected using an inexpensive consumer heart rate monitor device (Polar-H7) in a case-control study., Results: The SVM algorithm yielded excellent discrimination in the training data with a sensitivity of 99.2% and a specificity of 99.5% for AF. In the validation data, the SVM algorithm correctly identified AF in 79/79 cases; sensitivity 100% (95% CI 95.4%-100%) and non-AF in 328/336 cases; specificity 97.6% (95% CI 95.4%-99.0%)., Conclusions: An inexpensive wearable heart rate monitor and machine learning algorithm can be used to detect AF with very high accuracy and has the capability to transmit ECG data which could be used to confirm AF. It could potentially be used for intermittent screening or continuously for prolonged periods to detect paroxysmal AF. Further work could lead to cost-effective and accurate estimation of AF burden and improved risk stratification in AF., Competing Interests: MB is affiliated with Leonardo MW Ltd but did not receive any funding from any organisation for this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To assess the frequency and impact of incidental findings (IF) on CT during work-up for transcatheter aortic valve intervention (TAVI)., Methods: A consecutive cohort of patients referred for consideration of TAVI who underwent a CT scan between 2009 and 2018 were studied retrospectively. CT reports were reviewed for the presence of IFs and categorised based upon their clinical significance: (a) insignificant-findings that did not require specific treatment or follow-up; (b) intermediate-findings that did not impact on the decision-making process but required follow-up; (c) significant-findings that either required urgent investigation or meant that TAVI was clinically inappropriate., Results: A total of 652 patients were included, whose median age was 82 years. One or more insignificant IF was found in 95.6% of patients. Intermediate IFs were documented in 5.4%. 91 (14%) patients had at least one significant IF. These included possible malignancy in 67 (74%). The ultimate decision to offer aortic valve intervention was only changed by the presence of an IF in 3.5% of cases., Conclusion: Clinically significant IFs are detected in more than 1 in 10 of patients undergoing CT as part of a TAVI work-up, although just over half of these patients still receive aortic valve intervention., Advances in Knowledge: This study is the largest UK cohort, which, when combined with a review of existing literature, provides a clear picture of the frequency and clinical impact of IFs found at CT for TAVI assessment.