Observational study of circulating endothelial cell profiles in patients with non-ST-elevation myocardial infarction stratified by plaque erosion or rupture identified by optical coherence tomography: The Plaque Erosion Pilot Study ii (PEPSii)

Introduction Myocardial infarction (MI) remains a leading global cause of death and disability. There is growing evidence that about 40% of MI cases have plaque erosion due to mass endothelial cell apoptosis and exposure of pro-thrombotic underlying extracellular matrix, in contrast to shearing of endothelial cells during more conventional plaque rupture events. This hypothesis suggests that circulating endothelial cells (CEC) would be higher in MI cases of plaque erosion compared to plaque rupture. Accordingly, I set up a study to measure levels of CEC in patients with non-ST elevation MI (NSTEMI) who underwent plaque morphology evaluation to stratify cases into plaque erosion or rupture. Methods This was an observational study which enrolled patients undergoing elective percutaneous coronary intervention (PCI), a feasibility group to establish and refine research methods, and NSTEMI undergoing PCI (cases). Peripheral venous blood samples were obtained to assess CEC and platelet-leukocyte aggregates (PLAs) using flow cytometry. Culprit plaques were imaged using optical coherence tomography (OCT) and independently classified as plaque rupture or erosion. CEC levels in NSTEMI patients were compared between plaque erosion and plaque rupture cases. Results Overall, 22 NSTEMI patients and 11 feasibility patients were recruited. Of the NSTEMI patients, 7 did not have plaque morphology, either due to missing data, or inability to agree on a classification. CEC levels, as a percent CD45-ve PBMCs, were significantly higher in the plaque erosion group (17.4%; n=7) compared to the plaque rupture group (9%; n=8: p=0.0012). PLA analysis showed no significant differences between erosion and rupture (p=0.8665). Conclusion Higher levels of CEC in the plaque erosion group compared to rupture supports the hypothesis of mass endothelial cell denudation as a causative mechanism. Further research is needed to investigate trigger factors for erosion and to understand if specific therapeutic strategies are needed for these patients

Streamline-based three-dimensional peak-velocity tracing of transvalvular flow using four-dimensional flow cardiac magnetic resonance imaging for left ventricular diastolic assessment in aortic regurgitation: A case report

Background: Doppler transthoracic echocardiography is routinely performed to measure peak mitral inflow velocities in the assessment of left ventricular diastolic function. The limitations of echocardiography are well documented, but its accuracy in the measurement of transmitral peak velocity in the presence of aortic valve regurgitation has not yet been compared with four-dimensional flow cardiac magnetic resonance imaging. Four-dimensional flow cardiac magnetic resonance imaging offers time-resolved cross-sectional velocity information that can be used to investigate mitral inflow peak velocity. We present a case report demonstrating the potential superior capabilities of four-dimensional flow cardiac magnetic resonance imaging in accurately detecting mitral inflow velocities over Doppler echocardiography in patients with aortic regurgitation. Case presentation: A 67-year-old Caucasian female presented to our outpatient cardiology clinic with exertional dyspnea. Doppler transthoracic echocardiography identified moderate to severe aortic regurgitation. Mapping of mitral inflow peak velocities proved challenging with Doppler echocardiography. Additionally, four-dimensional flow cardiac magnetic resonance imaging with automated three-dimensional flow streamlines was performed, which allowed for more accurate detection of mitral inflow peak velocities. Conclusions: Doppler echocardiography has a limited role in mitral inflow assessment where aortic regurgitation is present. In such cases, four-dimensional flow cardiac magnetic resonance imaging is an alternative imaging technique that may circumvent this issue and allow mitral inflow assessment

Day case discharge of patients treated with drug coated balloon only angioplasty for de novo coronary artery disease:A single center experience

Objective: To report our initial experience with Drug Coated Balloon (DCB) only angioplasty and propose a protocol to achieve this safely. Background: There are no articles published in the literature currently regarding the safety of same day discharge in patients treated with DCB-only angioplasty. Methods: Retrospective review of all our patients treated with DCB-only angioplasty from Sept 2017 to April 2018 with identification of potential complications relating to same day discharge. Results: A total of 100 consecutive patients who underwent elective DCB-only angioplasty for de novo coronary artery disease and were discharged on the same day as the procedure were included. In 99% no cardiac symptoms relating to the procedure requiring urgent hospitalisation or urgent investigations were identified. One patient was readmitted the next day requiring stenting of the previously treated lesion. Our 30 day mortality was zero. Some 97 hospital bed days were saved with 100 patients treated. Conclusion: Elective day-case DCB-only angioplasty according to our local protocol is safe and cost-effective and should be considered for the majority of the patients

Development and evaluation of student transition writing mentoring

Flying Start, an inter-institutional NTFS project, developed and evaluated programmes in which university students mentored A-level and other pre-university students in academic writing. Feedback showed that the pre-university mentees found the mentors easy to talk to and believed the programme would help them write better at university. Focus groups revealed that mentees would have liked better preparation for the programmes; that interpersonal mentor-mentee interactions affected both sets of students’ experiences; and that mentees valued working with mentors on the aspects of writing that were programme targets. Before-and-after measures showed limited changes in approaches to learning, no changes in understanding of the core criteria for university writing, but small improvements in quality of writing. The evaluation provides the basis for recommendations about wider use of pre-university interventions in academic writing, and about ways the approach could be adapted for different settings.This project was part of the Flying Start programme, funded by a National Teaching Fellowship Project grant awarded to Lin Norton and James Elander

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial

BACKGROUND: Adjuvant chemotherapy for patients with early breast cancer improves outcomes but its toxicity affects patients' quality of life (QOL). The UK TACT2 trial investigated whether accelerated epirubicin improves time to recurrence and if oral capecitabine is non-inferior to cyclophosphamide, methotrexate, and fluorouracil (CMF) for efficacy with less toxicity. Results showed no benefit for accelerated epirubicin and capecitabine was non-inferior. As part of the QOL substudy, we aimed to assess the effect of chemotherapies on psychological distress, physical symptoms, and functional domains. METHODS: TACT2 was a multicentre, phase 3, open-label, parallel-group, randomised, controlled trial done in 129 UK centres. Participants were aged 18 years or older with histologically confirmed node-positive or high-risk node-negative invasive primary breast cancer, who had undergone complete excision, and due to receive adjuvant chemotherapy. Patients were randomly assigned (1:1:1:1) to four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either CMF (600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1–14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1–14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs 1–3 vs ≥4), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). QOL was one of the secondary outcomes and is reported here. All patients from a subset of 44 centres were invited to complete QOL questionnaires (Hospital Anxiety and Depression Scale [HADS] and European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire 30-item core module [QLQ-C30] and Quality of Life Questionnaire breast module [QLQ-BR23]) at baseline, end of standard or accelerated epirubicin, end of CMF or capecitabine, and at 12 and 24 months after randomisation. The QOL substudy prespecified two coprimary QOL outcomes assessed in the intention-to-treat population: overall QOL (reported elsewhere) and HADS total score. Prespecified secondary QOL outcomes were EORTC QLQ-C30 subscales of physical function, role function, and fatigue and EORTC QLQ-BR23 subscales of sexual function and systemic therapy side-effects. This trial is registered with ISRCTN, ISRCTN68068041, and ClinicalTrials.gov, NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (20 [0·5%] of whom were male) were enrolled in TACT2; 1281 (85·8%) of 1493 eligible patients were included in the QOL substudy. Eight (0·6%) participants in the QOL substudy were male and 1273 (99·4%) were female. Median follow-up was 85·6 months (IQR 80·6–95·9). Analysis was performed on the complete QOL dataset (as of Sept 15, 2011) when all participants had passed the 24-month timepoint. Prerandomisation questionnaires were completed by 1172 (91·5%) patients and 1179 (92·0%) completed at least one postrandomisation questionnaire. End-of-treatment HADS depression score (p=0·0048) and HADS total change score (p=0·0093) were worse for CMF versus capecitabine. Accelerated epirubicin led to worse physical function (p=0·0065), role function (p<0·0001), fatigue (p=0·0002), and systemic side-effects (p=0·0001), but not sexual function (p=0·36), compared with standard epirubicin during treatment, but the effect did not persist. Worse physical function (p=0·0048), sexual function (p=0·0053), fatigue (p<0·0001), and systemic side-effects (p<0·0001), but not role functioning (p=0·013), were seen for CMF versus capecitabine at end of treatment; these differences persisted at 12 months and 24 months. INTERPRETATION: Accelerated epirubicin was associated with worse QOL than was standard epirubicin but only during treatment. These findings will help patients and clinicians make an informed choice about accelerated chemotherapy. CMF had worse QOL effects than did capecitabine, which were persistent for 24 months. The favourable capecitabine QOL compared with CMF supports its use as an adjuvant option after neoadjuvant chemotherapy in patients with triple-negative breast cancer

Cardiovascular examination using hand-held cardiac ultrasound

Echocardiography is the first-line imaging modality for assessing cardiac function and morphology. The miniaturisation of ultrasound technology has led to the development of hand-held cardiac ultrasound (HCU) devices. The increasing sophistication of available HCU devices enables clinicians to more comprehensively examine patients at the bedside. HCU can augment clinical exam findings by offering a rapid screening assessment of cardiac dysfunction in both the Emergency Department and in cardiology clinics. Possible implications of implementing HCU into clinical practice are discussed in this review paper

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial.

BACKGROUND: Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both. METHODS: In this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6-95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81-1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3-87·3) of patients receiving standard epirubicin and 87·1% (85·6-88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85-1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1-4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5-8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine. INTERPRETATION: We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche

Diagnostic accuracy of handheld cardiac ultrasound device for assessment of left ventricular structure and function: systematic review and meta-analysis

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

Kat-ARC accelerated 4D flow CMR: clinical validation for transvalvular flow and peak velocity assessment

Background: To validate the k-adaptive-t autocalibrating reconstruction for Cartesian sampling (kat-ARC), an exclusive sparse reconstruction technique for four-dimensional (4D) flow cardiac magnetic resonance (CMR) using conservation of mass principle applied to transvalvular flow.   Methods: This observational retrospective study (2020/21-075) was approved by the local ethics committee at the University of East Anglia. Consent was waived. Thirty-five patients who had a clinical CMR scan were included. CMR protocol included cine and 4D flow using Kat-ARC acceleration factor 6. No respiratory navigation was applied. For validation, the agreement between mitral net flow (MNF) and the aortic net flow (ANF) was investigated. Additionally, we checked the agreement between peak aortic valve velocity derived by 4D flow and that derived by continuous-wave Doppler echocardiography in 20 patients.   Results: The median age of our patient population was 63 years (interquartile range [IQR] 54–73), and 18/35 (51%) were male. Seventeen (49%) patients had mitral regurgitation, and seven (20%) patients had aortic regurgitation. Mean acquisition time was 8 ± 4 min. MNF and ANF were comparable: 60 mL (51−78) versus 63 mL (57−77), p = 0.310). There was an association between MNF and ANF (rho = 0.58, p < 0.001). Peak aortic valve velocity by Doppler and 4D flow were comparable (1.40 m/s, [1.30−1.75] versus 1.46 m/s [1.25−2.11], p = 0.602) and also correlated with each other (rho = 0.77, p < 0.001).   Conclusions: Kat-ARC accelerated 4D flow CMR quantified transvalvular flow in accordance with the conservation of mass principle and is primed for clinical translation