bluuebunny/crossref_metadata_2025 huggingface dataset:
How to approach problems in dementia
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

There are several general strategies for managing problems in individuals with dementia. The ABCs of Behavior Change method identifies the antecedents and consequences surrounding a behavior, which can help you discover its cause, track it, and try different interventions to change it. The 4Rs—reassure, reconsider, redirect, and relax—provide some rules of thumb that you can use even in middle of a difficult situation. Lastly, the Three Time Principles can help you improve communication by taking your time, asking for only one thing at a time, and offering timely praise. We recommend that you try the 4Rs first, then the Three Time Principles, and finally the ABCs of Behavior Change.
How to manage language problems
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

Although language may become impaired by dementia, communication with your loved one is still possible. Speak clearly and slowly in a quiet environment. Help them obtain hearing aids, if needed. Reading and writing may be beneficial for those who have hearing or speech problems and mild dementia. Speech therapy may also benefit those with mild dementia and trouble talking. Pictures can often compensate for a variety of comprehension and communication problems. Gestures, body language, facial expression, tone of voice, and other nonlinguistic and nonverbal communication can be useful, both in person and over a video phone. Lastly, remember that emotional communication is often preserved in dementia.
How to manage problems with bodily functions
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

Although dementia can disrupt many bodily functions, there are ways you can help your loved one and yourself. Determine the cause of any falls and work proactively to prevent future ones. If their walking is impaired, work with a physical therapist to improve it. To reduce incontinence, use a toileting schedule, decrease fluid intake before bed, and plan ahead when you go on outings. Make meals more enticing by increasing the flavor and spice of food. Use heavy silverware and mugs to dampen tremors. Improve swallowing and reduce choking by altering the consistency of solid foods and liquids and consider a swallowing evaluation. Reduce the difficulties inherent in activities requiring skilled or complicated movements to the extent possible. Lessen scratching and picking by treating medical problems and dry skin; cover the arms if needed.
Why and how should you care for yourself?
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

Caregivers experience higher rates of emotional and physical illness. They are often so focused on taking good care of others that they put themselves last. This is particularly true for the sandwich generation caring for aging parents and growing children. Remember, you can’t pour from an empty cup. In order to care for others, you must take care of yourself. This means scheduling time for your physical and emotional health. Exercise regularly. Sleep well. Eat a healthy diet. Limit alcohol intake. Get medical care. Maintain your social connections. Take time for yourself. Learn relaxation techniques. Seek professional help when needed. Look for the joys of caregiving.
The Meaning of Mortality in Modern Life
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This chapter contextualizes Managing Cancer and Living Meaningfully (CALM) in relation to growing societal interest in the psychological impact of disease and the central role of healthcare providers in managing the threat of mortality and the end of life. There has been increasing recognition that the enormous investment in biotechnology and aggressive medical interventions for advanced disease has not been matched by complementary attention to the human dimensions of these conditions. There is now a growing public voice of patients and their families for more support in managing the psychological, emotional, and spiritual elements of advanced disease. The global palliative care movement emerged to address these unmet needs, but there has been less systematic attention in this field to the relief of psychological than physical suffering. CALM is a psychosocial intervention that is uniquely integrated with oncology and palliative care and focused on the psychological and social dimensions of advanced cancer.
One Thousand Lives
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This chapter provides an overview of the foundational contributions of early leaders in psychosocial oncology and palliative care that informed the development of the Managing Cancer and Living Meaningfully (CALM) intervention. This includes the collective works of such pioneers as Kübler-Ross, Glaser and Strauss, and Pattison, which were instrumental in the development of psychosocial interventions such as CALM. The research conducted by our team with advanced cancer patients and their families over two decades is also described, highlighting the longitudinal Will to Live Study. In that study over 700 patients with advanced cancer were assessed at baseline and over 400 were followed longitudinally until the end of life, deepening our understanding of their experience over the trajectory of this disease. The findings of this research confirmed the need for an intervention such as CALM and helped to shape its nature and form.
Mentalization and Mortality
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This chapter elucidates the concepts of mentalization and double awareness. Mentalization refers to the ability to reflect on and describe one’s own mental state and that of others and to connect feelings, thoughts, and beliefs to behaviours. This capacity varies amongst individuals and may fluctuate, based on the affective state, the relational context, and the nature of the conversation. Though it is often considered to be an individual capacity, we have argued that mentalization is a relational construct that is co-produced within therapeutic conversations. A mentalization-based therapy, such as CALM, can help patients to “think about their thinking,” and to consider multiple and alternate ways of viewing their situation. Mentalization may be supported by gentle invitations to patients to consider multiple perspectives and to expand the possibilities for living while facing the end of life, a capacity that we have termed “double awareness.” Using detailed conversation analysis, this chapter illustrates the process by which therapists encourage mentalization in CALM therapy.
Treatment Decisions and the Therapeutic Process
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This chapter considers the challenges of treatment decision-making for patients with incurable disease and the benefits of having a neutral space for reflection. Though respect for patients’ autonomy, shared decision-making, and informed consent are considered to be central to modern healthcare, adherence to these principles may seem illusory when patients are desperate and when the risks and benefits of treatment are ambiguous. The potential challenges to patient autonomy and informed consent are explored in this chapter, with particular reference to the context of phase one trials. In this setting, the intent of the treatment may easily be misconstrued by patients (therapeutic misconception) and the chances of benefits versus risks incorrectly estimated by them (therapeutic misestimation). This chapter explores the value of Managing Cancer and Living Meaningfully (CALM) in providing a neutral space for reflection and in allowing patients to explore their preferences regarding treatment while also considering the views of their healthcare providers and family members.
The Experience of CALM Training
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This chapter discusses the central role of Managing Cancer and Living Meaningfully (CALM) training and supervision in refining the CALM intervention and in building a supportive community of peers for clinicians. The elements of CALM training are outlined. In both the introductory and advanced CALM workshops, actual cases have been vital in illustrating CALM content and process. Representative clinical encounters have been provided with the aid of trained actors or by presentation of actual videotaped CALM sessions. These workshops have been highly rated by trainees, with clinician attendees often feeling inspired and supported in their work as a result of CALM training. The benefits of CALM training are evident in the implementation of CALM in various settings in Asia, Europe, and in North and South America.
From Our Clinic, Across the Globe
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This chapter outlines the engagement of both local and international colleagues with Managing Cancer and Living Meaningfully (CALM) and highlights its universal themes and applicability across various cultures and settings. The Global CALM program, which has trained thousands of individuals to date, is introduced and the keys to successful CALM implementation in international sites are presented. Finally, several current CALM research projects are summarized and the expanding international research supported by the Global CALM program is described.
The Structure and Process of CALM
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This chapter delineates the features that have fostered success in Managing Cancer and Living Meaningfully (CALM) therapy. Patient characteristics, the format, session tasks, and process elements of CALM that have been associated with positive outcomes are described. The importance of the therapeutic relationship in the context of advanced and life-threatening disease, and the need for empathic attunement, genuineness, deep listening, emotional presence, and regular supervision and peer support are highlighted. General guidelines and tasks for the first, middle, and final session are outlined. Finally, the key elements of the CALM therapeutic process that contribute to its therapeutic effect are outlined.
Utilizing Measures in Clinical Practice and Supervision
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This chapter specifies the quantitative measures that are regularly administered as part of Managing Cancer and Living Meaningfully (CALM) and describes the role of ongoing peer supervision in CALM therapy. The value of administering quantitative measures assessing death anxiety, attachment security, depression, quality of life at the end of life, and perceived clinical benefit is described. The format of CALM supervision is outlined and the benefits of ongoing peer supervision for ensuring treatment integrity, fostering skill development, refining the intervention, and managing the tensions inherent in psychotherapeutic work in the context of advanced cancer are emphasized.
Patient Rights and Practitioner Duties
Authors: Gross Michael L.
Published: June 2021

In military medicine, the goals of war transform patient rights and practitioner duties. Attention to conserving mission readiness and maintaining one’s fitness for duty limits soldiers’ rights to refuse standard medical care, initiate DNR (Do Not Resuscitate) orders, maintain privacy, and demand confidentiality. At the same time, however, military medical practitioners are expected to maintain impartiality and neutrality. In wartime, both are problematic. The imperative of military necessity may override impartiality while medical staff members tending compatriot warfighters are not neutral. Special, associative duties of care, moreover, may demand preferential treatment for compatriots at the expense of the medical needs of others. Citing dual loyalty, some observers call on military medical personnel to choose between their medical and military obligations. Dual loyalty, however, is a false dichotomy that obscures the moral tension between collective and individual interests coloring all aspects of political and military ethics.
Detainees and Prisoners of War
Authors: Gross Michael L.
Published: June 2021

International humanitarian law requires equal care for detainees. Following disclosures of abuse at Abu Ghraib, Iraq, multinational forces sought to provide detainees with relatively high standards of care. One result was to cause resentment among host-nation allies who suffered inferior care at local facilities. Abu Ghraib also triggered an intense public debate about the role of medical professionals in enhanced interrogation. Ultimately, the American government declined to prosecute service personnel because enhanced interrogation was not manifestly unlawful. There were, therefore, no grounds for any military officer, or any person of ordinary sense and understanding, to refuse orders to participate in interrogation sessions. Force feeding animates a similar debate about detainee rights. Opposition to force feeding invokes patient self-determination. Arguments supporting force feeding question an inmate’s ability to freely refuse food, affirm the state’s duty to preserve life, and recognize that captured combatants forfeit their right to strike.
Medical Diplomacy and the Battle for Hearts and Minds
Authors: Gross Michael L.
Published: June 2021

Medical diplomacy leverages health care to win hearts and minds, pacify war-torn communities, and gather intelligence. Charging that medical diplomacy exploits vulnerable patients, critics chastise military medicine for repudiating the neutrality it requires to deliver good care. Military medicine, however, is not neutral. But it must be effective and looking at the wars in Vietnam, Iraq, and Afghanistan, medical diplomacy does not usually offer good care. MEDCAPs (Medical Civic Action Programs) and PRTs (Provincial Reconstruction Teams) fail to provide civilians with quality treatment. Suggestions for improvements abound and if medical diplomacy proves effective, then humanitarian force may utilize medicine for military advantage, pacification, and stabilization during armed conflict. At the same time, humanitarian war requires close cooperation between military forces and civilian-relief NGOs (nongovernmental organizations). Ideally, the former provides security and funding, while the latter work with local officials and stakeholders to build health care infrastructures and restore confidence in the government.
Sleep and Health
Authors: Tubbs Andrew S. , Grandner Michael A.
Published: June 2021

Sleep is a core component of human physiology, supporting physical, mental, and emotional health. Unfortunately, insufficient sleep and insomnia are increasingly common problems both in the United States and around the world. Poor sleep is strongly associated with diabetes, obesity, and other cardiometabolic diseases. Pro-inflammatory states associated with disrupted sleep schedules and insufficient sleep are hypothesized as risk factors for cancer. Sleep disturbance impairs cognition and memory, increasing the likelihood of accidents and drowsy driving. Poor sleep is a common and exacerbating feature of many mental illnesses and may impair treatment response. Finally, the burden of insufficient sleep is calculated both in financial costs and increased mortality. Given this evidence, clinicians should recognize and treat disturbed sleep to decrease the risk of disease and improve overall quality of life.
The Gastrointestinal System, Nutrition, and Sleep
Authors: Colón José
Published: June 2021

Dating back to 400 bc, Hippocrates of Kos recognized the importance of nutrition and gut health, as well as that of sleep, in maintaining wellness. The gastrointestinal system (GI) is one of the largest organ system of the body and was once viewed as merely for alimentation and energy production. We now recognize the GI system’s influence on nearly every body system through the gut–brain connection and that it has bidirectional correlates with sleep health. Historical medicinal treatments that aided sleep and nervousness commonly were equally used for GI ailments. Within the GI system melatonin and neurotransmitters are synthesized and affect sleep. Circadian disturbances affect our microbiome and impact GI disorders such as gastroesophageal reflux, irritable bowel syndrome, and inflammatory bowel disease. Sleep restriction influences the types of foods eaten, and nutrition influences sleep health on both macronutrient and micronutrient levels. In 1989, J. Allen Hobson said “More has been learned about sleep in the last 60 years than in the preceding 6,000.” Today we may say the same thing about the microbiome, but what we know about the bidirectional nature of GI and sleep health is only the tip of the iceberg.
Ayurveda and Sleep
Authors: Porter Valencia
Published: June 2021

Sleep disturbances are widespread issues that are caused by and further aggravate various lifestyle-related factors that can impact health and disease. The use of prescription medications may not address the root cause of sleep disturbance, and many patients are concerned about addiction, abuse, and adverse effects of sleep medications. An Ayurvedic approach addressing causative lifestyle factors and the unique individual should be considered when managing sleep problems. This includes lifestyle modifications, with a balanced daily routine that is aligned with nature’s rhythms, calming the mind and body through sensory inputs, and specific techniques such as massage, meditation, yoga, and use of Ayurvedic herbs.
Insomnia and Integrative Therapies
Authors: Maurer Robert , Dedhia Param
Published: June 2021

Because sleep and health are innately connected, insomnia is among the most common challenges to both the quantity and quality of sleep. In addition to developing an understanding of insomnia, available therapies must be examined. Although of the treatment discussions for sleep disorders have relied on pharmacology, these are often not effective or challenged by untoward side effects. Therefore approaches beyond medications are needed. This chapter explores the definition of insomnia and therapeutic approaches focused on cognitive-behavioral therapy for insomnia (CBT-I), mindfulness-based therapies for insomnia (MBTI), yoga, tai chi, heart rate variability, biofeedback, electrical stimulation, exercise, and nutrition.
Sleep-Related Parasomnias
Authors: Lewis-Croswell Jaclyn L. , Colón José
Published: June 2021

Ever since there have been written historical narratives, sleep anomalies have been noted, from medieval paintings of demons terrorizing an individual in their sleep, to biblical revelations in dreams and nightmares, to tales of somnambulism from Shakespeare to Disney. Mysterious parasomnias have been recognized well before they could be classified into the International Classification of Sleep Disorders. With the invention in the 1950s of the electroencephalogram, generations of sleep researchers have been able to classify once mysterious sleep anomalies as either rapid eye movement (REM) or NREM parasomnias. Some parasomnias may be benign and self-limited, such as sleepwalking in a child. Others may lead to injury or can be a sign of other neurological disorders, such as REM sleep behavior disorder. Some can terrify patients and are commonly underreported, such as sleep paralysis, which has been confused by some as modern-day alien abductions. The treatment of parasomnias depends on proper identification based on well-established criteria. Subsequently, integrative approaches to the treatment of these disorders may be applied.
Treatment of Pediatric Sleep Disorders
Authors: Chin Chana , Perez Iris A.
Published: June 2021

Sleep problems are common in childhood and are associated significant morbidities negatively impacting the patient and family and thus necessitating early intervention and treatment. This chapter is focused on management addressing the etiology and predisposing and precipitating factors of sleep disorders spanning from infancy to childhood and adolescence. Current recommendations for safe infant sleep, promotion of sleep hygiene strategies in childhood, and treatment options of representative pediatric sleep disorders such as sleep-disordered breathing, insomnia, sleep-related movement disorders, circadian rhythm disorders, and hypersomnia are reviewed. Additionally, management of sleep disorders unique to medical disorders such as Prader-Willi syndrome, Down syndrome, and autism also are addressed.
The Rationale for Radial Artery Access in Neurointerventional Surgery
Authors: Sur Samir , Chen Stephanie H. , Jabbour Pascal M. , Peterson Eric C.
Published: June 2021

Over 20 years of investigation and experience have gone into pioneering the radial approach for cardiac interventions. This has shown the technique to be superior to the traditional transfemoral technique for a variety of reasons. Neurointerventionalists have until recently been unaware of this innovation and are only starting to use it in their practice. Most of the data from the interventional cardiology journey into radial access is unknown to the neurointerventionalist audience, and concepts that underpin radial access are unfamailiar. Even basic concepts such as radial arterial anatomy, collateral circulation of the hand, and low rates of ischemic complications have been siloed in the cardiology literature. The core rationale for the transradial approach is reviewed.
Diagnostic Angiography
Authors: Lebovitz Jonathon , Storey Christopher , Peterson Eric C. , Jabbour Pascal M.
Published: June 2021

Performing diagnostic cerebral angiograms via the transradial approach is a safe alternative to the transfemoral route. When transitioning one’s practice, the importance of a proper set-up that minimizes frustration is paramount. New catheters and sheaths have led to increased adoption of the transradial technique. From the cardiac literature we have learned that the transradial approach is safer, but more important it is preferred by patients because it requires shorter postoperative recovery and less pain with ambulation. Learning to utilize a Simmons catheter as in any type 3 arch will allow one to continue to improve efficiency and integrate the transradial approach into one’s practice.
Closure Techniques
Authors: Sajja Kalyan , Peterson Eric C. , Jabbour Pascal M.
Published: June 2021

The superficial location of the radial artery access site eliminates the need for overly specialized closure devices. Manual compression is considered the gold standard technique. Closure devices in their many iterations are designed to work by applying continuous pressure using an adjustable balloon. They are arguably superior to manual compression as they exert a continuous and gentle pressure on the artery. The simplest, and cheapest devices might be the best ones. A good closure technique ensures compression with a “just needed” intensity to maintain anterograde flow. A good technique also incorporates the principle of patent hemostasis with or without prophylactic ulnar artery occlusion while keeping the whole process relatively simple. These techniques result in fewer radial artery occlusions and other complications. Lower complications ensure patency of the radial artery for future procedures.
Development and Pathology of Key Functions
Authors: Taylor Eric
Published: June 2021

This chapter will describe some key functions that are vulnerable to genetic and environmental changes affecting the brain. Motor function, attention, memory, executive function, communication, social understanding and empathy, reality testing, and emotional regulation will be considered separately. Their typical development and the consequences of alterations for psychopathology will be described as the basis for understanding the complex and overlapping results of brain dysfunctions. The brain substrates for such functions are outlined. None of them is a unitary process. They have complex and developing relationships with the diagnoses of attention deficit, autism, language, coordination, learning, and tic disorders. All of them have significant roles to play beyond diagnoses in the development of children and young people.
Autism Spectrum Disorder and Early-Onset Psychoses
Authors: Taylor Eric
Published: June 2021

This chapter covers the profiles of difficulties in relating, to other people and the world, that are included in the international schemes of classification as spectra of autism, schizophrenia, and psychosis. In autism, there is a marked reduction in, or oddity of, social communication, and an increase of repetitive and stereotyped behaviours. In psychoses, including schizophrenia and catatonia, there is disordered testing of reality (resulting in hallucinations, delusions, and disorganized speech), and deficits in volition (involving apathy, social isolation, and lack of initiative). These are described as they present in children and young people, together with their prevalence and the coexistent problems of emotion and behaviour that occur frequently. The longitudinal course is considered up to the transition into adult life. Potential causes and pathophysiology are considered in so far as they apply specifically to these disorders.
Tourette and Learning Impairments
Authors: Taylor Eric
Published: June 2021

This chapter describes disorders of motor control, language, and learning. Tics are sudden, stereotyped, repetitive, unwanted movements, and a severe form is called Tourette disorder. Their strong association with obsessional disorders and attention deficit hyperactivity disorder (ADHD) is described. Developmental coordination disorder is a group of problems suggesting immaturity in control, both of fine adjustments and of large movements of the limbs. Impairments of language development include receptive, expressive, and pragmatic problems, and can extend to signed language. Problems in learning to read and write and acquire other skills needed for school learning are very frequent in the population. Neuropsychological formulations have been influential in guiding policy and practice in schools. Generalized learning difficulties are conceptualized as intellectual disability.
Psychiatric Consequences of Brain Syndromes
Authors: Taylor Eric
Published: June 2021

This chapter outlines the nature of common and notable brain disorders that have psychiatric consequences for children and young people. All are often managed by paediatric disciplines in European, Australian, and North American countries. Psychiatrists, however, are often the lead discipline in countries where the medical aspects are considered as less important than the mental. In most countries, physical and mental specialists need to work together with enough understanding of each other’s role that there is no gap in the provision of service. Recognizing multiple morbidity is key. This chapter therefore covers the basics of medical diagnosis and treatment as well as what is known about psychological intervention. Epilepsy, cerebral palsy, hydrocephalus, acquired traumatic injury to the head, localized structural lesions, and endocrine disorders are all described in the chapter. In addition, functional neurological disorders are considered, in order to inform joint diagnostic and therapeutic approaches.
Psychological Interventions
Authors: Taylor Eric
Published: June 2021

Psychological interventions to promote the quality of life in people with neurodevelopmental difficulties have a range of targets and are not confined to reducing the symptoms. This chapter will describe methods and the trial evidence for them according to their purposes. Explanation and psychoeducation are key methods of helping children, young people, and their families to understand their condition and the limitations it imposes. Symptomatic interventions for tics, hallucinations, impaired impulse control, and disorganization are often applied outside the limitations of single diagnostic categories. Other approaches aim to teach skills to help transdiagnostically with associated problems such as communication difficulties, anxiety, aggression, and self-injury. Yet others aim to alleviate adverse environments, such as isolation from peers, which are encountered by people with any or all of the disorders described in this book. The interventions used include supportive counselling, behavioural techniques, and cognitive methods to create change. Many have been evaluated by controlled trial, and the results will be described as the evidence base to establish which therapies, and for which children, should be priorities for health, education, and care services to provide.
Echocardiography in the cath lab: Fusion imaging and use of intracardiac echocardiography
Authors: Fernández-Golfín Covadonga , Zamorano José Luis
Published: June 2021

Structural heart disease interventions represent a new branch of percutaneous treatments rapidly expanding. Imaging, mainly transoesophageal echocardiography is essential to guide the procedures along with fluoroscopy. In the last year, fusion of both imaging modalities is available with dedicated software that allows the visualization of both echo and fluoro in a single fused image. These systems allow a better anatomic depiction of the different structures allowing safer and faster procedures with a better communication between the interventionalists and the imagers. In this chapter we will review the basic principles of these fusion system and main uses as well as the role of intracardiac echocardiography in the cath lab.
Aortic valve regurgitation
Authors: Magne Julien , Lancellotti Patrizio
Published: June 2021

Transthoracic echocardiography (TTE) is the first-line imaging tool to assess aortic valve (AV), aorta, and subsequent aortic regurgitation (AR). The parasternal long-axis view is classically used to measure the left outflow tract, the aortic annulus, and the aortic sinuses. Leaflet thickening and morphology can be visualized from this window as well as from the parasternal short-axis view and the apical five-chamber view. Nevertheless, 2D TTE may be limited and not enabling correct identification of the anatomy and causes of AR. In this situation, 3D echocardiography and cardiac magnetic resonance (CMR) could provide better delineation of the AV morphology. In some cases, transoesophageal echocardiography (TOE) could be required, more particularly for assessing the aortic root dimensions.
Echocardiography and detection of coronary artery disease
Authors: Edvardsen Thor , Sitges Marta , Sicari Rosa
Published: June 2021

Non-invasive imaging modalities play an important role in the evaluation and management of patients with known or suspected coronary heart disease (CAD). This chapter will describe how we should use echocardiography in acute and chronic CAD at rest and during stress. In patients with established or suspected CAD, echocardiography provides useful information on the status of global and segmental myocardial function, the presence of functional mitral regurgitation and potentially of other signs of myocardial ischaemia. Echocardiography can be used to identify complications such as severe ventricular failure, acute mitral regurgitation, papillary muscle rupture, wall rupture, left ventricular (LV) thrombus, and cardiac tamponade. Inducible ischaemia is typically evaluated by stress echocardiography and will also be discussed in this chapter.
MDCT and detection of coronary artery disease
Authors: Achenbach Stephan , Maurovich-Horvat Pál
Published: June 2021

After the first introduction of CT angiography (CTA) in 1992, further technological advances, such as more powerful X-ray tubes, faster gantry rotation times, multiple parallel detector rings and decreased slice thickness led to progressively better and more stable image quality for visualization of the coronary arteries. Today, multidetector-row CT (MDCT) with gantry rotation times up to 240 milliseconds, a temporal resolution of up to 75 milliseconds, coverage in z-direction of up to 16 cm per rotation, and almost isotropic spatial resolution of as little as 0.4 mm allow for high-resolution, accurate imaging of the coronary artery wall and lumen. The quantification of calcified coronary atherosclerotic plaque burden (‘calcium score’) using native scans and the additional detection of non-calcified plaque and luminal narrowing through contrast-enhanced image acquisition (‘coronary CTA’) have established themselves as routine techniques in clinical practice which can be used not in all, but in many patients.
Cardiac resynchronization therapy: Selection of candidates
Authors: Delgado Victoria , Voigt Jens-Uwe
Published: June 2021

Cardiac resynchronization therapy (CRT) is an established therapy for patients with heart failure who remain symptomatic despite optimal medical treatment. Guideline recommendations for patient selection have been published by all major scientific societies including the ESC and are regularly updated. Unfortunately, the rate of patients who do not respond to CRT remains stable in the range of 30–40%, even in indication class I. In the selection of patients with heart failure who may benefit from cardiac resynchronization therapy (CRT), evaluation of left ventricular mechanics and dyssynchrony, extent, and location of myocardial scar and cardiac venous anatomy are most important. Multimodality imaging is pivotal to obtain this information and understand how CRT exerts its effects. This chapter will review the current state-of-the-art of multimodality imaging to select patients for CRT implantation.
Cardiac imaging in cardio-oncology
Authors: Asteggiano Riccardo , Lancellotti Patrizio , Galderisi Maurizio , Ederhy Stephane , Moonen Marie
Published: June 2021

Every patient before, during and after a cancer treatment, may need an imaging evaluation to manage their clinic path. Essentially will be required methods able to evaluate very accurately left ventricular function, structure, and morphology, coronary diseases, valvular heart diseases, pericardial diseases, vascular diseases, amyloidosis, myocarditis, and pulmonary hypertension. Echocardiographic methods are the most diffuse, easy to use, with low costs, and without radiation use, but are subject to difficulties in evaluation for many technic reasons. Where echocardiography is not able to give correct information, cardiac magnetic resonance (CMR) is the most promising imaging tool, also if costs and availability may preclude its diffuse use. On the other hand scintigraphy methods, due to their radiation related risk, are less utilized. The chapter analyses the main pathologic cancer related toxicities and the most useful imaging methods to be used in clinical practice.
EyeDiseases: an integrated resource for dedicating to genetic variants, gene expression and epigenetic factors of human eye diseases
Authors: Yuan Jian , Chen Fukun , Fan Dandan , Jiang Qi , Xue Zhengbo , Zhang Ji , Yu Xiangyi , Li Kai , Qu Jia , Su Jianzhong
Published: June 2021

Eye diseases are remarkably common and encompass a large and diverse range of morbidities that affect different components of the visual system and visual function. With advances in omics technology of eye disorders, genome-scale datasets have been rapidly accumulated in genetics and epigenetics field. However, the efficient collection and comprehensive analysis of different kinds of omics data are lacking. Herein, we developed EyeDiseases (https://eyediseases.bio-data.cn/), the first database for multi-omics data integration and interpretation of human eyes diseases. It contains 1344 disease-associated genes with genetic variation, 1774 transcription files of bulk cell expression and single-cell RNA-seq, 105 epigenomics data across 185 kinds of human eye diseases. Using EyeDiseases, we investigated SARS-CoV-2 potential tropism in eye infection and found that the SARS-CoV-2 entry factors, ACE2 and TMPRSS2 are highly correlated with cornea and keratoconus, suggest that ocular surface cells are susceptible to infection by SARS-CoV-2. Additionally, integrating analysis of Age-related macular degeneration (AMD) GWAS loci and co-expression data revealed 9 associated genes involved in HIF-1 signaling pathway and voltage-gate potassium channel complex. The EyeDiseases provides a valuable resource for accelerating the discovery and validation of candidate loci and genes contributed to the molecular diagnosis and therapeutic vulnerabilities with various eyes diseases.
Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES)
Authors: Barratt Jonathan , Andric Branislav , Tataradze Avtandil , Schömig Michael , Reusch Michael , Valluri Udaya , Mariat Christophe
Published: June 2021

Background

Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD).

Methods

This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin (Hb) within 10.0–12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defined as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (non-inferiority margin, −15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous (IV) iron use, change in mean arterial pressure (MAP) and time to hypertension occurrence. Adverse events were assessed.

Results

Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval 5.66–17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first IV iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+ [MACE: 0.81 (0.52–1.25), P = 0.339; MACE+: 0.90 (0.61–1.32), P = 0.583].

Conclusions

Roxadustat is a viable option to treat anaemia in NDD CKD patients maintaining Hb levels for up to 104 weeks.
ATRT-09. IDENTIFICATION OF POTENTIAL GENETIC DRIVERS OF METHOTREXATE (MTX) RESISTANCE IN ATYPICAL TERATOID RHABDOID TUMOURS (ATRT) THROUGH A GENOME-WIDE RNAI SCREEN
Authors: Kannappan Sunand , Gupa Mehul , Kang SungMyung , Tran Andy Son , Thakur Satbir Singh , Jain Mohit , Narendran Aru
Published: June 2021

ATRT of the CNS constitute a group of rare and aggressive early childhood tumors with poor prognosis. While there are differing chemotherapeutic regimens for ATRT, high-dose MTX is a crucial component of many therapeutic protocols. Currently, the biological mechanisms contributing to the generation of MTX resistance in ATRT are unknown. To identify genes involved in MTX resistance in ATRT, an unbiased genome-wide RNAi screen on ATRT cell lines was conducted using 24,000 distinct shRNAs covering 8,000 genes. ATRT cells were transfected with a retrovirus containing pRS-shRNA vectors and treated with puromycin for selection. The resulting cells were treated with MTX to identify resistant clones and resistant colonies were then isolated and amplified individually. Presence of shRNA inserts in each colony was determined by PCR using pRS forward and reverse primers. PCR products within each of the three resistant colonies were sequenced, leading to the identification of three distinct genes, TGIF1, HIF3A and PGAM2, as potential indicators of resistance. Western blotting verified depletion of these proteins in their respective colonies. Proliferation assays were then conducted on cells from each resistant colony alongside control cells to confirm that the identified drivers conferred resistance. Sensitivity to MTX was significantly lower in TGIF1-depleted (IC50=212±8.48nM, n=3), HIF3A-depleted (IC50=52±4.68nM, n=3) and PGAM2-depleted (IC50=41±4.13nM, n=3) cells compared to control cells (IC50=19±2.87nM, n=3), (p<0.001). In addition, more than 60% of TGIF1, HIF3A, and PGAM2-depleted cells survived the maximum MTX treatment (100nM), while less than 20% of control cells survived this treatment. Our study using an unbiased genome-wide RNAi screen approach has shown that depletion of TGIF1, HIF3A and PGAM2 are potential molecular markers of MTX resistance in ATRT. Screening for their occurrence may help to identify patients at high risk of MTX resistance and may also serve as targets for future novel therapeutics development.
BIOL-04. CYTOPLASM PROTEIN GFAP MAGNETIC BEADS CONSTRUCTION AND APPLICATION AS CELL SEPARATION TARGET FOR BRAIN TUMORS
Authors: Zhao Yang , Ma Jie
Published: June 2021

Background

It is very important to develop a highly efficient cerebrospinal fluid (CSF) detection system with diagnosis and prediction function, for which the detection of circulating tumor cells (CTCs) in CSF is a good choice. In contrast to the past use of epithelial EpCAM as CTCs separation target, a cytoplasm protein of GFAP antibody was first selected to construct highly-sensitive immunomagnetic liposome beads (IMLs). The validation and efficiency of this system in capturing CTCs for brain tumors were measured both in vitro and in vivo. The associations between the numbers of CTCs in patients with their clinical characteristics were further analyzed.

Results

Our data show that CTCs can be successfully isolated from CSF and blood samples from 32 children with brain tumors. The numbers of CTCs in CSF were significantly higher than those in blood. The level of CTCs in CSF was related to the type and location of the tumor rather than its stage. The higher the CTCs number is, the more possibly the patient will suffer from poor prognosis. Genetic testing in GFAP CTC-DNA by sanger sequencing, q-PCR and NGS methods indicated that the isolated CTCs (GFAP+/EGFR+) are the related tumor cell. For example, the high expression of NPR3 gene in CSF CTCs was consistent with that of tumor tissue.

Conclusions

The results indicated that GFAP-IML CTCs isolation system, combined with an EGFR immunofluorescence assay of antitumor marker, can serve as a brand-new method for the identification of CTCs for brain tumors. Via lumbar puncture, a minimally invasive procedure, this technique may play a significant role in the clinical diagnosis and drug evaluation of brain tumors.
BIOL-07. MIR-212 FUNCTIONS AS A TUMOR SUPPRESSOR GENE IN GROUP 3 MEDULLOBLASTOMA VIA TARGETING NUCLEAR FACTOR I/B (NFIB)
Authors: Perumal Naveenkumar , Kanchan Ranjana , Doss David , Atri Pranita , Venkata Ramakanth Chirravuri , Thapa Ishwor , Nasser Mohd , Batra Surinder , Mahapatra Sidharth
Published: June 2021

Medulloblastoma (MB), the most frequent malignant pediatric brain tumor is subdivided into four primary subgroups, i.e. wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-myc amplification distinguish high-risk group 3 tumors, which are associated with rapid metastasis, recurrence and early mortality. We sought to identify the role of miR-212, which resides on chromosome 17p13.3, in the pathophysiology of group 3 MB. RNA expression analyses revealed dramatically reduced levels of miR-212 in group 3 tumors and cell lines mainly through epigenetic silencing via histone modifications (deacetylation). Restoring in vitro miR-212 expression reduced tumor cell proliferation, colony formation, wound healing, migration and invasion with decreased p-AKT and p-ERK levels in group 3 MB cell lines. Interestingly, a shift in differential c-myc phosphorylation (from serine-62 to threonine-58) was also discovered with miR-212 expression, resulting in reduced total c-myc levels, concurrent with elevated cellular apoptosis. In turn, pro-apoptotic binding partners of c-myc, i.e. Bin-1 and P19ARF, were upregulated in these cells. These findings were recapitulated in stable inducible miR-212 expressing tumor cells. Using a combination of transcriptomic data and a dual luciferase assay, we isolated an important oncogenic target of miR-212, i.e, NFIB, a nuclear transcription factor implicated in metastasis and recurrence. Increased expression of NFIB was confirmed in group 3 tumors, with poor survival shown in high NFIB-expressing patients. As prior, transient NFIB silencing in vitro reduced not only tumor cell proliferation, colony formation, wound healing, migration and invasion, but also medullosphere formation along with decreased expression of stem cell markers (Nanog, Oct4, Sox2, CD133), confirming its role in tumor recurrence possibly via augmenting tumor stemness. Taken together, these results substantiate the tumor suppressive role of miR-212 in group 3 MB and provide a potential new oncogenic target implicated in tumor recurrence, NFIB.
EMBR-01. CLASS I HDAC INHIBITORS AND PLK1 INHIBITORS SYNERGIZE IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Valinciute Gintvile , Ecker Jonas , Selt Florian , Hielscher Thomas , Schmidt Christin , Sigaud Romain , Ridinger Johannes , Gatzweiler Charlotte , Picard Daniel , Oppermann Sina , Blattner-Johnson Mirjam , Jones David T W , Oehme Ina , Kool Marcel , Remke Marc , Pfister Stefan M , Witt Olaf , Milde Till
Published: June 2021

Background

Medulloblastoma (MB) is one of the most common malignant pediatric CNS tumors. Patients with Group 3 MBs harboring MYC amplification exhibit low survival rates. Surviving patients suffer from therapy-induced sequelae, which calls for new targeted therapy strategies. We and others have previously shown the sensitivity of MYC-amplified MB to class I histone deacetylase (HDAC) inhibition. After demonstrating that the MYC target gene PLK1 is significantly downregulated upon class I HDACi treatment, we hypothesized that inhibition of both HDACs and PLK1 could have synergistic effects.

Methods

Cell metabolic activity changes upon HDAC and PLK1 inhibitor treatment were measured in MYC-amplified and non-amplified MB cell lines, as well as in an additional MYC-inducible cell line. The interaction effect of both inhibitors was determined by computation of the combination index (CI) using the Chou-Talalay method. Results were validated assessing cell viability, cell cycle, and apoptosis induction. Transcription profile changes after combination treatment were evaluated.

Results

MYC-amplified MB cell lines were more sensitive than non-amplified cell lines to PLK1i treatment, showing IC50 in clinically achievable concentration ranges. Inhibition of class I HDACs and PLK1 synergistically reduced cell metabolic activity in lower concentrations in MYC-amplified compared to non-amplified MB cell lines. We also observed a significant loss of viability and cells in G1 phase, as well as induction of apoptosis after combination treatment in MYC-amplified cells. MYC target gene sets were significantly downregulated in the MYC-amplified cell line HD-MB03 after treatment with combination. We demonstrated reduction of MYC protein levels upon PLK1i treatment. In vivo evaluation of combination treatment using orthotopic Group 3 MYC-amplified MB PDX models is ongoing.

Conclusion

Our data suggest that MYC-amplification is a predictive marker for PLK1i treatment in MB. The combination of HDACi and PLKi could be a candidate therapy for future clinical trials for MYC-amplified group 3 MB.