Considerations on the Design of Lipid-based mRNA Vaccines Against Cancer.

Throughout the last decades, mRNA vaccines have been developed as a cancer immunotherapeutic and the technology recently gained momentum during the COVID-19 pandemic. Recent promising results obtained from clinical trials investigating lipid-based mRNA vaccines in cancer therapy further highlighted the potential of this therapy. Interestingly, while the technologies being used in authorized mRNA vaccines for the prevention of COVID-19 are relatively similar, mRNA vaccines in clinical development for cancer vaccination show marked differences in mRNA modification, lipid carrier, and administration route. In this review, we describe findings on how these factors can impact the potency of mRNA vaccines in cancer therapy and provide insights into the complex interplay between them. We discuss how lipid carrier composition can affect passive targeting to immune cells to improve the efficacy and safety of mRNA vaccines. Finally, we summarize strategies that are established or still being explored to improve the efficacy of mRNA cancer vaccines and include next-generation vaccines that are on the horizon in clinical development.

European Society of Cardiology Core Curriculum for cardio-oncology.

Cardio-oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio-oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy-related cardiovascular toxicity (CTR-CVT); (iii) risk stratification, prevention and monitoring protocols for CTR-CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long-term survivorship programmes and cardio-oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio-oncology services; (viii) research in cardio-oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio-oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists.

Detection of Medication Taking Using a Wrist-Worn Commercially Available Wearable Device.

PURPOSE: Medication nonadherence is a persistent and costly problem across health care. Measures of medication adherence are ineffective. Methods such as self-report, prescription claims data, or smart pill bottles have been used to monitor medication adherence, but these are subject to recall bias, lack real-time feedback, and are often expensive. METHODS: We proposed a method for monitoring medication adherence using a commercially available wearable device. Passively collected motion data were analyzed on the basis of the Movelet algorithm, a dictionary learning framework that builds person-specific chapters of movements from short frames of elemental activities within the movements. We adapted and extended the Movelet method to construct a within-patient prediction model that identifies medication-taking behaviors. RESULTS: Using 15 activity features recorded from wrist-worn wearable devices of 10 patients with breast cancer on endocrine therapy, we demonstrated that medication-taking behavior can be predicted in a controlled clinical environment with a median accuracy of 85%. CONCLUSION: These results in a patient-specific population are exemplar of the potential to measure real-time medication adherence using a wrist-worn commercially available wearable device.

Competency-based cardiac imaging for patient-centred care. A statement of the European Society of Cardiology (ESC). With the contribution of the European Association of Cardiovascular Imaging (EACVI), and the support of the Association of Cardiovascular Nursing & Allied Professions (ACNAP), the Association for Acute CardioVascular Care (ACVC), the European Association of Preventive Cardiology (EAPC), the European Association of Percutaneous Cardiovascular Interventions (EAPCI), the European Heart Rhythm Association (EHRA), and the Heart Failure Association (HFA) of the ESC.

Imaging plays an integral role in all aspects of managing heart disease and cardiac imaging is a core competency of cardiologists. The adequate delivery of cardiac imaging services requires expertise in both imaging methodology-with specific adaptations to imaging of the heart-as well as intricate knowledge of heart disease. The European Society of Cardiology (ESC) and the European Association of Cardiovascular Imaging have developed and implemented a successful education and certification programme for all cardiac imaging modalities. This programme equips cardiologists to provide high quality competency-based cardiac imaging services ensuring they are adequately trained and competent in the entire process of cardiac imaging, from the clinical indication via selecting the best imaging test to answer the clinical question, to image acquisition, analysis, interpretation, storage, repository, and results dissemination. This statement emphasizes the need for competency-based cardiac imaging delivery which is key to optimal, effective and efficient, patient care.

Competency-based cardiac imaging for patient-centred care. A statement of the European Society of Cardiology (ESC). With the contribution of the European Association of Cardiovascular Imaging (EACVI), and the support of the Association of Cardiovascular Nursing & Allied Professions (ACNAP), the Association for Acute CardioVascular Care (ACVC), the European Association of Preventive Cardiology (EAPC), the European Association of Percutaneous Cardiovascular Interventions (EAPCI), the European Heart Rhythm Association (EHRA), and the Heart Failure Association (HFA) of the ESC.

Imaging plays an integral role in all aspects of managing heart disease and cardiac imaging is a core competency of cardiologists. The adequate delivery of cardiac imaging services requires expertise in both imaging methodology-with specific adaptations to imaging of the heart-as well as intricate knowledge of heart disease. The European Society of Cardiology (ESC) and the European Association of Cardiovascular Imaging have developed and implemented a successful education and certification programme for all cardiac imaging modalities. This programme equips cardiologists to provide high quality competency-based cardiac imaging services ensuring they are adequately trained and competent in the entire process of cardiac imaging, from the clinical indication via selecting the best imaging test to answer the clinical question, to image acquisition, analysis, interpretation, storage, repository, and results dissemination. This statement emphasizes the need for competency-based cardiac imaging delivery which is key to optimal, effective and efficient, patient care.

Total Hip Arthroplasty With Prophylactic Fixation of Greater Trochanter and Distal Femur in a Patient With a History of Multiple Myeloma and Breast Cancer.

Multiple myeloma is the most common primary malignancy of the bone marrow and may present as bone pain and/or pathologic fracture(s) in affected patients. Treatment of bone lesions typically consists of chemotherapy and radiation and may include prophylactic fixation in patients meeting specific criteria. This report reviews a case of a 74-year-old female with a history of multiple myeloma and breast cancer, previously treated with chemotherapy and radiation, who sustained a pathologic femoral neck fracture with associated ipsilateral lesions of the femoral shaft and peritrochanteric region. This patient received a total hip arthroplasty with a greater trochanteric claw plate and extended femoral stem for prophylactic fixation of the distal femur. In this report, the current literature surrounding the use of extended femoral stems for prophylactic fixation of femoral diaphyseal lesions will be reviewed and the above case will be presented. This case serves as a bridge between orthopedic oncology and arthroplasty as an extended femoral stem was used to prevent future pathologic fracture of distal femur lesions.

Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer.

Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4-45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6-3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.

A requirement for astrocyte IP3R2 signaling for whisker experience-dependent depression and homeostatic upregulation in the mouse barrel cortex.

Changes to sensory experience result in plasticity of synapses in the cortex. This experience-dependent plasticity (EDP) is a fundamental property of the brain. Yet, while much is known about neuronal roles in EDP, very little is known about the role of astrocytes. To address this issue, we used the well-described mouse whiskers-to-barrel cortex system, which expresses a number of forms of EDP. We found that all-whisker deprivation induced characteristic experience-dependent Hebbian depression (EDHD) followed by homeostatic upregulation in L2/3 barrel cortex of wild type mice. However, these changes were not seen in mutant animals (IP3R2-/-) that lack the astrocyte-expressed IP3 receptor subtype. A separate paradigm, the single-whisker experience, induced potentiation of whisker-induced response in both wild-type (WT) mice and IP3R2-/- mice. Recordings in ex vivo barrel cortex slices reflected the in vivo results so that long-term depression (LTD) could not be elicited in slices from IP3R2-/- mice, but long-term potentiation (LTP) could. Interestingly, 1 Hz stimulation inducing LTD in WT paradoxically resulted in NMDAR-dependent LTP in slices from IP3R2-/- animals. The LTD to LTP switch was mimicked by acute buffering astrocytic [Ca2+] i in WT slices. Both WT LTD and IP3R2-/- 1 Hz LTP were mediated by non-ionotropic NMDAR signaling, but only WT LTD was P38 MAPK dependent, indicating an underlying mechanistic switch. These results demonstrate a critical role for astrocytic [Ca2+] i in several EDP mechanisms in neocortex.

Differentiation of Hebbian and homeostatic plasticity mechanisms within layer 5 visual cortex neurons.

Cortical layer 5 contains two major types of projection neuron known as IB (intrinsic bursting) cells that project sub-cortically and RS (regular spiking) cells that project between cortical areas. This study describes the plasticity properties of RS and IB cells in the mouse visual cortex during the critical period for ocular dominance plasticity. We find that RS neurons exhibit synaptic depression in response to both dark exposure (DE) and monocular deprivation (MD), and their homeostatic recovery from depression is dependent on TNF-α. In contrast, IB cells demonstrate opposite responses to DE and MD, potentiating to DE and depressing to MD. IB cells' potentiation depends on CaMKII-autophosphorylation and not TNF-α. IB cells show mature synaptic properties at the start of the critical period while RS cells mature during the critical period. Together with observations in somatosensory cortex, these results suggest that differences in RS and IB plasticity mechanisms are a general cortical property.

Substrate-activated expression of a biosynthetic pathway in Escherichia coli.

Microbes can facilitate production of valuable chemicals more sustainably than traditional chemical processes in many cases: they utilize renewable feedstocks, require less energy intensive process conditions, and perform a variety of chemical reactions using endogenous or heterologous enzymes. In response to the metabolic burden imposed by production pathways, chemical inducers are frequently used to initiate gene expression after the cells have reached sufficient density. While chemically inducible promoters are a common research tool used for pathway expression, they introduce a compound extrinsic to the process along with the associated costs. We developed an expression control system for a biosynthetic pathway for the production of d-glyceric acid that utilizes galacturonate as both the inducer and the substrate, thereby eliminating the need for an extrinsic chemical inducer. Activation of expression in response to the feed is actuated by a galacturonate-responsive transcription factor biosensor. We constructed variants of the galacturonate biosensor with a heterologous transcription factor and cognate hybrid promoter, and selected for the best performer through fluorescence characterization. We showed that native E. coli regulatory systems do not interact with our biosensor and favorable biosensor response exists in the presence and absence of galacturonate consumption. We then employed the control circuit to regulate the expression of the heterologous genes of a biosynthetic pathway for the production d-glyceric acid that was previously developed in our lab. Productivity via substrate-induction with our control circuit was comparable to IPTG-controlled induction and significantly outperformed a constitutive expression control, producing 2.13 ± 0.03 g L-1  d-glyceric acid within 6 h of galacturonate substrate addition. This work demonstrated feed-activated pathway expression to be an attractive control strategy for more readily scalable microbial biosynthesis.

Measuring real consumption and consumer price index bias under lockdown conditions.

Millions of goods and services are now unavailable in many countries due to the current coronavirus pandemic, dramatically impacting on the construction of key economic statistics used for informing policy. This situation is unprecedented; hence, methods to address it have not previously been developed. Current advice to national statistical offices from the International Monetary Fund, Eurostat and the United Nations is shown to result in downward bias in the consumer price index (CPI) and upward bias in real consumption. We conclude that, to produce a meaningful CPI within the lockdown period, it is necessary to establish a continuous consumer expenditure survey.

Mesure de la consommation réelle et des biais par défaut de l'indice des prix à la consommation en période de confinement. En raison de la pandémie actuelle de COVID­19, des millions de biens et de services sont présentement indisponibles dans de nombreux pays, entravant significativement l'élaboration de statistiques économiques clés visant à éclairer les politiques. Cette situation est sans précédent, et aucune méthode n'a encore été développée pour y remédier. Les avis dispensés aux organismes nationaux de statistiques par le Fonds monétaire international, Eurostat et les Nations Unies se traduisent par des biais systématiques par défaut quant à l'indice des prix à la consommation (IPC), et par des biais par excès quant à la consommation réelle. Notre conclusion est que pour produire un IPC significatif lors d'un confinement, il est nécessaire de procéder à une enquête continue sur les dépenses de consommation.

The European Society of Cardiology - A Digital Educator.

The mission statement of the European Society of Cardiology (ESC) is "to reduce the burden of cardiovascular disease". The ESC is the leading scientific society for cardiovascular health care professionals across Europe and increasingly the world. Recognising the need for democratisation of education in cardiology, the ESC has for many years embraced the digital world within its education programme. As in all areas of medicine, the COVID-19 pandemic required an agile response to be able to continue to provide not only a digital congress but also education, training and assessment in an almost totally digital world. In this paper we will describe the digital learning activities of the ESC, the successes and the challenges of the transformation that has taken place in the last 18 months as well as an overview of the vision for education, training and assessment in the post-COVID digital era. We understand the need to provide a portfolio of educational styles to suit a diverse range of learners. It is clear that digital CME provides opportunities but it is likely that it will not entirely replace in-person learning. In planning for the future, we regard the provision of digital CME as central to fulfiling our mission.

Level 1 of Entrustable Professional Activities in adult echocardiography: a position statement from the EACVI regarding the training and competence requirements for selecting and interpreting echocardiographic examinations.

The goal of Level 1 training in echocardiography is to enable the trainee to select echocardiography appropriately for the evaluation of a specific clinical question, and then to interpret the report. It is not the goal of Level 1 training to teach how to perform the examination itself-that is the goal of higher levels of training. However, understanding the principles, indications, and findings of this crucial technique is valuable to many medical professionals including outside cardiology. This should be seen as part of a general understanding of cardiac imaging modalities. The purpose of this position statement is to define the scope and outline the general requirements for Level 1 training and competence in echocardiography. Moreover, the document aims to make a clear distinction between Level 1 competence in echocardiography and focus cardiac ultrasound (FoCUS).

COVID-19 and its impact on the cardiovascular system.

OBJECTIVES: The clinical impact of SARS-CoV-2 has varied across countries with varying cardiovascular manifestations. We review the cardiac presentations, in-hospital outcomes and development of cardiovascular complications in the initial cohort of SARS-CoV-2 positive patients at Imperial College Healthcare National Health Service Trust, UK. METHODS: We retrospectively analysed 498 COVID-19 positive adult admissions to our institute from 7 March to 7 April 2020. Patient data were collected for baseline demographics, comorbidities and in-hospital outcomes, especially relating to cardiovascular intervention. RESULTS: Mean age was 67.4±16.1 years and 62.2% (n=310) were male. 64.1% (n=319) of our cohort had underlying cardiovascular disease (CVD) with 53.4% (n=266) having hypertension. 43.2%(n=215) developed acute myocardial injury. Mortality was significantly increased in those patients with myocardial injury (47.4% vs 18.4%, p<0.001). Only four COVID-19 patients had invasive coronary angiography, two underwent percutaneous coronary intervention and one required a permanent pacemaker implantation. 7.0% (n=35) of patients had an inpatient echocardiogram. Acute myocardial injury (OR 2.39, 95% CI 1.31 to 4.40, p=0.005) and history of hypertension (OR 1.88, 95% CI 1.01 to 3.55, p=0.049) approximately doubled the odds of in-hospital mortality in patients admitted with COVID-19 after other variables had been controlled for. CONCLUSION: Hypertension, pre-existing CVD and acute myocardial injury were associated with increased in-hospital mortality in our cohort of COVID-19 patients. However, only a low number of patients required invasive cardiac intervention.

Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness.

A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.

Adapting the role of handheld echocardiography during the COVID-19 pandemic: A practical guide.

The COVID-19 pandemic has altered our approach to inpatient echocardiography delivery. There is now a greater focus to address key clinical questions likely to make an immediate impact in management, particularly during the period of widespread infection. Handheld echocardiography (HHE) can be used as a first-line assessment tool, limiting scanning time and exposure to high viral load. This article describes a potential role for HHE during a pandemic. We propose a protocol with a reporting template for a focused core dataset necessary in delivering an acute echocardiography service in the setting of a highly contagious disease, minimising risk to the operator. We cover the scenarios typically encountered in the acute cardiology setting and how an expert trained echocardiography team can identify such pathologies using a limited imaging format and include cardiac presentations encountered in those patients acutely unwell with COVID-19.

Training, competence, and quality improvement in echocardiography: the European Association of Cardiovascular Imaging Recommendations: update 2020.

The primary mission of the European Association of Cardiovascular Imaging (EACVI) is 'to promote excellence in clinical diagnosis, research, technical development, and education in cardiovascular imaging'. Echocardiography is a key component in the evaluation of patients with known or suspected cardiovascular disease and is essential for the high quality and effective practice of clinical cardiology. The EACVI aims to update the previously published recommendations for training, competence, and quality improvement in echocardiography since these activities are increasingly recognized by patients, physicians, and payers. The purpose of this document is to provide the general requirements for training and competence in echocardiography, to outline the principles of quality evaluation, and to recommend a set of measures for improvement, with the ultimate goal of raising the standards of echocardiographic practice. Moreover, the document aims to provide specific guidance for advanced echo techniques, which have dramatically evolved since the previous publication in 2009.

The effect of concomitant COVID-19 infection on outcomes in patients hospitalized with heart failure.

AIMS: Patients with cardiovascular disease appear particularly susceptible to severe COVID-19 disease, but the impact of COVID-19 infection on patients with heart failure (HF) is not known. This study aimed to quantify the impact of COVID-19 infection on mortality in hospitalized patients known to have HF. METHODS AND RESULTS: We undertook a retrospective analysis of all patients admitted with a pre-existing diagnosis of HF between 1 March and 6 May 2020 to our unit. We assessed the impact of concomitant COVID-19 infection on in-hospital mortality, incidence of acute kidney injury, and myocardial injury. One hundred and thirty-four HF patients were hospitalized, 40 (29.9%) with concomitant COVID-19 infection. Those with COVID-19 infection had a significantly increased in-hospital mortality {50.0% vs. 10.6%; relative risk [RR] 4.70 [95% confidence interval (CI) 2.42-9.12], P < 0.001} and were more likely to develop acute kidney injury [45% vs. 24.5%; RR 1.84 (95% CI 1.12-3.01), P = 0.02], have evidence of myocardial injury [57.5% vs. 31.9%; RR 1.81 (95% CI 1.21-2.68), P < 0.01], and be treated for a superadded bacterial infection [55% vs. 32.5%; RR 1.67 (95% CI 1.12-2.49), P = 0.01]. CONCLUSIONS: Patients with HF admitted to hospital with concomitant COVID-19 infection have a very poor prognosis. This study highlights the need to regard patients with HF as a high-risk group to be shielded to reduce the risks of COVID-19 infection.