Three-dimensional tumour microenvironment reconstruction and tumour-immune interactions' analysis

Tumours arise within complex 3D microenvironments, but the routine 2D analysis of tumours often underestimates the spatial heterogeneity. In this paper, we present a methodology to reconstruct and analyse 3D tumour models from routine clinical samples allowing 3D interactions to be analysed at cellular resolution. Our workflow involves cutting thin serial sections of tumours followed by labelling of cells using markers of interest. Serial sections are then scanned, and digital multiplexed data are created for computational reconstruction. Following spectral unmixing, a registration method of the consecutive images based on a pre-alignment, a parametric and a non-parametric image registration step is applied. For the segmentation of the cells, an ellipsoidal model is proposed and for the 3D reconstruction, a cubic interpolation method is used. The proposed 3D models allow us to identify specific interaction patterns that emerge as tumours develop, adapt and evolve within their host microenvironment. We applied our technique to map tumour-immune interactions of colorectal cancer and preliminary results suggest that 3D models better represent the tumor-immune cells interaction revealing mechanisms within the tumour microenvironment and its heterogeneity

Fusion pacing with biventricular, left ventricular-only and multipoint pacing in cardiac resynchronisation therapy: Latest evidence and strategies for use

Despite advances in the field of cardiac resynchronisation therapy (CRT), response rates and durability of therapy remain relatively static. Optimising device timing intervals may be the most common modifiable factor influencing CRT efficacy after implantation. This review addresses the concept of fusion pacing as a method for improving patient outcomes with CRT. Fusion pacing describes the delivery of CRT pacing with a programming strategy to preserve intrinsic atrioventricular (AV) conduction and ventricular activation via the right bundle branch. Several methods have been assessed to achieve fusion pacing. QRS complex duration (QRSd) shortening with CRT is associated with improved clinical response. Dynamic algorithm-based optimisation targeting narrowest QRSd in patients with intact AV conduction has shown promise in people with heart failure with left bundle branch block. Individualised dynamic programming achieving fusion may achieve the greatest magnitude of electrical synchrony, measured by QRSd narrowing

Gland segmentation in gastric histology images: detection of intestinal metaplasia

Gastric cancer is one of the most frequent causes of cancer-related deaths worldwide. Gastric intestinal metaplasia (IM) of the mucosa of the stomach has been found to increase the risk of gastric cancer and is considered as one of the precancerous lesions. Therefore, early detection of IM may have a valuable role in histopathological risk assessment regarding the possibility of progression to cancer. Accurate segmentation and analysis of gastric glands from the histological images plays an important role in the diagnostic confirmation of IM. Thus, in this paper, we propose a framework for segmentation of gastric glands and detection of IM. More specifically, we propose the GAGL-Net for the segmentation of glands. Then, based on two features of the extracted glands we classify the tissues into normal and IM cases. The results showed that the proposed gland segmentation approach achieves an F1 score equal to 0.914. Furthermore, the proposed methodology shows great potential for the IM detection achieving an accuracy score equal to 96.6%. To evaluate the efficiency of the proposed methodology we used a publicly available dataset and we created the GAGL dataset consisting of 59 Whole Slide Images (WSI) including both IM and normal cases

Tertiary lymphoid structures (TLS) identification and density assessment on H&E-stained digital slides of lung cancer

Tertiary lymphoid structures (TLS) are ectopic aggregates of lymphoid cells in inflamed, infected, or tumoral tissues that are easily recognized on an H&E histology slide as discrete entities, distinct from lymphocytes. TLS are associated with improved cancer prognosis but there is no standardised method available to quantify their presence. Previous studies have used immunohistochemistry to determine the presence of specific cells as a marker of the TLS. This has now been proven to be an underestimate of the true number of TLS. Thus, we propose a methodology for the automated identification and quantification of TLS, based on H&E slides. We subsequently determined the mathematical criteria defining a TLS. TLS regions were identified through a deep convolutional neural network and segmentation of lymphocytes was performed through an ellipsoidal model. This methodology had a 92.87% specificity at 95% sensitivity, 88.79% specificity at 98% sensitivity and 84.32% specificity at 99% sensitivity level based on 144 TLS annotated H&E slides implying that the automated approach was able to reproduce the histopathologists’ assessment with great accuracy. We showed that the minimum number of lymphocytes within TLS is 45 and the minimum TLS area is 6,245μm2. Furthermore, we have shown that the density of the lymphocytes is more than 3 times those outside of the TLS. The mean density and standard deviation of lymphocytes within a TLS area are 0.0128/μm2 and 0.0026/μm2 respectively compared to 0.004/μm2 and 0.001/μm2 in non-TLS regions. The proposed methodology shows great potential for automated identification and quantification of the TLS density on digital H&E slides

Stress echocardiography in valvular heart disease.

This is an original manuscript / preprint of an article published by Taylor & Francis in Expert Review of Cardiovascular Therapy on 10 Oct 2018, available online: https://doi.org/10.1080/14779072.2018.1532791INTRODUCTION: The management of patients with heart valve disease can be complex. Patients may have symptoms disproportionate to the severity or the severity may be unclear. In addition, the optimal timing of intervention in patients with severe disease may be controversial. Areas covered: This article examines the role of stress echocardiography for assessment of patients with low-flow, low-gradient aortic stenosis, asymptomatic severe valve disease and patients where symptoms are discordant to the resting severity of valve disease. Expert commentary: Stress echocardiography helps clinicians determine the true severity of valve disease and may identify the cause of symptoms in patients with only mild/moderate disease. The data provided by stress echocardiography will help determine the appropriate management strategy and the correct timing of intervention

Try to see it my way: exploring the co-design of visual presentations of well-being through a workshop process

Aims: A 10-month project funded by the NewMind network sought to develop the specification of a visualisation toolbox that could be applied on digital platforms (web- or app- based) to support adults with lived experience of mental health difficulties to present and track their personal well-being in an multi-media format.Methods: A participant co-design methodology, Double Diamond from the DesignCouncil (Great Britain),was used consisting of 4 phases: Discover - a set of literature and app searches of well-being and health visualisation material; Define – an initial workshop with participants with lived experience of mental health problems to discuss well-being and visualisation techniques and to share personal visualisations; Develop – a second workshop to add detail to personal visualisations e.g., forms of media to be employed, degree of control over sharing. Deliver – to disseminate the learning from the exercise. Results: Two design workshops were held in December 2017 and April 2018 with 13 and 12 experts-by-experience involved respectively, including 2 peer researchers (co-authors) and 2 individual-carer dyads in each workshop, with over 50% of those being present in both workshops. Twenty detailed visualisations were produced, the majority focussing on highly personal and detailed presentations of well-being.Discussion: Whilst participants concurred on a range of typical dimensions of well-being, the individual visualisations generated were in contrast to the techniques currently employed by existing digital well-being apps and there was a great diversity in preference for different visualisation types. Participants considered personal visualisations to be useful as self-administered interventions or as a step towards seeking help, as well as being tools for self-appraisal.Conclusions: The results suggest that an authoring approach using existing apps may provide the high degree of flexibility required. Training on such tools, delivered via a module on a recovery college course, could be offered

ECGI targeted ablation for persistent AF not responding to pulmonary vein isolation: Results of a two-staged strategy (TARGET AF2)

Background: Mechanisms sustaining persistent atrial fibrillation (AF) remain unclear. / Objectives: The study sought to evaluate both the clinical outcomes and response to ablation of potential drivers in patients with recurrent persistent AF recurrence following pulmonary vein isolation (PVI). / Methods: A total of 100 patients with persistent AF of 1.5 revolutions or focal activations. Cycle lengths were measured pre- and postablation. The primary outcome was freedom from atrial arrhythmia off antiarrhythmic drugs at 1 year as per guidelines. / Results: Of 37 patients recruited, 26 had recurrent AF and underwent ECGI-guided ablation of PDs. An average of 6.4 ± 2.7 PDs were targeted per patient. The mean ablation time targeting PDs was 15.5 ± 6.9 minutes. An ablation response occurred in 20 patients (AF termination in 6, cycle length prolongation ≥10% in 14). At 1 year, 14 (54%) of 26 patients were free from arrhythmia, and 12 (46%) of 26 were off antiarrhythmic drugs. Considering the 96 patients who completed follow-up out of the original cohort of 100 patients undergoing cryoablation in this staged strategy, freedom from arrhythmia at 1 year following the last procedure was 72 (75%) of 96, or 70 (73%) of 96 off antiarrhythmic drugs. / Conclusions: In patients with recurrent AF despite PVI, ECGI-guided ablation caused an acute response in a majority with reasonable long-term outcomes

ECGI targeted ablation for persistent AF not responding to pulmonary vein isolation: Results of a two-staged strategy (TARGET AF2)

BACKGROUND: Mechanisms sustaining persistent atrial fibrillation (AF) remain unclear. OBJECTIVES: The study sought to evaluate both the clinical outcomes and response to ablation of potential drivers in patients with recurrent persistent AF recurrence following pulmonary vein isolation (PVI). METHODS: A total of 100 patients with persistent AF of 1.5 revolutions or focal activations. Cycle lengths were measured pre- and postablation. The primary outcome was freedom from atrial arrhythmia off antiarrhythmic drugs at 1 year as per guidelines. RESULTS: Of 37 patients recruited, 26 had recurrent AF and underwent ECGI-guided ablation of PDs. An average of 6.4 ± 2.7 PDs were targeted per patient. The mean ablation time targeting PDs was 15.5 ± 6.9 minutes. An ablation response occurred in 20 patients (AF termination in 6, cycle length prolongation ≥10% in 14). At 1 year, 14 (54%) of 26 patients were free from arrhythmia, and 12 (46%) of 26 were off antiarrhythmic drugs. Considering the 96 patients who completed follow-up out of the original cohort of 100 patients undergoing cryoablation in this staged strategy, freedom from arrhythmia at 1 year following the last procedure was 72 (75%) of 96, or 70 (73%) of 96 off antiarrhythmic drugs. CONCLUSIONS: In patients with recurrent AF despite PVI, ECGI-guided ablation caused an acute response in a majority with reasonable long-term outcomes

Long term conservation of electrical synchrony by multipoint pacing with dynamic atrioventricular delays

Introduction Automatic adjustment of atrioventricular delay (AVD) with SyncAV has been shown to improve electrical synchronization. However, the long term effects of SyncAV optimization on electrical synchrony are unknown. Purpose Evaluate the effect of SyncAV programming on 6-month (6mo) QRS duration during biventricular (BiV) and left ventricle only MultiPoint Pacing (MPP). Methods Patients with LBBB and QRS duration (QRSd) ≥ 150 ms scheduled for CRT-P/D device implantation with quadripolar LV lead were enrolled in this prospective study. QRSd was measured post-implant from 12-lead surface ECG by blinded experts during the following pacing modes: intrinsic conduction, MPP (MPP=RV+LV1+LV2) and LV-only MPP (LVMPP=LV1+LV2). For each mode, SyncAV was enabled (e.g. MPP+SyncAV) with the patient-tailored SyncAV offset that minimized QRSd. Patients were then randomized 1:1 to receive MPP+SyncAV or LVMPP+SyncAV with the optimal offset identified at implant, and QRSd was re-evaluated at the 6mo follow-up. Results Fifty-nine patients (72% male, 41% ischemic, 26% ejection fraction, 166 ms intrinsic QRSd) completed device implant and QRSd assessment. Relative to intrinsic conduction at implant, the MPP+SyncAV group (n=30) had a QRSd reduction of 26% at implant (162 to 122 ms, p<0.001), and 20% at 6mo (162 to 130 ms, p<0.001). The LVMPP+SyncAV group (n=29) had a QRSd reduction of 24% at implant (165 to 128 ms, p<0.001), and 15% at 6mo (165 to 140 ms, p<0.001). In the MPP+SyncAV group, 28/30 (93%) of patients had more than 10% reduction in QRSd with respect to intrinsic at implant, with 27/30 (90%) maintaining this trend at 6 mo follow up. With LVMPP+SyncAV pacing, only 25/29 (86%) of patients had more than 10% reduction in QRSd with respect to intrinsic at implant, and this reduced to 18/29 (62%) maintaining this trend at 6 mo follow up. Conclusion MPP combined with SyncAV significantly improved acute electrical synchrony at implant in CRT patients with LBBB, as assessed by QRSd reduction. Significant QRSd reduction was maintained at 6 months post-implant by both biventricular and LV-only MPP configurations