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Purpose: Inhibition of monocarboxylate transporter (MCT) 1–mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer. Patients and Methods: This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics. Results: During dose escalation, 40 patients received AZD3965 at 5–30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity. Conclusions: AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

Purpose:Inhibition of monocarboxylate transporter (MCT) 1–mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer.Patients and Methods:This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics.Results:During dose escalation, 40 patients received AZD3965 at 5–30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity.Conclusions:AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

supplementary data: Methods, tables, figure.

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Background Coronary artery disease (CAD) is a concerning late outcome for cancer survivors. However, uniform surveillance guidelines are lacking. Aim To harmonise international recommendations for CAD surveillance for survivors of childhood, adolescent and young adult (CAYA) cancers. Methods A systematic literature review was performed and evidence graded using the Grading of Recommendations, Assessment, Development and Evaluation criteria. Eligibility included English language studies, a minimum of 20 off-therapy cancer survivors assessed for CAD, and 75% diagnosed prior to age 35 years. All study designs were included, and a multidisciplinary guideline panel formulated and graded recommendations. Results 32 of 522 identified articles met eligibility criteria. The prevalence of CAD ranged from 0 to 72% and was significantly increased compared to control populations. The risk of CAD was increased among survivors who received radiotherapy exposing the heart, especially at doses ≥15 Gy (moderate-quality evidence). The guideline panel agreed that healthcare providers and CAYA cancer survivors treated with radiotherapy exposing the heart should be counselled about the increased risk for premature CAD. While the evidence is insufficient to support primary screening, monitoring and early management of modifiable cardiovascular risk factors are recommended. Initiation and frequency of surveillance should be based on the intensity of treatment exposures, family history, and presence of co-morbidities but at least by age 40 years and at a minimum of every 5 years. All were strong recommendations. Conclusion These systematically assessed and harmonised recommendations for CAD surveillance will inform care and guide research concerning this critical outcome for CAYA cancer survivors.

Introduction Relevant clinical information is vital to inform the analytical and interpretative phases of most investigations. The aim of this study is to evaluate the impact of implementation of Computerised Provider Order Entry (CPOE), featuring order-specific electronic Order Entry Forms (eOEFs), on the quality and quantity of clinical information included with investigation requests. Methods The CPOE module of a commercially available Electronic Health Record (Cerner Millennium), was implemented at a large, tertiary care centre. The Laboratory Information Management System was interrogated to collect data on specimens sent for microbiological culture one year before implementation of CPOE (2018), immediately post-implementation (2019), and 6 months post-implementation (2020). An interrupted time series analysis was performed, using text mining, to evaluate the quality and quantity of free-text clinical information. Results In total, 39,919 specimens were collected from 16,458 patients. eOEFs were used to place 10,071 out of 13,735 orders in 2019 (73.3%), and 9155 out of 12,229 orders in 2020 (74.9%). No clinical details were included with 653 out of 39,919 specimens (1.6%), of which 22 (3.4%) were ordered using eOEFs. The median character count increased from 14 in 2018, to 41 in 2019, and 38 in 2020. An anti-infective agent was specified in 581 out of 13,955 requests (4.2%) in 2018, 5545 out of 13,735 requests (40.4%) in 2019, and 5215 out of 12,229 requests (42.6%) in 2020. Ciprofloxacin or piperacillin-tazobactam (Tazocin) were mentioned in the clinical details included with 421 out of 15,335 urine culture requests (2.7%), of which 406 (96.3%) were ordered using eOEFs. Subsequent detection of in vitro non-susceptibility led to a change in anti-infective therapy for 5 patients. Conclusions Implementation of CPOE, featuring order-specific eOEFs, significantly and sustainably improves the quality and quantity of clinical information included with investigation requests, resulting in changes to patient management that would not otherwise have occurred.

The subspecialty of cardio-oncology aims to reduce cardiovascular morbidity and mortality in patients with cancer or following cancer treatment. Cancer therapy can lead to a variety of cardiovascular complications, including left ventricular systolic dysfunction, pericardial disease, and valvular heart disease. Echocardiography is a key diagnostic imaging tool in the diagnosis and surveillance for many of these complications. The baseline assessment and subsequent surveillance of patients undergoing treatment with anthracyclines and/or human epidermal growth factor (EGF) receptor (HER) 2-positive targeted treatment (e.g. trastuzumab and pertuzumab) form a significant proportion of cardio-oncology patients undergoing echocardiography. This guideline from the British Society of Echocardiography and British Cardio-Oncology Society outlines a protocol for baseline and surveillance echocardiography of patients undergoing treatment with anthracyclines and/or trastuzumab. The methodology for acquisition of images and the advantages and disadvantages of techniques are discussed. Echocardiographic definitions for considering cancer therapeutics-related cardiac dysfunction are also presented.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

AimsCardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with heart failure (HF) and electrical dyssynchrony. The European Society of Cardiology (ESC) Guidelines provide evidence-based recommendations indicating optimal patient selection for CRT implantation in both the 2013 European Heart Rhythm Association (EHRA) and the 2016 Heart Failure Association (HFA) Guidelines. We assessed the adherence to guidelines and identified factors associated with guideline adherence.Methods and resultsIn 2016, the HFA and EHRA conducted the CRT Survey II in 42 ESC countries. The data collected were sufficient to evaluate adherence to guidelines in 8021 patients. Of these, 67% had a Class I guideline indication for CRT implantation, which was significantly correlated with female gender (1.70, P ConclusionImplanters in ESC member states demonstrate a high degree of adherence to ESC guidelines with 98% of implants having a documented Class I, IIa or IIb indication. Cardiac resynchronization therapy implantation without a Class I indication was more likely in men, patients age ≥75 years, with HF of ischaemic origin and in patients admitted to hospital acutely.

Bevacizumab is an anti-vascular endothelial growth factor monoclonal antibody that may prolong survival in ovarian and cervical cancer when given in combination with chemotherapy. It works by blocking the signalling pathways that are required for tumour angiogenesis, potentially limiting the cancer's ability to grow and spread. Hypertension is a known side effect of all angiogenesis inhibitors and could lead to interruption or premature discontinuation of effective anti-cancer treatment. Hypertension may also act as a barrier to the initiation of such treatment. In this review, we aim to present clear and practical recommendations on the management of blood pressure in ovarian and cervical cancer patients before, during and after bevacizumab treatment. This guidance covers considerations before initiating bevacizumab therapy and recommendations on the management of patients who develop hypertension, or who experience worsening of pre-existing hypertension, during bevacizumab treatment, and once the course of bevacizumab has been completed. These recommendations were developed collaboratively by a group of clinicians, comprising cardiologists, oncologists, a general practitioner and specialist oncology nurses, with expertise and practical experience in either oncology or hypertension. The aim of these recommendations is to support oncologists with hypertension assessment and management to facilitate starting or continuing bevacizumab.

Accurate identification of seizure-generating brain tissue is challenging, particularly when MRI shows no clear abnormality or extensive abnormality. Plummer et al. achieve this non-invasively by analysing the earliest detectable part of the electromagnetic seizure signal recordable across the head surface. Their findings challenge current practice with its reliance on invasive intracranial monitoring., Drug-resistant focal epilepsy is a major clinical problem and surgery is under-used. Better non-invasive techniques for epileptogenic zone localization are needed when MRI shows no lesion or an extensive lesion. The problem is interictal and ictal localization before propagation from the epileptogenic zone. High-density EEG (HDEEG) and magnetoencephalography (MEG) offer millisecond-order temporal resolution to address this but co-acquisition is challenging, ictal MEG studies are rare, long-term prospective studies are lacking, and fundamental questions remain. Should HDEEG-MEG discharges be assessed independently [electroencephalographic source localization (ESL), magnetoencephalographic source localization (MSL)] or combined (EMSL) for source localization? Which phase of the discharge best characterizes the epileptogenic zone (defined by intracranial EEG and surgical resection relative to outcome)? Does this differ for interictal and ictal discharges? Does MEG detect mesial temporal lobe discharges? Thirteen patients (10 non-lesional, three extensive-lesional) underwent synchronized HDEEG-MEG (72–94 channel EEG, 306-sensor MEG). Source localization (standardized low-resolution tomographic analysis with MRI patient-individualized boundary-element method) was applied to averaged interictal epileptiform discharges (IED) and ictal discharges at three phases: ‘early-phase’ (first latency 90% explained variance), ‘mid-phase’ (first of 50% rising-phase, 50% mean global field power), ‘late-phase’ (negative peak). ‘Earliest-solution’ was the first of the three early-phase solutions (ESL, MSL, EMSL). Prospective follow-up was 3–21 (median 12) months before surgery, 14–39 (median 21) months after surgery. IEDs (n = 1474) were recorded, seen in: HDEEG only, 626 (42%); MEG only, 232 (16%); and both 616 (42%). Thirty-three seizures were captured, seen in: HDEEG only, seven (21%); MEG only, one (3%); and both 25 (76%). Intracranial EEG was done in nine patients. Engel scores were I (9/13, 69%), II (2/13,15%), and III (2/13). MEG detected baso-mesial temporal lobe epileptogenic zone sources. Epileptogenic zone OR [odds ratio(s)] were significantly higher for earliest-solution versus early-phase IED-surgical resection and earliest-solution versus all mid-phase and late-phase solutions. ESL outperformed EMSL for ictal-surgical resection [OR 3.54, 95% confidence interval (CI) 1.09–11.55, P = 0.036]. MSL outperformed EMSL for IED-intracranial EEG (OR 4.67, 95% CI 1.19–18.34, P = 0.027). ESL outperformed MSL for ictal-surgical resection (OR 3.73, 95% CI 1.16–12.03, P = 0.028) but was outperformed by MSL for IED-intracranial EEG (OR 0.18, 95% CI 0.05–0.73, P = 0.017). Thus, (i) HDEEG and MEG source solutions more accurately localize the epileptogenic zone at the earliest resolvable phase of interictal and ictal discharges, not mid-phase (as is common practice) or late peak-phase (when signal-to-noise ratios are maximal); (ii) from empirical observation of the differential timing of HDEEG and MEG discharges and based on the superiority of ESL plus MSL over either modality alone and over EMSL, concurrent HDEEG-MEG signals should be assessed independently, not combined; (iii) baso-mesial temporal lobe sources are detectable by MEG; and (iv) MEG is not ‘more accurate’ than HDEEG—emphasis is best placed on the earliest signal (whether HDEEG or MEG) amenable to source localization. Our findings challenge current practice and our reliance on invasive monitoring in these patients.

Modelling the interactions that arise from neural dynamics in seizure genesis is challenging but important in the effort to improve the success of epilepsy surgery. Dynamical network models developed from physiological evidence offer insights into rapidly evolving brain networks in the epileptic seizure. A major limitation of previous studies in this field is the dependence on invasive cortical recordings with constrained spatial sampling of brain regions that might be involved in seizure dynamics. Here, we propose a novel approach, virtual intracranial electroencephalography (ViEEG), that combines non-invasive ictal magnetoencephalographic imaging (MEG), dynamical network models and a virtual resection technique. In this proof-of-concept study, we show that ViEEG signals reconstructed from MEG alone preserve critical temporospatial characteristics for dynamical approaches to identify brain areas involved in seizure generation. Our findings demonstrate the advantages of non-invasive ViEEG over the current presurgical ‘gold-standard’ – intracranial electroencephalography (iEEG). Our approach promises to optimise the surgical strategy for patients with complex refractory focal epilepsy.

Background Immune checkpoint inhibitors (ICIs) may cause potentially life-threatening adverse events (AEs), but the risk of cardiotoxicity has not been fully investigated. It is also unknown whether ICI combinations increase cardiotoxicity compared with single ICI. We aimed to assess the cardiotoxicity of ICI in a range of tumour types. Methods This systematic review and meta-analysis was conducted according to PRISMA guidelines (PROSPERO registration number: CRD42020183524). A systematic search of PubMed, MEDLINE, Embase databases, and conference proceedings was performed up to 30 June 2020. All randomised clinical trials comparing ICI with other treatments (primary objective) or dual-agent ICI versus single-agent ICI (secondary objective) in any solid tumour were included. Pooled risk ratios (RRs) with 95% confidence intervals (95% CIs) for cardiotoxicity events were calculated using random effect models. Results Eighty studies including 35,337 patients were included in the analysis (66 studies with 34,664 patients for the primary endpoint and 14 studies with 673 patients for the secondary endpoint). No significant differences in terms of cardiac AEs were observed between ICI and non-ICI groups (RR 1.14, 95% CI 0.88–1.48, p = 0.326) nor between dual ICI and single ICI groups (RR 1.91, 95% CI 0.52–7.01, p = 0.329). Myocarditis incidence did not significantly differ between ICI and non-ICI groups (RR 1.11, 95% CI 0.64–1.92, p = 0.701) nor between dual ICI and single ICI groups (RR 1.10, 95% CI 0.31–3.87, p = 0.881). No differences were observed in subgroup analyses according to tumour type, setting of disease, treatment line, and type of treatment. Conclusion The use of ICI as single or combination regimens is not associated with increased risk of cardiotoxicity.

Anthracycline chemotherapy remains a key component of cancer treatment regimens in both paediatric and adult patients. A significant issue with their use is the development of anthracycline-induced cardiotoxicity (AIC), with subclinical AIC and clinical heart failure observed in 13.8% and 3.1% of patients, respectively. The major clinical complication of AIC is the development of late-onset cardiotoxicity, occurring several years after drug administration, presenting as life-threatening heart failure (HF). Determining the relationship between subclinical AIC and late-onset HF, strategies for mitigation of AIC, and impacts upon the cancer survivor population remains a complex challenge. Administration of drugs targeting the angiotensin system, specifically angiotensin converting enzyme inhibitors (ACEi), have been reported to reduce AIC in the clinic. Whilst the therapeutic effect of ACEi in management of left ventricular systolic dysfunction and consequent HF is principally through optimisation of cardiac haemodynamics, the mechanism involved with mitigation of late-onset AIC several years after anthracycline exposure are currently unknown. Using a variety of human cardiomyocyte in vitro models we have previously demonstrated induction of cardiomyocyte hypertrophy by angiotensin II and anthracyclines. Importantly, selective blockade of the angiotensin II receptor 1 (ATR1) on cardiomyocytes mitigated the anthracycline-induced hypertrophic response, implicating synergism between AIC and angiotensin signalling in cardiomyocytes. Adult human ventricular cardiac myocyte AC10 cell-line were treated in vitro with a range of clinically relevant doxorubicin doses for clinically appropriate durations, with AT1 receptor gene expression evaluated using semi-quantitative PCR. Our results confirm a positive correlation between clinically-relevant concentration of doxorubicin and induction of genetic expression of ATR1 in AC10 cells, with up to 200% increases in ATR1 expression observed. Maximal doxorubicin-induced gene expression being observed at 8 and 24-hours, respectively. These preliminary results agreeing with clinical exposure parameters for this drug with protein expression studies being optimised to support these gene expression study results. Our preliminary studies also imply patients developing AIC carry a deleted polymorphism within intron 16 of the ACE gene and increased systemic levels of the ACE product angiotensin II, both with a known association to hypertrophic cardiomyopathy. Taken together, these data support our mechanistic hypothesis that a relationship exists between AIC and modulation of the angiotensin signalling pathway in cardiomyocytes, involving structural cellular changes and asymptomatic cardiac hypertrophy. An elevation in angiotensin II levels, potentially through polymorphisms in ACE, could thereby exacerbate anthracycline-induced hypertrophy and promote the development of late-onset anthracycline-induced HF. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Cancer Research UK funded PhD

The management of chronic myeloid leukaemia (CML) has seen considerable change in the last several years. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of CML in adults and children.

Background The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes in human epidermal growth factor receptor 2 (HER2) positive early, potentially curable breast cancer. Twelve months��� trastuzumab tested in the registration trials was adopted for standard adjuvant treatment in 2006. Subsequently similar outcomes were demonstrated using 9 weeks trastuzumab. Shorter durations were therefore tested for non-inferiority. Objectives To establish whether 6 months��� adjuvant trastuzumab is non-inferior to 12 months in HER2-positive early breast cancer using a primary endpoint of 4-year disease-free-survival (DFS). Design Phase III randomised, controlled, non-inferiority trial. Setting 152 NHS Hospitals. Participants 4088 patients with HER2-positive early breast cancer planned to receive both chemotherapy and trastuzumab. Intervention Randomisation (1:1) between six months��� or twelve months��� trastuzumab. Main outcomes Primary endpoint was DFS four years after diagnosis. Secondary endpoints were overall survival (OS), cost effectiveness, and cardiac function during trastuzumab. Assuming a 4-year DFS rate of 80% with 12 months, 4000 patients were required to demonstrate non-inferiority of 6-months (5% 1-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life years (QALYs) were estimated by within-trial analysis and a lifetime decision-analytic model. Results Between 4th October 2007 and 31st July 2015, 2045 patients were randomised to 12-months��� trastuzumab and 2043 to 6-months. Sixty-nine percent had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% had trastuzumab sequentially after chemotherapy; 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years median follow-up with 389 (10%) deaths, and 566 (14%) DFS events, 4-year DFS rates for the 4088 patients were 89.5% (95% CI, 88.1-90.8) in the 6-month group and 90.3% (95% CI 88.9- 91.5) in the 12-month group (Hazard Ratio 1.10; 90% CI 0.96���1.26, non-inferiority p=0.01), demonstrating non-inferiority of 6-months��� trastuzumab. Congruent results were found for OS (non-inferiority p=0.0003), and landmark analyses 6 months from starting trastuzumab (non-inferiority p=0.03 (DFS) and p=0.006 (OS)). 6-months��� trastuzumab resulted in fewer patients reporting adverse events of severe grade (365/1929 (19%) versus 460/1935 (24%) 12-month patients, p=0.0003) or stopping early because of cardiotoxicity (61/1977 (3%) versus 146/1941 (8%) 12-month patients, p, National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98).

Objective Magnetoencephalography (MEG) kurtosis beamforming is an automated localization method for focal epilepsy. Visual examination of virtual sensors, which are source activities reconstructed by beamforming, can improve performance but can be time-consuming for neurophysiologists. We propose a framework to automate the method and evaluate its effectiveness against surgical resections and outcomes. Methods We retrospectively analyzed MEG recordings of 13 epilepsy surgery patients who had one-year minimum post-operative follow-up. Kurtosis beamforming was applied and manual inspection was confined to morphological clusters. The region with the Maximum Interictal Spike Frequency (MISF) was validated against prospectively modelled sLORETA solutions and surgical resections linked to outcome. Results Our approach localized spikes in 12 out of 13 patients. In eight patients with Engel I surgical outcomes, beamforming MISF regions were concordant with surgical resection at overlap level for five patients and at lobar level for three patients. The MISF regions localized to spike onset and propagation modelled by sLORETA in two and six patients, respectively. Conclusions Automated beamforming using MEG can predict postoperative seizure freedom at the lobar level but tends to localize propagated MEG spikes. Significance MEG beamforming may contribute to non-invasive procedures to predict surgical outcome for patients with drug-refractory focal epilepsy.

Recent advances in immune therapy for cancer have significantly improved the clinical outcomes of patients with advanced cancers, where prognosis has historically been very poor. With these new treatments have come new toxicities and, as the use of immunotherapy increases, we will see an increasing incidence of immune-related adverse events, with patients presenting as an emergency. It is important that all cardiologists, and other physicians who see these patients, are aware of life-threatening immune-related toxicities, in addition to their recommended investigation and treatment. We describe a patient with acute cardiotoxicity secondary to immune therapy to illustrate the complexity of these adverse cardiovascular events, providing recommendations for screening, diagnosis and management.

Polymer semiconductors show unique combinations of mechanical and optoelectronic properties that strongly depend on their microstructure and morphology. Here, we have used a model p-conjugated bithiophene repeat unit to incorporate optoelectronic functionality into an aliphatic polyamide backbone by solution-phase polycondensation. Intermolecular hydrogen bonding between the amide groups ensured stable short-range order in the form of lamellar crystalline domains in the resulting semiaromatic polyamides, which could be processed from the melt and exhibited structural and thermomechanical characteristics comparable with those of existing engineering polyamides. At the same time, however, pulse-radiolysis time-resolved microwave conductivity measurements indicated charge carrier mobilities that were an order of magnitude greater than previously observed in bithiophene-based materials. Our results hence provide a convincing demonstration of the potential of amide hydrogen bonding interactions for obtaining unique combinations of mechanical and optoelectronic properties in thermoplastic polymers.

Colloidal silica nanoparticles (NPs) modified with eight different silane coupling agents were incorporated into an amorphous poly(tetramethylene oxide)-based polyurethane–urea copolymer matrix at a concentration of 10¿wt % (4.4¿vol %) in order to investigate the effect of their surface chemistry on the structure–property behavior of the resulting nanocomposites. The rigid amorphous fraction (RAF) of the nanocomposite matrix as determined by differential scanning calorimetry and dynamic mechanical analysis was confirmed to vary significantly with the surface chemistry of the NPs and to be strongly correlated with the bulk mechanical properties in simple tension. Hence, nanocomposites with an RAF of about 30¿wt % showed a 120% increase in Young's modulus, a 25% increase in tensile strength, a 15% decrease in elongation at break with respect to the neat matrix, which had no detectable RAF, whereas nanocomposites with an RAF of less than 5% showed a 60% increase in Young's modulus, a 10% increase in tensile strength and a 5% decrease in the elongation at break.

The morphologies in a variety of diglycidyl ether of 4,4′-dihydroxy-α-methylstilbene-based liquid crystalline epoxy (LCE) formulations have been studied as matrices for high performance composites. Both the micrometer-scale and nanometer-scale LCE morphologies in infusion molded, uni-weave graphite fiber composites were investigated using reflected light optical microscopy, selected area electron diffraction, micro-Raman spectroscopy and transmission electron microscopy. The results suggest that, depending on the cure schedule and the LCE curative composition, the matrix morphologies in LCE composite can become very different. It is possible to achieve preferred molecular orientation along the graphite fibers if the LCE resin is slowly cured and has a high concentration of mesogenic segments.

A major issue in composite technology is matrix micro-cracking due to low-velocity impact damage, which may severely limit service lifetimes of composite parts. In a novel approach, remarkable levels of healing of impact damage are obtained using shape memory alloy (SMA) wires to close longitudinal cracks in woven glass fibre-reinforced polymer plates with an epoxy-polycaprolactone (EP-PCL) matrix that shows dual-phase continuity. Thermal actuation of SMA wires stitched through the thickness of the stacked glass fibre plies introduces compressive loads to the cracks thanks to anchoring of the SMA loops at the fabric surfaces and debonding of the intervening threads, which prevents local deformation of the SMA, so that crack closure by about 200 μm is achievable. Concomitant expansion of the vascular network formed by the molten PCL fills the compressed cracks, resulting in highly effective healing on cooling, as demonstrated by C-scan images. Specimens stitched with SMA wires hence show almost complete healing, i.e. damage area recovery of 85%, after low-velocity impact at up to 17 J followed by heat treatment at 150 °C. This represents a 55% improvement over previous results for unstitched EP-PCL composites, and hence significantly greater degrees of healing than so far reported for this range of impact energies and this type of system.

Cardiac resynchronization therapy (CRT) requires a high percentage of ventricular pacing (%Vp) to maximize its clinical benefits. Atrial fibrillation (AF) has been shown to reduce %Vp in CRT due to competition with irregular intrinsic atrioventricular (AV) conduction. We report the results of a prospective randomized crossover trial evaluating the amount of effective CRT delivered during AF with a novel algorithm (eCRTAF).The purpose of this study was to determine whether eCRTAF increases the amount of effective CRT delivered during AF compared to a currently available rate regularization algorithm.Patients previously implanted with a cardiac resynchronization therapy-defibrillator and with a history of AF and intact AV conduction received up to 4 weeks of control (Conducted AF Response) and up to 4 weeks of eCRTAF in a randomized sequence. The percent effective CRT (%eCRT) pacing, which excludes beats without left ventricular capture, %Vp, and mean heart rate (HR) were recorded during AF and sinus rhythm.The eCRTAF algorithm resulted in a significantly higher %eCRT during AF than control (87.8% ± 7.8% vs 80.8% ± 14.3%; P .001) and %Vp during AF than control (90.0% ± 5.9% vs 83.2% ± 11.9%; P.001), with a small but statistically significant increase in mean HR of 2.5 bpm (79.5 ± 9.7 bpm vs 77.0 ± 9.9 bpm; P.001).In a cohort of CRT patients with a history of AF, eCRTAF significantly increased %eCRT pacing and %Vp during AF with a small increase in mean HR. This algorithm may represent a novel noninvasive method of significantly increasing effective CRT delivery during AF, potentially improving CRT response.

510 Background: Trastuzumab (T) increases the incidence of cardiac events (CEs) in patients (pts) with early breast cancer (BC). Dual blockade with P+T improves BC outcomes and is the standard of care for high-risk HER2-positive BC pts following the phase 3 APHINITY trial that evaluated the addition of P or placebo (Pla) to T and chemotherapy (CT). We analyzed the cardiac safety of P+T in APHINITY. Methods: APHINITY eligibility required a left ventricular ejection fraction (LVEF) ≥55% at study entry. LVEF assessment was performed every 3 months (mos) during treatment, every 6 mos up to month 36, and yearly thereafter. Primary CE was defined as heart failure (HF) class III/IV and a significant decrease in LVEF of at least 10 percentage points from baseline and to

Periodontitis affects the attachment of natural teeth, and infection or inflammation associated with periodontitis may affect peri-implant tissues. Enamel matrix derivative (EMD) proteins provide stimulation for self-regeneration of the damaged tissue when applied to wide intrabony defects as part of a mixture with bone graft material. As a first step of the process enhancing cell proliferation and ligament formation, we demonstrated that EMD protein precipitation depends strongly on the physical and chemical characteristics of the bone grafts used in the mixture. To guarantee optimum protein-stimulated self regulation, the pH of the initial EMD formulation must therefore be adjusted between 3.9 and 4.2 in order to compensate the change in pH induced by the bone graft. Moreover, the interaction between the two components resulted in precipitates of different shape and size differently covering the grafts. This outcome might potentially have clinical implications on cell attachment and periodontal ligament extension, which deserve further in vitro and in vivo tests. (C) 2017 Elsevier B.V. All rights reserved.

Nonisothermally fusion bonded butt joints were prepared by overmolding thermoplastic elastomers (TPEs) onto isotactic polypropylene (iPP) inserts in order to investigate the effect of processing conditions on the bond strength and interfacial microstructure. The mold temperature (Tm) was the most important factor for bond strength, as determined from interfacial mechanical tests. Extensive melting and recrystallization took place at the surface of the iPP insert at high Tm, promoted by migration of plasticizer from the TPE, whereas the original structure of the iPP remained intact at low Tm. Bond strengths of at least 50% of the cohesive strength of the TPE were nevertheless obtained at low Tm, suggesting intimate contact between the TPE melt and the iPP surface to be sufficient to provide useful adhesive bond strengths in these materials. The influence of pressure was less marked than the Tm, high pressures not being necessary to achieve intimate contact for the bonding times of about 5 s used here. However, the combination of a low bonding pressure with a high Tm typically led to poor quality bonds in thick specimens owing to uncompensated shrinkage during solidification, and voiding at the interface and in the melt zone of the iPP insert. POLYM. ENG. SCI., 2017. © 2017 Society of Plastics Engineers

Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival.Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140).Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, pInterpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.Funding: UK National Institute for Health Research, Health Technology Assessment Programme.

All doctors are highly experienced at passing exams during medical school and in postgraduate training. However, for a number of trainees, notably those who have had a period out of programme to undertake research or for parental leave, the European Examination in General Cardiology (EEGC) is the first exam they will have sat in more than 4 years. In addition, the challenging and busy nature of cardiology training, annual review of competence progression and advanced modular training allocation process can allow little time or energy for revision. Finally, personal circumstances and responsibilities change as we get older, and this can pose additional difficulties, and at times conflict, when preparing for the exam. The British Cardiovascular Society (BCS) emails all cardiology trainees about the EEGC in November of their fifth Specialty Training year (ST5)—if you are in ST5 and don’t receive this email, you should contact the BCS and inform your training programme director. It is important that trainees understand the structure of the exam and the topics covered. This information is covered in detail in Behind the Scenes of the European Exam in General Cardiology, Heart 2019 and on the BCS, European Society of Cardiology (ESC) and theUnion of European Medical Specialists (UEMS) websites. ### Preparing the knowledge required to pass the exam Adult …

The European Examination in General Cardiology (EEGC) is a joint venture between the European Union of Medical Specialists, the European Society of Cardiology (ESC) and the participating National Cardiac Societies, including the British Cardiovascular Society (BCS). It provides a high-quality test of knowledge for cardiology trainees from 14 countries where it is used to support training. In the UK, the EEGC is taken in specialty training (ST)5, and can be retaken in ST6 and ST7 if necessary, and is approved by the GMC as a requirement for CCT. Development of the exam (figure 1) starts at the ESC Congress in August with a question writing meeting (a). Each question has a clinical scenario, a single question and five possible answers shown in alphabetical order. The questions are written and edited by groups of cardiologists from a range of countries and subspecialties. The knowledge tested is mapped to the curriculum …

Multiple myeloma (MM) is a plasma cell malignancy that accounts for 10% of hematological cancers. It predominantly affects elderly people; median age at diagnosis is 70 years. Consequently, many patients with MM have cardiovascular comorbidities or risk factors. MM can cause cardiac comorbidities such as cardiomyopathy and heart failure caused by cardiac amyloidosis and/or anemia. Some of the treatments used in MM can also affect cardiovascular health. Advances in pharmacotherapy for MM, such as the introduction of immunomodulators, proteasome inhibitors, histone deacetylase inhibitors, and monoclonal antibodies, have dramatically improved progression-free survival and life expectancy, but new agent classes are associated with adverse events that were not previously observed on a regular basis, including cardiovascular events. However, with careful risk assessment, monitoring, and prophylactic therapy, many of these cardiovascular complications can be managed or treated successfully. Most routine cardiovascular surveillance is undertaken by the treating hemato-oncologist, but a multidisciplinary approach involving cardiologists may help to optimize patient outcomes. In this review, we survey the cardiac complications commonly reported in patients with MM, discuss how they can be prevented and managed, and summarize the role cardiologists can play in delivering the best possible outcomes for patients with MM and cardiovascular comorbidities.

Survivorship statistics demonstrate that the incidence of cancer continues to rise worldwide, with a further 60% increase in diagnoses predicted by 2030 attributed to lifestyle risk factors, screening programmes resulting in earlier diagnosis but also the changing demographics of the population. More than a third of new cancer diagnoses and almost half of cancer survivors are now aged 70 years or older. Despite this increasing incidence, worldwide five-year cancer survival rates have improved significantly over the past two decades. After cancer, cardiovascular disease is the second most common cause of death in developed countries. With continued improvements in overall prognosis, patients with cancer have an increased exposure to cardiovascular risk factors resulting in higher cardiovascular morbidity and mortality, particularly in older patients. This relationship between cancer and cardiovascular disease is not surprising as they share the common risk factors of aging, smoking, obesity, and poor diet. In this review, we discuss the toxicity of cancer treatments on the cardiovascular system, particularly in older patients. We focus primarily on radiotherapy and anthracycline chemotherapy because of their chronic adverse effects and appraise approaches toward the detection and treatment of this toxicity to maximise survival and quality of life of older patients with cancer.

Blends of commercial epoxy monomer with a 4,4′-diaminodiphenylsulfone hardener and poly(e-caprolactone) (PCL) were evaluated for their potential as a self-healing matrix for fiber-reinforced composites, based on their room temperature toughness and stiffness and their capacity for healing when subjected to a moderate heating cycle. Analysis of the microstructure and thermal properties of the blends indicated three types of morphology to result from polymerization-induced phase separation during cure, depending on the PCL content, including an interconnected particulate epoxy phase and a co-continuous PCL phase above 23 vol% PCL. While the mechanical performance diminished with increasing PCL content, toughness recovery after healing at 150 °C for 30 min strongly increased. Blends with 25 vol% PCL showed a healing efficiency in excess of 70%, while retaining suitable room-temperature mechanical properties (a tensile modulus of 1.5 GPa and a tensile strength of about 20 MPa), and were concluded to be promising candidates for self-healing composites.

Background A clinical feasibility study was undertaken at a single center of long-term intra-cerebroventricular drug delivery of the anti-seizure medication valproic acid, into the cerebrospinal fluid (CSF) in order to treat drug resistant focal seizures, using an implantable infusion system. The primary objective was to establish the dose range of VPA administered in this manner. Secondarily, safety, pharmacokinetics (PK) and a preliminary estimate of effectiveness were evaluated. Methods In this single arm study, five adult subjects, with 29–234 focal onset seizures per month from a seizure focus involving the mesial temporal lobe were implanted with the system (clinicaltrials.gov identifier NCT02899611). Oral valproic acid (VPA) had previously been ineffective in all subjects. Post-surgery, pharmacokinetic studies of CSF infused VPA were performed. Valproic acid doses were increased stepwise in a standardised protocol. Findings The procedure and implantation were well-tolerated by all subjects. Four subjects responded with > 50% seizure reduction at the highest tested dose of 160 mg/day. Two subjects experienced extended periods of complete seizure freedom. All five subjects reported significant quality of life improvement. No clinical dose limiting side effects were encountered and there was no evidence of local periventricular toxicity in three subjects who were evaluated with imaging (T2 MRI). Side effects included nausea and appetite loss but were not dose-limiting. Mean CSF valproic acid levels were 45 μg per ml (range 20–120 μg per ml), with corresponding serum levels of 4–14 μg per ml. Subjects have received therapy for up to 2.5 years in total . The efficacy analysis presented focuses on the period of time with the current pump with a mean 12.5 months, range 11.5–15 months. Pump failure requiring reimplantation was a significant initial issue in all subjects but resolved with use of pumps suitably compatible with long-term exposure to valproic acid. Interpretation The study demonstrated that chronic intraventricular administration of valproic acid is safe and effective in subjects with medically refractory epilepsy over many months. The procedure for implanting the infusion system is safe and well-tolerated. High CSF levels are achieved with corresponding low serum levels and this therapy is shown to be effective despite unsuccessful earlier use of oral valproate preparations. Drug side effects were minimal. Funding The study was funded by Cerebral Therapeutics Inc., Suite 137 12635 East Montview Blvd Aurora CO 80045.

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Background:\ud \ud Cardiac resynchronisation therapy (CRT) reduces morbidity and mortality in appropriately selected patients with heart failure and is strongly recommended for such patients by guidelines. A European Society of Cardiology (ESC) CRT survey conducted in 2008–2009 showed considerable variation in guideline adherence and large individual, national and regional differences in patient selection, implantation practice and follow-up. Accordingly, two ESC associations, the European Heart Rhythm Association and the Heart Failure Association, designed a second prospective survey to describe contemporary clinical practice regarding CRT.\ud Methods and results:\ud \ud A survey of the clinical practice of CRT-P and CRT-D implantation was conducted from October 2015 to December 2016 in 42 ESC member countries. Implanting centres provided information about their hospital and CRT service and were asked to complete a web-based case report form collecting information on patient characteristics, investigations, implantation procedures and complications during the index hospitalisation. The 11 088 patients enrolled represented 11% of the total number of expected implantations in participating countries during the survey period; 32% of patients were aged ≥75 years, 28% of procedures were upgrades from a permanent pacemaker or implantable cardioverter-defibrillator and 30% were CRT-P rather than CRT-D. Most patients (88%) had a QRS duration ≥130 ms, 73% had left bundle branch block and 26% were in atrial fibrillation at the time of implantation. Large geographical variations in clinical practice were observed.\ud Conclusion:\ud \ud CRT Survey II provides a valuable source of information on contemporary clinical practice with respect to CRT implantation in a large sample of ESC member states. The survey permits assessment of guideline adherence and demonstrates variations in patient selection, management, implantation procedure and follow-up strategy.

The indication of pacemaker/AICD removal are numerous. Serious complication can occur during their removal, severe tricuspid regurgitation is one of the complication. The occurrence of PFO is not uncommon among adult population. Shunting across PFO in most circumstance is negligible, but in some necessitates closure due to hypoxemia. We report a case of 62 year old man, while undergoing AICD removal, had an emergency sternotomy for cardiac tamponade. Postoperatively, he experienced profound hypoxemia refractory to oxygen therapy. Transthoracic Echocardiogram was performed to rule out intracardiac shunts at an early stage, but it was difficult to obtain an good imaging windows poststernotomy. A small pulmonary emboli was noted on CTPA, but was not sufficient to account for the level of hypoxemia and did not resolve with anticoagulation. Transesophageal echocardiogram showed flail septal tricuspid valve with severe TR and bidirectional shunt through large PFO. Patient was posted for surgery, tricuspid valve was replaced and PFO surgically closed. Subsequently, patient recovered well ad was discharged to home. Cause of hypoxemia might be due to respiratory or cardiac dysfunction. But for hypoxemia refractory to oxygen therapy, transoesophageal echocardiogram should be always considered and performed early as an diagnostic tool in post cardiac surgical patients.