bluuebunny/crossref_metadata_2025 huggingface dataset:
Repetitive transcranial magnetic stimulation for neuropathic pain: a randomized multicentre sham-controlled trial
Authors: Attal Nadine , Poindessous-Jazat Frédérique , De Chauvigny Edwige , Quesada Charles , Mhalla Alaa , Ayache Samar S , Fermanian Christophe , Nizard Julien , Peyron Roland , Lefaucheur Jean-Pascal , Bouhassira Didier
Published: June 2021

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks.

We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18–75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281.

A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: −0.048 ± 0.02; 95% CI: −0.09 to −0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: −0.003 ± 0.01; 95% CI: −0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2).

Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.
Consensus on the application of negative pressure wound therapy of diabetic foot wounds
Authors: Ji Shizhao , Liu Xiaobin , Huang Jie , Bao Junmin , Chen Zhaohong , Han Chunmao , Hao Daifeng , Hong Jingsong , Hu Dahai , Jiang Yufeng , Ju Shang , Li Hongye , Li Zongyu , Liang Guangping , Liu Yan , Luo Gaoxing , Lv Guozhong , Ran Xingwu , Shi Zhongmin , Tang Juyu , Wang Aiping , Wang Guangyi , Wang Jiangning , Wang Xin , Wen Bing , Wu Jun , Xu Hailin , Xu Maojin , Ye Xiaofei , Yuan Liangxi , Zhang Yi , Xiao Shichu , Xia Zhaofan
Published: June 2021

Because China is becoming an aging society, the incidence of diabetes and diabetic foot have been increasing. Diabetic foot has become one of the main health-related killers due to its high disability and mortality rates. Negative pressure wound therapy (NPWT) is one of the most effective techniques for the treatment of diabetic foot wounds and great progress, both in terms of research and its clinical application, has been made in the last 20 years of its development. However, due to the complex pathogenesis and management of diabetic foot, irregular application of NPWT often leads to complications, such as infection, bleeding and necrosis, that seriously affect its treatment outcomes. In 2020, under the leadership of Burns, Trauma and Tissue Repair Committee of the Cross-Straits Medicine Exchange Association, the writing group for ‘Consensus on the application of negative pressure wound therapy of diabetic foot wounds’ was established with the participation of scholars from the specialized areas of burns, endocrinology, vascular surgery, orthopedics and wound repair. Drawing on evidence-based practice suggested by the latest clinical research, this consensus proposes the best clinical practice guidelines for the application and prognostic evaluation of NPWT for diabetic foot. The consensus aims to support the formation of standardized treatment schemes that clinicians can refer to when treating cases of diabetic foot.
Driftage: a multi-agent system framework for concept drift detection
Authors: Vieira Diogo Munaro , Fernandes Chrystinne , Lucena Carlos , Lifschitz Sérgio
Published: June 2021

Background

The amount of data and behavior changes in society happens at a swift pace in this interconnected world. Consequently, machine learning algorithms lose accuracy because they do not know these new patterns. This change in the data pattern is known as concept drift. There exist many approaches for dealing with these drifts. Usually, these methods are costly to implement because they require (i) knowledge of drift detection algorithms, (ii) software engineering strategies, and (iii) continuous maintenance concerning new drifts.

Results

This article proposes to create Driftage: a new framework using multi-agent systems to simplify the implementation of concept drift detectors considerably and divide concept drift detection responsibilities between agents, enhancing explainability of each part of drift detection. As a case study, we illustrate our strategy using a muscle activity monitor of electromyography. We show a reduction in the number of false-positive drifts detected, improving detection interpretability, and enabling concept drift detectors’ interactivity with other knowledge bases.

Conclusion

We conclude that using Driftage, arises a new paradigm to implement concept drift algorithms with multi-agent architecture that contributes to split drift detection responsability, algorithms interpretability and more dynamic algorithms adaptation.
A glutamine ‘tug-of-war’: targets to manipulate glutamine metabolism for cancer immunotherapy
Authors: Pallett Laura J , Dimeloe Sarah , Sinclair Linda V , Byrne Adam J , Schurich Anna
Published: June 2021

Within the tumour microenvironment (TME), there is a cellular ‘tug-of-war’ for glutamine, the most abundant amino acid in the body. This competition is most evident when considering the balance between a successful anti-tumour immune response and the uncontrolled growth of tumour cells that are addicted to glutamine. The differential effects of manipulating glutamine abundance in individual cell types is an area of intense research and debate. Here, we discuss some of the current strategies in development altering local glutamine availability focusing on inhibition of enzymes involved in the utilisation of glutamine and its uptake by cells in the TME. Further studies are urgently needed to complete our understanding of glutamine metabolism, to provide critical insights into the pathways that represent promising targets and for the development of novel therapeutic strategies for the treatment of advanced or drug resistant cancers.
Human Immunodeficiency Virus (HIV) Genetic Diversity Informs Stage of HIV-1 Infection Among Patients Receiving Antiretroviral Therapy in Botswana
Authors: Ragonnet-Cronin Manon , Golubchik Tanya , Moyo Sikhulile , Fraser Christophe , Essex Max , Novitsky Vlad , Volz Erik
Published: June 2021

Background

Human immunodeficiency virus (HIV)-1 genetic diversity increases during infection and can help infer the time elapsed since infection. However, the effect of antiretroviral treatment (ART) on the inference remains unknown.

Methods

Participants with estimated duration of HIV-1 infection based on repeated testing were sourced from cohorts in Botswana (n = 1944). Full-length HIV genome sequencing was performed from proviral deoxyribonucleic acid. We optimized a machine learning model to classify infections as < or >1 year based on viral genetic diversity, demographic, and clinical data.

Results

The best predictive model included variables for genetic diversity of HIV-1 gag, pol, and env, viral load, age, sex, and ART status. Most participants were on ART. Balanced accuracy was 90.6% (95% confidence interval, 86.7%–94.1%). We tested the algorithm among newly diagnosed participants with or without documented negative HIV tests. Among those without records, those who self-reported a negative HIV test within <1 year were more frequently classified as recent than those who reported a test >1 year previously. There was no difference in classification between those self-reporting a negative HIV test <1 year, whether or not they had a record.

Conclusions

These results indicate that recency of HIV-1 infection can be inferred from viral sequence diversity even among patients on suppressive ART.
HIV-1 non-group M phenotypic susceptibility in vitro to bictegravir and cabotegravir
Authors: Martin Charlène , Gracias Ségolène , Charpentier Charlotte , Descamps Diane , Le Hingrat Quentin , Plantier Jean-Christophe , Alessandri-Gradt Elodie
Published: June 2021

Objectives

HIV-1 group O (HIV-1/O) is one of the four HIV-1 groups and is endemic in Cameroon, representing 1% of HIV-1 infections in the population. Around 50% of the strains of this group naturally show a mutation (Y181C) providing them with resistance to NNRTIs and making therapeutic management more difficult. Today, the WHO recommends the use of integrase strand transfer inhibitors (INSTIs) as first-line treatment. Bictegravir and cabotegravir are the two most recent INSTIs. Because of the genetic polymorphism of HIV-1/O, studies are required to evaluate their phenotypic susceptibility to these two drugs.

Patients and methods

We performed a phenotypic study on a large panel including 41 HIV-1/O clinical isolates and other rare non-group M HIV-1 (2 HIV-1/N and 1 HIV-1/P) to evaluate in vitro susceptibility to bictegravir and cabotegravir.

Results

The results showed an overall susceptibility of non-group M strains to the two drugs compared with HIV-1 group M. There was no difference between the mean (min–max) IC50 of HIV-1/M [1.86 (0.93–4.12) and 5.24 (1.76–12.41) nM for bictegravir and cabotegravir, respectively] and HIV-1/non-M [2.17 (0.03–9.47) and 4.88 (0.02–15.64) nM for bictegravir and cabotegravir, respectively]. However, we found a significant difference between IC50 values for bictegravir and cabotegravir in the whole panel (P value < 0.001).

Conclusions

This study has shown encouraging results regarding the clinical use of these drugs in HIV-1/non-M-infected patients, which will need to be confirmed with clinical data.
Comparative activity of posaconazole and systemic azole agents against clinical isolates of filamentous fungi from a global surveillance programme
Authors: Carvalhaes Cecilia G , Rhomberg Paul R , Pfaller Michael , Castanheira Mariana
Published: June 2021

Objectives

The activity of mould-active azoles was evaluated against 397 filamentous fungi causing invasive mould infections (IMI) worldwide. In addition, a tentative posaconazole epidemiological cut-off value (ECV) against Aspergillus fumigatus was investigated.

Methods

Isolates were susceptibility tested by the CLSI reference broth microdilution methods. Species identification was confirmed by MALDI-TOF and/or sequencing analysis.

Results

Aspergillus spp. (81.9%) remained the most common organism causing IMI worldwide; approximately two-thirds of Aspergillus spp. recovered were A. fumigatus. In general, more than 90% of 220 A. fumigatus isolates were wild type (WT) to all mould-active azoles, except itraconazole (84.5% WT). The voriconazole non-susceptible (NS) A. fumigatus rate was 7.7% overall and was higher in Europe (12.9%) than in the other regions (0%–5.8%). Posaconazole (MIC50/MIC90, 0.25/0.5 mg/L) showed similar or slightly higher activity than voriconazole (MIC50/MIC90, 0.5/0.5 mg/L) and isavuconazole (MIC50/MIC90, 0.5/1 mg/L) against A. fumigatus. The mould-active azoles displayed similar activity against non-fumigatus Aspergillus (WT rates >93%), but differences were observed among the main species/sections. Posaconazole, voriconazole, and isavuconazole inhibited at their respective ECVs 100%, 97.0%, and 100% of A. section Nigri; 100%, 100%, and 93.8% of A. section Terrei; and 97.3%, 100%, and 100% of A. section Flavi isolates. Posaconazole displayed potency greater than or equal to the other azoles against the Mucorales group and Scedosporium spp.

Conclusions

Posaconazole and other mould-active azoles showed good activity against Aspergillus spp. causing IMI, but clinicians should be aware of regional rates of voriconazole-NS A. fumigatus.
Which other disorders cause dementia?
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

In addition to Alzheimer’s disease, other brain disorders of aging that affect thinking and memory include vascular dementia, dementia with Lewy bodies, Parkinson’s disease dementia, behavioral variant frontotemporal dementia, primary progressive aphasia that has logpenic, semantic, and non-fluent agrammatic variants, and normal pressure hydrocephalus. Each produces characteristic changes in thinking, memory, language, behavior, and/or movement that allow you and the doctor to know when to consider them as possible causes of your loved one’s dementia. Note that the dementia of every individual is unique, so the symptoms and signs that they will manifest are all different. However, when dementias reach the moderate to severe stage, most dementias looks similar, despite having different causes.
How to manage sleep problems
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

When you get a good night’s rest, you’re better able to tackle the most challenging dementia issues. On the other hand, when your sleep is poor, even small difficulties can cause you to feel frustrated and irritable. And if that’s true for you with a healthy brain, think about how important sleep is for your loved one with dementia. Poor sleep can cause many problems in those with dementia—not to mention often disrupting your own sleep! Although sleep problems are common in dementia, most of them can be managed without medications. Start by using a sleep log. Work to improve your loved one’s sleep habits and modify their daily routines to improve sleep. Be alert for disorders such as sleep apnea and abnormal sleep movements; let your loved one’s doctor know if you suspect them.
What are some ways to sustain your relationship?
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

There are many activities that you can enjoy with your loved one. Visiting museums, attending the theater, watching movies, and listening to music are just a few. You may both enjoy having a massage, strolling on a nature walk, or filling in an adult coloring book—even if you never pursued such pastimes before. Exercise is good for everyone and is a wonderful way to spend time with your loved one. Most people enjoy the touch and warmth of human contact and, for couples, sexual intimacy can be an important aspect of your relationship. Lastly, participating in meaningful activities—including research, advocacy, and providing support to others—can provide an important sense of purpose in life for you and your loved one.
Rationale, Foundations, and Goals of CALM
Authors: Rodin Gary , Hales Sarah
Published: June 2021

This chapter introduces the Managing Cancer and Living Meaningfully (CALM) treatment manual. It summarizes the intent and purpose of the manual, which outlines the essential features of the CALM intervention and provides clinical examples to elucidate its implementation. Although it has been challenging to manualize the key therapeutic elements of a semi-structured intervention such as CALM, treatment manuals are essential to ensure the reliability and integrity of treatment delivery.
Military Medical Ethics in Contemporary Armed Conflict
Authors: Gross Michael L.
Published: June 2021

Beleaguered countries struggling against aggression or powerful nations defending others from brutal regimes mobilize medicine to wage just war. As states funnel medical resources to maintain unit readiness and conserve military capabilities, numerous ethical challenges foreign to peacetime medicine ensue. Force conservation drives combat hospitals to prioritize warfighter care over all others. Civilians find themselves bereft of medical attention; prison officials force feed hunger-striking detainees; policymakers manage health care to win the hearts and minds of local nationals; and scientists develop neuro-technologies or nanosurgery to create super soldiers. When the fighting ends, intractable moral dilemmas rebound. Postwar justice demands enormous investments of time, resources, and personnel. But losing interest and no longer zealous, war-weary nations forget their duties to rebuild ravaged countries abroad and rehabilitate their war-torn veterans at home. Addressing these incendiary issues, Military Medical Ethics in Contemporary Armed Conflict integrates the ethics of medicine and the ethics of war. Medical ethics in times of war is not identical to medical ethics in times of peace but a unique discipline. Without war, there is no military medicine, and without just war, there is no military medical ethics. Military Medical Ethics in Contemporary Armed Conflict revises, defends, and rebuts wartime medical practices, just as it lays the moral foundation for casualty care in future conflicts.
Care and Compensation for Civilian Victims of War
Authors: Gross Michael L.
Published: June 2021

Lacking bed space, Coalition military hospitals in Iraq and Afghanistan declined to admit any civilian except those injured by multinational forces. There are, however, no firm moral grounds for granting collateral casualties a special right to medical attention. Military necessity justifies preferential care for civilians who can contribute to a counterinsurgency, not those suffering collateral damage. Money, not medicine, is a better vehicle to assuage resentment among wounded civilians. Considering the rights of compatriots, allies, civilians, and detainees, five ethical principles govern the distribution of medical care during war: military-medical necessity, associative duties, liability for collateral or accidental harm, beneficence, and urgent medical need. Judging by the number of patients each principle reaches, the cost of care, and the feasibility of implementation, necessity and associative duties best serve military medicine. Once patients assemble by identity and military status, urgent medical need governs care within each group.
Circadian Rhythms and Homeostatic Mechanisms for Sleep Regulation
Authors: Hilditch Cassie J. , Flynn-Evans Erin E.
Published: June 2021

This chapter examines circadian rhythms and homeostatic mechanisms for sleep regulation. It reviews the current evidence describing the two-process model of sleep regulation and how to assess disruption to either of these sleep drives. This chapter also reviews the role of the photic and non-photic resetting of the circadian rhythm and describes how some aspects of modern society can cause sleep and circadian disruption. Further, this chapter describes how misalignment between the circadian rhythm and sleep homeostasis, such as occurs during jet lag and shift-work, can lead to sleep disruption. The short- and long-term consequences of circadian misalignment are also reviewed.
Mind–Body Interventions and Sleep: Dealing with Stress and Improving Emotional Wellness
Authors: von Garnier Sophie , Shapiro Shauna L. , Ong Jason C.
Published: June 2021

Research has shown that sleep is essential to our physical and mental well-being. In this chapter, the authors discuss the relationships between psychological functioning, stress, and sleep, demonstrating that sleep plays a key role in cognitive and emotional processes and mental health. They also illustrate how various psychological factors contribute to sleep disturbance and explore different relaxation techniques shown to improve sleep quality, including deep breathing, guided imagery, progressive muscle relaxation, and mindfulness meditation. Finally, the authors examine Mindfulness-Based Therapy for Insomnia, a pioneering intervention that integrates cognitive-behavioral therapy (CBT) and mindfulness training.
Toward a Positive Psychology of Sleep
Authors: Wickwire Emerson M.
Published: June 2021

Positive psychology is the domain of psychological research and practice that seeks to understand and enhance human flourishing. As such, positive psychology and sleep medicine are natural bedfellows because a primary goal of sleep disorders treatments is to improve patient quality of life. The purpose of this chapter is to propose a positive psychology of sleep and to review the theoretical, empirical, and clinical aspects of positive sleep. A rapidly expanding scientific literature demonstrates important bidirectional associations between sleep and positive mood states. Insufficient and disturbed sleep are associated with diminished positive affect. Preliminary evidence suggests that positive psychology interventions hold great promise to improve quality of life and outcomes in sleep disorders treatments, particularly behavioral sleep interventions. Although high-quality outcomes data remain scant, clinicians will find positive psychology interventions natural adjuncts to their evidence-based sleep medicine practices, with minimal risk of harm and great potential benefit.
Integrative Dream Medicine
Authors: Naiman Rubin
Published: June 2021

Although dreaming was integral to the ancient Asklepian practices that form the roots of contemporary medicine, its clinical relevance has been obscured by a scientific bias against the phenomenology or personal meaning of dreams. Rapid eye movement (REM) sleep and dreaming play critical roles in neurological and mental health, particularly memory consolidation, mood regulation, and personal transcendence. Despite this, the epidemic of REM/dream deprivation and its health ramifications has not been adequately acknowledged or addressed. All clinicians should advise patients of the general health benefits of REM/dreaming and incorporate relevant screening and treatment for REM/dream deficiencies into their practices. REM/dream issues must be explicitly addressed in sleep medicine, especially in the treatment of insomnia disorder, sleep apnea, narcolepsy, and nightmares. This should include psychotherapeutic dreamwork, which views REM/dreaming as an endogenous healing process. Promoting REM/dream health also calls for concerted public health initiatives.
Manual Medicine and Sleep
Authors: Kurisu Michael
Published: June 2021

Manual medicine and manipulative techniques encompass a wide array of techniques that provide structural, vascular, and energetic manipulation to influence musculoskeletal and general health. Manual medicine requires special focus on the physical exam in order to determine the most efficacious manipulative and physical therapy techniques. Manual medicine has been shown to be of benefit independently and adjunctively in the treatment of a number of musculoskeletal and pain conditions. There is a small but growing body of evidence in support of specific manual medicine techniques to treat insomnia and other aspects of sleep disorders.
Carotid Stenting
Authors: Khanna Omaditya , Mouchtouris Nikolaos , Peterson Eric C. , Jabbour Pascal M.
Published: June 2021

Several large-scale studies have corroborated the indications for carotid artery revascularization in patients who present with carotid artery stenosis. The two treatment options are carotid endarterectomy and carotid artery stent, both of which show equipoise in outcomes, and although the latter is associated with increased risk of periprocedural stroke, it confers the benefit of shorter procedural and recovery times. Currently, radial artery access is rarely used for placement of carotid artery stents, both among neurosurgeons and vascular surgeons. However, radial artery access for carotid stent placement has been shown to be safe and efficacious, and it confers the benefit of reduced access-site complications and improved patient satisfaction measures. In this chapter, aimed at practitioners who would like to incorporate radial artery access into their clinical practice, we review the evaluation and management of carotid artery stenosis and present an operative technique for carotid artery stent placement via radial artery access.
Access-Site Complications of the Transfemoral Approach
Authors: Chen Stephanie H. , Jabbour Pascal M. , Peterson Eric C.
Published: June 2021

The radial access route has significantly lower complications compared to the femoral access route. Often users have become used to the femoral approach and its attendant complications but it is worth reviewing that despite its minimally invasive nature as opposed to open craniotomy, endovascular transfemoral access is certainly not without risk. These risks include life threatening retroperiotenal hematoma formation and local hematoma formation as well as limb threatening occlusion of the femoral artery, which is an end artery thus must be urgently revascularlized in the event of compromise. The complications of femoral access are reviewed as well as strategies for management.
Future Directions
Authors: Sweid Ahmad , Peterson Eric C. , Jabbour Pascal M.
Published: June 2021

The transradial approach (TRA) reduces mortality, morbidity, access-site complications, hospital cost, and length of stay while maximizing patient satisfaction. The overall lag between the introduction of the transradial approach and its widespread use within the neurointerventional niche is due to a variety of factors, including perceived difficulties in navigation, lack of exposure during training, and complexity of the neurointerventional procedures. With more training programs converting to TRA, a new generation of fellows will be trained in the technique; in addition to that, a lot of work is on the way to develop new catheters dedicated for TRA.
New technical developments in cardiac CT: Anatomy, fractional flow reserve (FFR), and machine learning
Authors: Achenbach Stephan , Leipsic Jonathan , Min James
Published: June 2021

Computed tomography (CT), in the context of cardiac imaging, faces numerous challenges. The heart is a complex, three-dimensional organ, which moves very rapidly and has small dimensions. The coronary arteries, the main target of cardiac CT imaging, are especially difficult to visualize by any non-invasive technique. All the same, technology progress has made the use of CT for cardiac and coronary diagnosis possible. For selected applications, including ruling out coronary artery stenoses in low-risk individuals, CT has become a clinical tool. This chapter describes the progress of CT technology, from the first commercially available CT scanner that permitted visualization of the heart with high temporal and spatial resolution in the late 1980s, to today’s incarnations that utilize radiomics and artificial intelligence.
Intraoperative transoesophageal echocardiography for valvular surgery
Authors: Maalouf Joseph F. , Michelena Hector I.
Published: June 2021

Intraoperative transoesophageal echocardiography (IOTEE) is widely used to guide valvular heart disease (VHD) surgery. The critical role of IOTEE is to aid the surgeon in tailoring the surgical approach to the specific mechanism(s) of valve dysfunction in patients with mitral or aortic regurgitation undergoing valve repair surgery, identify all valvular abnormalities that may warrant intervention, and to assess in a timely manner the results of the operative intervention upon coming off cardiopulmonary bypass (pump) thus allowing immediate correction of less-than-satisfactory results before the patient leaves the operating room (OR). IOTEE is also useful to monitor results of concurrent interventions such as coronary artery bypass graft surgery and aorta aneurysm repair, and to evaluate post-bypass biventricular function.
Valvular prostheses
Authors: Badano Luigi P. , Muraru Denisa
Published: June 2021

Prosthetic heart valves may be mechanical or bioprosthetic. Mechanical valves, which are composed primarily of metal or carbon alloys, are classified according to their design as ball-caged, single-tilting-disc, or bileaflet-tilting-disc valves. In ball-cage valves, the occluder is a sphere which is contained by a metal ‘cage’ when the valve is in its open position, and fills the orifice when the valve is in its closed position. In single-tilting-valves, the occluder is a single circular disc which is constrained in its motion by a cage, a central strut, or a slanted slot in the valve ring, therefore it opens at an angle less than 90° to the sewing ring plane. In bileaflet-tilting-disc valves there two occluders, two semicircular discs that open forming three orifices, a central one and two lateral ones. Biological tissue valves prostheses may be heterografts, which are composed of porcine, bovine, or equine tissue (valvular or pericardial), or homografts, which are preserved human aortic valves. Heterografts include stented and stentless bioprostheses. In stented valves, the biological tissue of the valve is mounted on a rigid stent (plastic or metallic) covered with fabric. Conversely stentless bioprostheses use the patient’s native aortic root as the valve stent. The absence of a stent and sewing ring cuff make it possible to implant a larger valve for a given native annulus size, resulting in a larger effective orifice area (EOA).
Transcatheter pulmonic valve replacement
Authors: Pushparajah Kuberan , Frigiola Alessandra
Published: June 2021

Right ventricular outflow tract dysfunction is the most frequent residual lesion following repair of various congenital heart diseases and can be characterized by predominant pulmonary valve stenosis, regurgitation, or a combination of both lesions. The need to replace the malfunctioning pulmonary valve in order to avoid detrimental effects on right ventricular function is widely recognized. While a surgical approach was the only possible option until less than two decades ago, advances in the medical field have made it possible to replace such valves percutaneously in selected patients, with favourable anatomy, and with comparably good results. In more recent years, further developments of the percutaneous pulmonary valve design and technology have allowed an increasing number of patients to be suitable for this preferred approach due to the less invasive nature and quicker recovery time.
Assessment of viability
Authors: Pierard Luc A. , Gargiulo Paola , Perrone-Filardi Pasquale , Gerber Bernhard , Selvanayagam Joseph B.
Published: June 2021

Ischaemic left ventricular (LV) dysfunction due to coronary artery disease (CAD) is steadily increasing as a consequence of the ageing of the population and of improved survival of patients with acute coronary syndromes and currently represents the first cause of heart failure (HF). Myocardial function is dependent on blood supply, as anaerobic reserve is minimum due to a nearly maximal arteriovenous oxygen extraction. At rest, myocardial blood flow remains normal even in the presence of severe coronary artery stenosis (up to 85% diameter stenosis) by coronary autoregulation. In the presence of transstenotic pressure gradient due to epicardial coronary stenosis, arteriolar dilatation maintains normal myocardial flow at rest but with a progressive reduction in flow reserve. When arteriolar dilatation is maximal, autoregulation is exhausted and myocardial ischaemia develops. The limit of autoregulation depends on myocardial oxygen demand and is influenced by heart rate. Tachycardia increases oxygen demand and supply is reduced because of a decreased diastolic perfusion time. In the presence of acute ischaemia, there is a close relation between subendocardial perfusion and transmural function. Indeed, the contribution of subendocardium to myocardial thickening largely exceeds the contribution of the subepicardium. Akinesia can therefore result from subendocardial ischaemia and transmural ischaemia is not necessary. This chapter looks at how viability of the different techniques for treating myocardial dysfunction is assessed.
Infiltrative cardiomyopathy
Authors: Lombardi Massimo , Pica Silvia , Camporeale Antonella , Gimelli Alessia , Pennell Dudley J.
Published: June 2021

Infiltrative cardiomyopathies are comprised of a variety of inherited or acquired conditions. Myocardial involvement is often part of a complex systemic disorder, but sometimes the disease can manifest predominantly in the heart. Clinical manifestations are heterogeneous, from mild symptoms to early cardiac death. A multimodality imaging approach by means of echocardiography, cardiovascular magnetic resonance (CMR), and molecular imaging is necessary; a comprehensive assessment of morphologic, functional, tissue, and metabolic changes is the key to improve the pathophysiologic understanding of these diseases, favouring early differential diagnosis and risk stratification of patients. Furthermore, quantitative, non-invasive assessment of tissue pathology is now available and plays a crucial role in the follow-up of patients affected by infiltrative cardiomyopathies, improving their management and potentially guiding the development of existing and new therapies.
Pericardial effusion and cardiac tamponade
Authors: Klein Allan , Cosyns Bernard , Schenone Aldo L.
Published: June 2021

Pericardial effusion (Peff) is a commonly encountered findings in clinical practice. It is usually asymptomatic, but can present as a life-threatening condition when cardiac tamponade ensues. The use of multimodality cardiac imaging has emerged as a crucial tool in the early detection and characterization of Peff and cardiac tamponade allowing prompt and effective treatment. Transthoracic echocardiography (TTE) is first-line imaging technique in the evaluation for Peff and cardiac tamponade. They key echocardiographic findings supporting cardiac tamponade include the presence of (1) cardiac chambers collapse; (2) an exaggerated ventricular interdependence; and (3) plethoric inferior vena cava (IVC). Advance cardiac imaging including transoesophageal echocardiography, cardiac CT, and cardiac MRI are reserved for complex cases with high suspicion for focal effusion or tamponade when TTE is unrevealing. Medical treatment of underlying cause is recommended for effusion without haemodynamic compromise, while emergent drainage is warranted when in cardiac tamponade.
Cardiac masses and tumours
Authors: López-Fernández Teresa , Buser Peter
Published: June 2021

The care for cancer patients has dramatically improved over the past century. Cardio-oncology, the multidisciplinary cardiovascular care of cancer patients, has been proposed as a new approach to improve prevention, early identification, and management of cardiotoxicity. However this field is not simply limited to complications of cancer therapies, it also encompasses cardiac neoplasias. Cardiac masses include tumours, thrombi, cysts, calcific lesions, vegetations, and other rare conditions. The present chapter will cover all these entities from the imaging diagnostic perspective. Although echocardiography is generally the first imaging tool used, tissue characterization by cardiac magnetic resonance (CMR) can be particularly helpful for differential diagnosis.
The role of echocardiography in adult congenital heart disease
Authors: Smith Lindsay A. , Friedberg Mark K. , Mertens Luc
Published: June 2021

Echocardiography plays a key role in the diagnosis and management of adult patients with congenital heart disease and is considered the first-line diagnostic technique. Apart from traditional cross-sectional imaging, three-dimensional echocardiography and strain and strain rate imaging were introduced for specific indications and for better describing anatomical details and functional consequences of the different congenital lesions. For specific indications, additional imaging may be required including cardiac magnetic resonance imaging and computational tomography. Especially in adult congenital heart disease, echocardiographic imaging may be limited by poor acoustic windows and additional evaluation using other imaging modalities may be required. Additionally, MRI and CT imaging have proven to be extremely valuable for evaluation of right ventricular size and function and for describing extracardiac anatomy (pulmonary arteries, pulmonary veins, and aorta).
pyrpipe: a Python package for RNA-Seq workflows
Authors: Singh Urminder , Li Jing , Seetharam Arun , Wurtele Eve Syrkin
Published: June 2021

The availability of terabytes of RNA-Seq data and continuous emergence of new analysis tools, enable unprecedented biological insight. There is a pressing requirement for a framework that allows for fast, efficient, manageable, and reproducible RNA-Seq analysis. We have developed a Python package, (pyrpipe), that enables straightforward development of flexible, reproducible and easy-to-debug computational pipelines purely in Python, in an object-oriented manner. pyrpipe provides access to popular RNA-Seq tools, within Python, via high-level APIs. Pipelines can be customized by integrating new Python code, third-party programs, or Python libraries. Users can create checkpoints in the pipeline or integrate pyrpipe into a workflow management system, thus allowing execution on multiple computing environments, and enabling efficient resource management. pyrpipe produces detailed analysis, and benchmark reports which can be shared or included in publications. pyrpipe is implemented in Python and is compatible with Python versions 3.6 and higher. To illustrate the rich functionality of pyrpipe, we provide case studies using RNA-Seq data from GTEx, SARS-CoV-2-infected human cells, and Zea mays. All source code is freely available at https://github.com/urmi-21/pyrpipe; the package can be installed from the source, from PyPI (https://pypi.org/project/pyrpipe), or from bioconda (https://anaconda.org/bioconda/pyrpipe). Documentation is available at (http://pyrpipe.rtfd.io).
ATRT-07. DEFINING LOST AND GAINED TRANSCRIPTIONAL REGULATORY NETWORKS IN ATYPICAL TERATOID RHABDOID TUMOR
Authors: Nesvick Cody , Zhang Liang , Wixom Alex , Hamdan Feda , Johnsen Steven , Daniels David
Published: June 2021

Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system cancer of infancy and early childhood that may occur anywhere along the neuraxis and is associated with a high rate of mortality. While contemporary multimodal therapeutic approaches have significantly improved overall survival, targeted therapy remains elusive, and treatment is often associated with significant morbidity. ATRT is unique in its genomic stability, with the only recurrent genetic abnormality being bi-allelic loss of the SMARCB1 gene, which encodes a core subunit of the BAF chromatin remodeling complex. The epigenetic mechanisms by which SMARCB1 loss leads to tumorigenesis are not yet well-defined and addressing this gap in understanding is necessary for creating efficacious, targeted therapeutics. To better understand the epigenetic features gained and lost in ATRT, we re-expressed SMARCB1 in a library of patient-derived and established ATRT cell lines of multiple molecular subtypes. SMARCB1 restoration significantly reduced or eliminated the proliferative and clonogenic capacity of each cell line. We performed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) and RNA sequencing (RNA-Seq) to define putative transcriptional regulatory networks that are gained and lost in ATRT. SMARCB1 restoration was associated with global changes in chromatin openness consistent with the creation of new regulatory elements throughout the genome, and these were associated with induction of a diverse developmental transcriptional signature. Motif enrichment analysis of regions with increased accessibility defined a small but consistent number of centrally enriched transcription factor motifs across cell lines indicative of putative pioneer factors whose functions may be lost in ATRT. Pertinent chromatin immunoprecipitation with sequencing (ChIP-Seq) data will be discussed in the context of lost and gained transcriptional regulatory networks in ATRT and normal cellular development.
BIOL-11. THE ROLE OF ABERRANT EXPRESSION OF PRDM6 IN THE DEVELOPING CEREBELLUM AND IN GROUP 4 MEDULLOBLASTOMA
Authors: Schmidt Christin , Carlson Annika , Weiss William , Schwer Bjoern
Published: June 2021

Group 4 medulloblastoma is the most common medulloblastoma subgroup with an intermediate prognosis and a high incidence of metastasis and late-onset relapse cases. Despite several comprehensive genomic studies in medulloblastoma, Group 4 medulloblastomas lack a unifying oncogenic driver and treatment targets. This subgroup is characterized by recurrent genetic alterations in chromatin modifiers, amplification of stemness genes, and enhancer hijacking events. 17% of Group 4 medulloblastoma cases are characterized by enhancer hijacking through tandem duplication of SNCAIP, resulting in high expression of PRDM6, a putative transcriptional repressor and histone methyltransferase. PRDM6 amplified medulloblastoma cases show additional mutations in other chromatin regulators, such as KDM6A, KMT2C and KMT2D, ZMYM3, and high MYCN expression. In this project, we investigate the impact and oncogenic potential of sustained PRDM6 expression in early neural stem cell populations and the developing mouse cerebellum. We drive expression of PRDM6 in human iPSC-derived neuroepithelial stem cells (NESCs) with and without high MYCN expression to study its implications in tumorigenesis. To test for tumor growth in vivo and changes in tumor progression as a function of PRDM6 activity, NESCs are injected into the cerebellum of adult mice. In order to elucidate impact of PRDM6 activity during embryonic cerebellar development, we also introduce PRDM6 expression into mouse embryonic stem cells (ESCs) for analysis via a new, in vivo cerebellar blastocyst complementation model. The latter approach is designed to ablate and repopulate early granule neural precursor cells in the embryonal cerebellum with progenitors derived from injected PRDM6-ESCs and thus to recapitulate pre- and postnatal cerebellar development in vivo. Together, our studies aim to understand the role of PRDM6 during normal cerebellar development and tumorigenesis and advance the understanding of the genetic drivers for Group 4 medulloblastoma.
EMBR-07. MYC BUT NOT MYCN GENERATES AGGRESSIVE GROUP 3 MEDULLOBLASTOMA BY ARF PATHWAY SUPPRESSION
Authors: Mainwaring Oliver , Weishaupt Holger , Hutter Sonja , Zhao Miao , Rosén Gabriela , Breinschmid Laura , Verbaan Annemieke , Sundström Anders , Annusver Karl , Kasper Maria , Swartling Fredrik
Published: June 2021

Medulloblastoma (MB), the most common malignant pediatric brain tumor, often harbor MYC amplifications and arise in the presence of a functional p53 suppressor protein. To elucidate the mechanism behind this inexplicable tumor development we generated an inducible, immunocompetent transgenic mouse model of MYC-driven MB. Tumors driven from the glutamate transporter promoter molecularly resembled aggressive Group 3 MB driven by an enriched photoreceptor program. They developed embryonically in a monoclonal fashion in the presence of a functional unmutated p53 gene. Compared to MYCN-expressing MB driven from the same promoter, we discovered pronounced silencing of the ARF suppressor upstream of p53. We similarly found significant methylation of the ARF promoter in MYC-amplified as compared to MYCN-amplified human MB samples. While MYCN-driven tumor malignancy was more sensitive to ARF depletion, it dramatically increased metastatic spread of MYC-driven tumors. DNMT inhibition could restore ARF levels in MYC-expressing tumors but did not show any therapeutic advantage in tumors in vivo. Computational modeling suggested the HSP90 protein to act as a more specific target and ARF could indeed be restored by the HSP90 inhibitor onalespib that promoted increased survival in our inducible animal model suggesting that HSP90 inhibition could be potentially used in patients affected by MYC-driven ARF-silenced cancer.
EMBR-09. EXAMINING THE ROLE OF THE DEVELOPMENTALLY ENCODED TRANSCRIPTION FACTOR, LHX9, IN GROUP 3 MEDULLOBLASTOMA
Authors: Injac Sarah , Rivas Bryan , Arabzade Amir , Zhao Yanhau , Parsons D William , Mack Stephen
Published: June 2021

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Despite major advances in our understanding of the biology of MB, novel treatments remain urgently needed. Using a chemical-genomics driven drug repositioning strategy, we identified the cardiac glycoside family of compounds as potential treatments for Group 3 MB. We subsequently demonstrated that single-agent treatment with digoxin prolongs survival in a patient-derived xenograft model (PDOX) of Group 3 MB to a degree comparable to radiation therapy, a mainstay in the treatment of MB. Finally, we examined the mechanism of digoxin-mediated cell killing using RNA-seq. This work identified LHX9, a member of the LIM homeobox family of transcription factors, as the gene most significantly down-regulated following treatment (Huang and Injac et al, Sci Trans Medicine, 2018). Homologs of LHX9 play key roles in cerebellar development via spatially and temporally restricted expression and LHX9 has been proposed as a core transcription factor (TF) in the regulatory circuitry of Group 3 tumors. Loss of function of other core TFs has been shown to impact MB growth. The role of LHX9 in MB, however, has not been previously experimentally evaluated. We now report that knockdown of LHX9 in MB-derived cell lines results in marked growth inhibition. RNA-seq analysis of LHX9-depleted cells showed changes which included alterations in extracellular matrix-receptor interactions and TGFb signaling. These findings raise the possibility that loss of LHX9 plays a major role in digoxin-mediated cell killing and that LHX9 represents a key dependency required for the growth of Group 3 MB. Clinical targeting of core TFs would represent a novel approach to targeting this devastating disease.
EMBR-12. TARGETING THE RNA-BINDING PROTEIN LIN28B IN GROUP 3 MEDULLOBLASTOMA
Authors: Shahab Shubin , Schnepp Robert , MacDonald Tobey , Kenney Anna
Published: June 2021

Medulloblastoma (MB) is the most common pediatric malignant brain tumor and is currently divided into WNT, SHH, Group 3 and Group 4 subtypes. Even with multimodal chemotherapy, radiotherapy and surgery, many children with Group 3 MBs do not survive. We have previously demonstrated an oncogenic role for the RNA-binding protein (RBP) LIN28B in neuroblastoma. LIN28B is a key regulator of let-7 family miRNAs, which in turn inhibit LIN28A/B and other oncogenes. LIN28B has also been found to be upregulated in Wilms tumor, hepatoblastoma, germ cell tumors, leukemia among others. We hypothesize that LIN28B plays an important role in Group 3 MB and that a better understanding of LIN28B and LIN28B-driven networks will reveal novel therapeutic vulnerabilities. LIN28B levels are highest in Group 3 MB patients, and its overexpression is associated with significantly worse survival. Here we demonstrate that down-regulation of LIN28B using shRNA results in significant reduction in cell proliferation by CellTiter-Glo and increased apoptosis by Caspase-Glo (as well as induction of cleaved PARP on immunoblots). In contrast overexpression of LIN28B increases Group 3 cell proliferation and tumor sphere formation The LIN28 inhibitor 1632 also leads to significant reduction in G3 MB cell proliferation. In addition, we find that PDZ-binding kinase (PBK) a downstream target of LIN28B is downregulated when LIN28B is depleted. PBK knock down also leads to decreased proliferation of Group 3 MB cells. Finally RNA-seq profiling following LIN28B depletion reveals additional components of the LIN28B pathway which may be amenable to therapeutic targeting. This work will help define the role for LIN28B in Group 3 MB aggressiveness and establish LIN28B and LIN28B-driven networks as novel therapeutic targets in these patients.