Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Improving the clinical understanding of hypertrophic cardiomyopathy by combining patient data, machine learning and computer simulations: A case study.

Most patients with hypertrophic cardiomyopathy (HCM), the most common genetic cardiac disease, remain asymptomatic, but others may suffer from sudden cardiac death. A better identification of those patients at risk, together with a better understanding of the mechanisms leading to arrhythmia, are crucial to target high-risk patients and provide them with appropriate treatment. However, this currently remains a challenge. In this paper, we present a successful example of implementing computational techniques for clinically-relevant applications. By combining electrocardiogram and imaging data, machine learning and high performance computing simulations, we identified four phenotypes in HCM, with differences in arrhythmic risk, and provided two distinct possible mechanisms that may explain the heterogeneity of HCM manifestation. This led to a better HCM patient stratification and understanding of the underlying disease mechanisms, providing a step further towards tailored HCM patient management and treatment.

Increasing medical students' engagement in public health: case studies illustrating the potential role of online learning.

BACKGROUND: The value of e-learning in medical education is widely recognized but there is little evidence of its value in teaching medical students about public health. Such evidence is needed because medical students' engagement with public health has been low. We present three recent case studies from UK medical schools to illustrate diverse ways in which online approaches can increase medical students' engagement with learning public health. METHODS: A comparative case study approach was used applying quantitative and qualitative data to examine engagement in terms of uptake/use amongst eligible students, acceptability and perceived effectiveness using an analytic framework based on Seven Principles of Effective Teaching. RESULTS: Across the three case studies, most (67-85%) eligible students accessed online materials, and rated them more favourably than live lectures. Students particularly valued opportunities to use e-learning flexibly in terms of time and place. Online technologies offered new ways to consolidate learning of key public health concepts. Although students found contributing to online discussions challenging, it provided opportunities for students to explore concepts in depth and enabled students that were uncomfortable speaking in face-to-face discussions to participate. CONCLUSIONS: E-learning can be applied in diverse ways that increase medical student engagement with public health teaching.

Validation of an obstetric comorbidity index in an external population.

OBJECTIVES: An obstetric comorbidity index has been developed recently with superior performance characteristics relative to general comorbidity measures in an obstetric population. This study aimed to externally validate this index and to examine the impact of including hospitalisation/delivery records only when estimating comorbidity prevalence and discriminative performance of the obstetric comorbidity index. DESIGN: Validation study. SETTING: Alberta, Canada. POPULATION: Pregnant women who delivered a live or stillborn infant in hospital (n = 5995). METHODS: Administrative databases were linked to create a population-based cohort. Comorbid conditions were identified from diagnoses for the delivery hospitalisation, all hospitalisations and all healthcare contacts (i.e. hospitalisations, emergency room visits and physician visits) that occurred during pregnancy and 3 months pre-conception. Logistic regression was used to test the discriminative performance of the comorbidity index. MAIN OUTCOME MEASURES: Maternal end-organ damage and extended length of stay for delivery. RESULTS: Although prevalence estimates for comorbid conditions were consistently lower in delivery records and hospitalisation data than in data for all healthcare contacts, the discriminative performance of the comorbidity index was constant for maternal end-organ damage [all healthcare contacts area under the receiver operating characteristic curve (AUC) = 0.70; hospitalisation data AUC = 0.67; delivery data AUC = 0.65] and extended length of stay for delivery (all healthcare contacts AUC = 0.60; hospitalisation data AUC = 0.58; delivery data AUC = 0.58). CONCLUSIONS: The obstetric comorbidity index shows similar performance characteristics in an external population and is a valid measure of comorbidity in an obstetric population. Furthermore, the discriminative performance of the comorbidity index was similar for comorbidities ascertained at the time of delivery, in hospitalisation data or through all healthcare contacts.

Radiation Oncology Opinions and Practice on Cardiotoxicity in Lung Cancer: A Cross-sectional Study by the International Cardio-oncology Society.

AIMS: Symptomatic radiation cardiotoxicity affects up to 30% patients with lung cancer and several heart substructure doses are associated with reduced overall survival. A greater focus on minimising cardiotoxicity is now possible due to advancements in radiotherapy technology and the new discipline of cardio-oncology, but uptake of emerging data has not been ascertained. A global cross-sectional analysis of Radiation Oncologists who treat lung cancer was therefore conducted by the International Cardio-Oncology Society in order to establish the impact of recently published literature and guidelines on practice. MATERIALS AND METHODS: A bespoke questionnaire was designed following an extensive review of the literature and from recurring relevant themes presented at Radiation Oncology and Cardio-Oncology research meetings. Six question domains were retained following consensus discussions among the investigators, comprising 55 multiple choice stems: guidelines, cardiovascular assessment, cardiology investigations, radiotherapy planning strategies, primary prevention prescribing and local cardio-oncology service access. An invitation was sent to all Radiation Oncologists registered with ICOS and to Radiation Oncology colleagues of the investigators. RESULTS: In total 118 participants were recruited and 92% were consultant physicians. The ICOS 2021 expert consensus statement was rated as the most useful position paper, followed by the joint ESC-ESTRO 2022 guideline. The majority (80%) of participants indicated that a detailed cardiovascular history was advisable. Although 69% of respondents deemed the availability of cardiac substructure auto-segmentation to be very/quite important, it was implemented by only a few, with the most common being the left anterior descending coronary artery V15. A distinct cardio-oncology service was available to 39% participants, while the remainder utilised general cardiology services. CONCLUSION: The uptake of recent guidelines on cardiovascular optimisation is good, but access to cardiology investigations and consultations, and auto-segmentation, represent barriers to modifying radiotherapy practices in lung cancer to reduce the risk of radiation cardiotoxicity.

An Integrated theory of false insights and beliefs under psychedelics.

Psychedelics are recognised for their potential to re-orient beliefs. We propose a model of how psychedelics can, in some cases, lead to false insights and thus false beliefs. We first review experimental work on laboratory-based false insights and false memories. We then connect this to insights and belief formation under psychedelics using the active inference framework. We propose that subjective and brain-based alterations caused by psychedelics increases the quantity and subjective intensity of insights and thence beliefs, including false ones. We offer directions for future research in minimising the risk of false and potentially harmful beliefs arising from psychedelics. Ultimately, knowing how psychedelics may facilitate false insights and beliefs is crucial if we are to optimally leverage their therapeutic potential.

European Society of Cardiology quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatment.

AIMS: To develop quality indicators (QIs) for the evaluation of the prevention and management of cancer therapy-related cardiovascular toxicity. METHODS AND RESULTS: We followed the European Society of Cardiology (ESC) methodology for QI development which comprises (i) identifying the key domains of care for the prevention and management of cancer therapy-related cardiovascular toxicity in patients on cancer treatment, (ii) performing a systematic review of the literature to develop candidate QIs, and (iii) selecting of the final set of QIs using a modified Delphi process. Work was undertaken in parallel with the writing of the 2022 ESC Guidelines on Cardio-Oncology and in collaboration with the European Haematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society. In total, 5 main and 9 secondary QIs were selected across five domains of care: (i) Structural framework, (ii) Baseline cardiovascular risk assessment, (iii) Cancer therapy related cardiovascular toxicity, (iv) Predictors of outcomes, and (v) Monitoring of cardiovascular complications during cancer therapy. CONCLUSION: We present the ESC Cardio-Oncology QIs with their development process and provide an overview of the scientific rationale for their selection. These indicators are aimed at quantifying and improving the adherence to guideline-recommended clinical practice and improving patient outcomes.

Making the case for a 'fifth wave' in public health.

This paper will argue that the UK has seen several phases of public health improvement since the Industrial Revolution, and that each of these can be linked to major shifts in thinking about the nature of society and health itself. The authors are not, however, attempting to delineate firm sequences of events (or imply causality) as this would require a level of analysis of the relationship between economy, society and culture which is beyond the scope of this paper. Rather, it is suggested that each phase of health improvement can be thought of in metaphorical terms as a 'wave'. The first wave is associated with great public works and other developments arising from social responses to the profound disruptions which followed the Industrial Revolution. The second wave saw the emergence of medicine as science. The third wave involved the redesign of our social institutions during the 20th Century and gave birth to the welfare state. The fourth wave has been dominated by efforts to combat disease risk factors and the emergence of systems thinking. Although a trough of public health activity continues from each wave, none exerts the same impact as when it first emerged. This paper will discuss the complex challenges of obesity, inequality and loss of wellbeing, together with the broader problems of exponential growth in population, money creation and energy usage. As exponential growth is unsustainable on a finite planet, inevitable change looms. Taken together, these analyses suggest that a fifth wave of public health development is now needed; one which will need to differ radically from its forerunners. The authors invite others to join them in envisioning its nature and in furthering the debate about future public health.

What Does a Cardio-oncology Service Offer to the Oncologist and the Haematologist?

Cardio-oncology is an emerging subspecialty arising from the need for multidisciplinary collaboration to address the increasing prominence of cardiovascular disease (CVD) among cancer patients. This overview outlines the case for establishing cardio-oncology services and defines the ways in which these services benefit cancer patients. The primary objective of cardio-oncology is to manage CVDs in order to allow cancer patients to complete the best cancer treatments safely and with minimal interruption. In the decades since the first discovery of heart failure induced by anthracycline chemotherapy, both cardiovascular and oncological science have advanced considerably. Cardio-oncology services aim to bring together expertise from these two fast moving fields in order to provide optimal evidence-based care for cancer patients with CVDs. Here we discuss the basis of cardio-oncology services by presenting their rationale and key components, as well as their essential roles in education, training and research. At each stage of the cancer care pathway, a cardio-oncology service can add value by ensuring cancer patients have timely access to specialist care backed up by cutting edge diagnostic tools and treatment options, as well as holistic supports. We highlight areas of recent and upcoming developments in the field that are likely to change established clinical practice. Improved cardiac imaging modalities can detect chemotherapy-related cardiac dysfunction earlier and are also essential for the prompt diagnosis of an expanding range of cardiovascular effects complicating newer cancer therapeutics, such as immune checkpoint inhibitors and other targeted therapies. Modern cancer therapy has dramatically improved cancer survival and as such CVD is becoming one of the principal determinants of overall outcome for cancer patients. A dedicated cardio-oncology service can facilitate the optimisation of cardiovascular treatment and enable the completion of cancer therapy. A multidisciplinary collaborative approach is key to achieving these objectives.

Fungal and bacterial coinfections increase mortality of severely ill COVID-19 patients.

BACKGROUND: SARS-CoV-2 predisposes patients to secondary infections; however, a better understanding of the impact of coinfections on the outcome of hospitalized COVID-19 patients is still necessary. AIM: To analyse death risk due to coinfections in COVID-19 patients. METHODS: The odds of death of 212 severely ill COVID-19 patients were evaluated, with detailed focus on the risks for each pathogen, site of infection, comorbidities and length of hospitalization. FINDINGS: The mortality rate was 50.47%. Fungal and/or bacterial isolation occurred in 89 patients, of whom 83.14% died. Coinfected patients stayed hospitalized longer and had an increased odds of dying (odds ratio (OR): 13.45; R2 = 0.31). The risk of death was increased by bacterial (OR: 11.28) and fungal (OR: 5.97) coinfections, with increased levels of creatinine, leucocytes, urea and C-reactive protein. Coinfections increased the risk of death if patients suffered from cardiovascular disease (OR: 11.53), diabetes (OR: 6.00) or obesity (OR: 5.60) in comparison with patients with these comorbidities but without pathogen isolation. The increased risk of death was detected for coagulase-negative Staphylococcus (OR: 25.39), Candida non-albicans (OR: 11.12), S. aureus (OR: 10.72), Acinetobacter spp. (OR: 6.88), Pseudomonas spp. (OR: 4.77), and C. albicans (OR: 3.97). The high-risk sites of infection were blood, tracheal aspirate, and urine. Patients with coinfection undergoing invasive mechanical ventilation were 3.8 times more likely to die than those without positive cultures. CONCLUSION: Severe COVID-19 patients with secondary coinfections required longer hospitalization and had higher risk of death. The early diagnosis of coinfections is essential to identify high-risk patients and to determine the right interventions to reduce mortality.

Mathematically aggregating experts' predictions of possible futures.

Structured protocols offer a transparent and systematic way to elicit and combine/aggregate, probabilistic predictions from multiple experts. These judgements can be aggregated behaviourally or mathematically to derive a final group prediction. Mathematical rules (e.g., weighted linear combinations of judgments) provide an objective approach to aggregation. The quality of this aggregation can be defined in terms of accuracy, calibration and informativeness. These measures can be used to compare different aggregation approaches and help decide on which aggregation produces the "best" final prediction. When experts' performance can be scored on similar questions ahead of time, these scores can be translated into performance-based weights, and a performance-based weighted aggregation can then be used. When this is not possible though, several other aggregation methods, informed by measurable proxies for good performance, can be formulated and compared. Here, we develop a suite of aggregation methods, informed by previous experience and the available literature. We differentially weight our experts' estimates by measures of reasoning, engagement, openness to changing their mind, informativeness, prior knowledge, and extremity, asymmetry or granularity of estimates. Next, we investigate the relative performance of these aggregation methods using three datasets. The main goal of this research is to explore how measures of knowledge and behaviour of individuals can be leveraged to produce a better performing combined group judgment. Although the accuracy, calibration, and informativeness of the majority of methods are very similar, a couple of the aggregation methods consistently distinguish themselves as among the best or worst. Moreover, the majority of methods outperform the usual benchmarks provided by the simple average or the median of estimates.

Enabling well-being in a time of radical change: Integrative public health for the 21st century.

We live in a rapidly changing world; one where existing models for and approaches to health appear to deliver diminishing returns, whilst new public health challenges emerge. This paper outlines an integrative approach to such challenges. Integral theory suggests that key dimensions of human experience, frequently presented in opposition to each other (e.g. subjective-objective; individual-collective), need to be understood as integral to the whole. This is relevant to the public health community because powerful forces within neglected dimensions can undermine or destroy our efforts in other dimensions. This is illustrated in this paper by focusing on the issue of well-being, which illustrates the interconnected ways in which people in affluent societies can suffer from particular problems arising in such society and contribute to broader, global problems. The integral framework is used to show how a more integrative approach to such challenges can transcend some neglected blind-spots within public health. It is argued that public health leaders and practitioners need to apply integrative forms of thinking to their own practice in order to respond more effectively to the complexity of contemporary public health problems.

The prevalence of iron deficiency and anemia and their impact on survival in patients at a cardio-oncology clinic.

BACKGROUND: Iron deficiency (ID) and anemia are common in both heart failure (HF) and cancer patients and are associated with poor quality of life and survival. The aims of this study were (1) to evaluate the prevalence, types, and confounding factors of ID and anemia in patients referred to cardio-oncology clinic, and (2) identify the association between iron metabolism parameters and survival of cardio-oncology patients. METHODS: We assessed iron, ferritin, hemoglobin concentrations, transferrin saturation (TSAT), cancer type, brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), kidney function, cardiovascular risk factors and survival in 599 patients who were referred to cardio-oncology clinic from 2011 to 2017. ID was defined by a TSAT < 20%, absolute iron deficiency (AID) with a serum ferritin level < 100 µg/L while serum ferritin level of ≥ 100 µg/L was considered as functional iron deficiency (FID) and TSAT ≥ 20% was considered as no ID. RESULTS: The prevalence of ID, AID, and FID was 46, 31, and 15% of study patients, respectively. Anemia was present in approximately half (54%) of the patients with any ID. Multivariate Cox analyses showed that male gender (HR 1.704 [1.207-2.404] p = 0.002); previous cancer history (HR 1.879 [1.079-3.272] p = 0.026); elevated BNP (HR 2.126 [1.258-3.590] p = 0.005); TSAT< 20% (HR 1.721 [1.214-2.439] p = 0.002); ferritin ≥ 100 µg/L (HR 2.008 [1.088-3.706] p = 0.026); serum iron concentration < 12 µmol/L (HR 2.292 [1.614-3.255] p < 0.001); FID (HR 2.538 [1.1618-3.981] p < 0.001) and anemia (HR 2.462 [1.734-3.495] p < 0.001) were significantly associated with increased risk of all-cause death. CONCLUSIONS: About half of cardio-oncology patients had anemia and iron deficiency, with the absolute type being twice as prevalent as the functional one. Patients with breast, gastrointestinal, and genitourinary cancer were affected more often. Both anemia and iron deficiency independently predicted all-cause mortality. Future studies are required to confirm ID as a risk factor and evaluate the clinical benefits of iron replacement therapy.

Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer.

AIMS: Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine. MATERIALS AND METHODS: A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were 'lenvatinib' and 'thyroid cancer'. RESULTS: Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic blood pressure ≥85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient's blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes. CONCLUSIONS: Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen.

The English Seasonal Flu Immunization Programme for Poultry Workers 2007: a challenging task.

BACKGROUND: English Primary Care Trusts (PCTs) immunized the poultry worker population with the seasonal influenza vaccine in the 2007 winter season. METHODS: In Warwickshire, the provision of vaccinations progressed in two phases: four weekday evening clinics were offered initially, then one weekend clinic was offered, plus on-site vaccination at three farms and vaccination in general practice. RESULTS: There were 253 registered premises in Warwickshire. Eighty-eight persons were vaccinated in five clinics; 131 persons were immunized on-site. Nobody attended their general practice for vaccination; the overall uptake rate was 32%, far exceeding the expected 20%. CONCLUSION: On-site vaccination during working hours was by far the most effective method of vaccinating this population; community clinics were not cost-effective, nor were general practices apparently accessed. The number of workers recorded in the contact list of registered poultry premises provided by DEFRA/DH has been shown to be unreliable; this has implications for the future implementation and evaluation of this programme. Immigrant workers within the poultry worker population make communication about the benefits of vaccination and access to primary care an issue, both factors which impact on uptake. Strategies for engaging smaller farms, immigrant and non-registered workers need to be developed.

Is intrapartum asphyxia preventable?

The contribution of intrapartum events to asphyxia-related mortality and morbidity and the degree to which it may be prevented are controversial. We examined trends in asphyxia-related mortality and morbidity in a single large regional perinatal centre. Between 1994 and 2005, the rate of asphyxia fell from 2.86/1000 births in 1994 to 0.91/1000 births in 2005 (P < 0.001). Hypoxic-ischaemic encephalopathy of all grades fell from 2.41 to 0.77/1000 live births (P < 0.001). This substantial and steady fall in the rate of asphyxia-related mortality and morbidity over a 12-year period suggests that a significant proportion of cases of intrapartum asphyxia may be preventable.