bluuebunny/crossref_metadata_2025 huggingface dataset:
Concussion in Children
Authors: Brody David L.
Published: May 2019

Rules for children under 12 years of age with concussion: (1) Take the history twice: Once from the child and once from the parents or guardians. Young children can reliably report headache, nausea, balance problems, problems concentrating, and irritability. Other concerns, as well as preinjury problems, should be assessed from the parents or guardians. (2) Use age-appropriate language and simplified assessments of severity. Consider using the Child SCAT5. (3) Carefully assess for secondary-gain factors. A child may over-report or under-report symptoms to please the parents or guardians. (4) With regard to return to school, sports, and daily life, help the parents or guardians find the “middle way”: Not too protective and not too lax. Most children do not need to be “cocooned” or totally isolated from all stimuli. (5) In complex concussion, assess for attention deficit and atypical presentations of migraine, depression, and anxiety. (6) Consider treatment with glucose (e.g., 100 to 200 calories of a high glycemic index snack or drink 20 minutes prior to school or rehabilitation-related activity) to improve cognitive performance and reduce pain. This seems to be specific to children and does not appear to be effective in adults. Consider using the Child SCAT5.
Scheduling Return Visits
Authors: Brody David L.
Published: May 2019

Various concerns are taken into consideration in scheduling return visits to a concussion clinic. Some of the most commonly encountered are listed here:

Active, immediately dangerous issue (e.g., suicidal, homicidal): Admit to hospital

Active, time sensitive issue: Within 1 week

Active, potentially dangerous issue: 1 to 3 weeks

Active, severely impairing issue: 1 to 2 months

Patient starting a new medication that requires monitoring: 1 week to 3 months

Typical patient with moderate issues: 3 months

Stable patient, medications requiring monitoring: 6 months

Stable patient, no new medications, and no medication requiring monitoring: 1 year
Microcircuitry of the Neocortex
Authors: Ramaswamy Srikanth , Muller Eilif B. , Reimann Michael , Markram Henry
Published: May 2019

The neocortex is a sheet of neurons organized into six layers, each receiving and projecting to specific brain areas depending on the neocortical region. This neuronal sheet, with some exceptions, displays very little horizontal and anatomical segregation, but it is dynamically segregated into functional modules during stimulation. Excitatory pyramidal cells (PCs) are the principal neurons in the neocortical microcircuit. Inhibitory interneurons in the neocortical microcircuit are found in all six layers and are highly diverse in their somatic, dendritic, and axonal morphologies. While knowledge about the anatomy and physiology of neocortical neurons and synapses has increased tremendously over the past several decades, much remains to be learned about their functional role in shaping the network dynamics of neocortical microcircuitry.
Hippocampus: Intrinsic Organization
Authors: Somogyi Peter , Klausberger Thomas
Published: May 2019

The hippocampus, together with the subiculum, represent an associational area of the cerebral cortex that is intimately involved in mnemonic processes. Through its connections with other areas of the temporal lobe, the prefrontal cortex (PFC) and subcortical areas, it contributes to the encoding, association, consolidation, and recall of representations of the external and internal world in the combined firing rates and spike timing of glutamatergic pyramidal and granule cells. Pyramidal cell assemblies are formed and segregated from other assemblies by the dynamic strengthening and weakening of glutamatergic synaptic weights both on pyramidal cells and GABAergic interneurons. Interneurons, generate postsynaptic cell domain and brain state–dependent rhythmic changes in excitability, which are key for the formation, consolidation, and recall of representations. The chapter attempts to allocate explicit roles for some GABAergic neurons, based on their firing patterns in vivo as observed in identified neurons.
The Neuronal Circuit for Simple Forms of Learning in Aplysia
Authors: Hawkins Robert D. , Bailey Craig H. , Kandel Eric R.
Published: May 2019

The gill- and siphon-withdrawal reflex of Aplysia is a simple defensive behavior that is mediated in part by a monosynaptic pathway. Despite this remarkable simplicity, the reflex can be modified by several forms of learning, including habituation, dishabituation, sensitization, and classical and operant conditioning. The forms of learning that have been explored in research studies exhibit many of the behavioral properties of learning in mammals, suggesting that they may involve similar neuronal mechanisms. In 1984, we proposed cellular mechanisms for several higher-order features of conditioning and incorporated those ideas in a quantitative model that simulated a broad range of behavioral properties. In this chapter, we summarize the current body of knowledge about the behavior, circuitry, and cellular and molecular mechanisms of learning and memory of the reflex. We then review our original model and suggest how recent advances may explain some of the behavioral properties that this model could not.
Fly Optic Lamina as a Guide to Neural Circuit Design
Authors: Laughlin Simon B.
Published: May 2019

Lamina circuits are designed to transfer information effectively and efficiently from photoreceptors to interneurons in the face of two neural constraints: limited dynamic range and synaptic noise. The design uses analogue signals to achieve high information rates, high gain synapses releasing vesicles at high rate to reduce the effects of synaptic noise, and predictive coding to remove redundancy. To increase synaptic efficiency predictive coding is implemented pre-synaptically, using unorthodox non-vesicular mechanisms. To optimize information uptake, the lamina circuit continuously adapts to input statistics over a wide range of input levels. The lamina circuit demonstrates a widely employed circuit motif because its equivalent, in the vertebrate retina’s outer plexiform layer (OPL) has similar properties. The motif’s functional advantages were established in lamina because it is more amenable to reverse engineering. Indeed, the fly lamina exemplifies several principles of neural design that apply widely throughout brains.
Olfactory Bulb
Authors: Shepherd Gordon M. , Migliore Michele , Cavarretta Francesco
Published: May 2019

The olfactory bulb is the site of the first synaptic processing of the olfactory input from the nose. It is present in all vertebrates (except cetaceans) and a the analogous antennal lobe in most invertebrates. With its sharply demarcated cell types and histological layers, and some well-studied synaptic interactions, it is one of the first and clearest examples of the microcircuit concept in the central nervous system. The olfactory bulb microcircuit receives the information in the sensory domain and transforms it into information in the neural domain. Traditionally, it has been considered analogous to the retina in processing its sensory input, but that has been replaced by the view that it is more similar to the thalamus or primary visual cortex in processing its multidimensional input. This chapter describes the main synaptic connections and functional operations and how they provide the output to the olfactory cortex
The Superior Colliculus
Authors: Isa Tadashi , Kasai Masatoshi , Veale Richard
Published: May 2019

The superior colliculus (SC) is a midbrain center that integrates sensory input and transforms the information into a command signal to initiate behaviors, such as orienting to an object that attracts attention or escaping from a predator. It is a laminar structure composed of two primary layers: the superficial layer and the deeper layer. There are interactions between the layers, and there are also interactions within each layer. This chapter first summarizes recent studies on the intrinsic circuits in the SC, and discusses the neural circuits involved in these interlaminar and intralaminar interactions. Then, it describes how extrinsic GABAergic and cholinergic inputs to the SC modulate the activity of SC local circuits.
The Lamprey Postural Circuit
Authors: Deliagina Tatiana G. , Zelenin Pavel V. , Orlovsky Grigory N.
Published: May 2019

The lamprey has two principal behavioral states—a quiescent state, when it is attached to the substrate with its sucker mouth; and an active state, when it locomotes. It is capable of several forms of locomotion, but it actively stabilizes its body orientation in space only during the main form, fast forward swimming. During fast forward swimming, orientation of the lamprey in the sagittal (pitch) and transversal (roll) planes is stabilized in relation to the gravity vector by means of the postural control systems driven by vestibular input. Any deviations from the stabilized orientation are reflected in vestibular signals, which cause corrective motor responses. In the pitch and yaw planes, the corrections occur due to the body bending in the corresponding plane. In the roll plane, the corrections occur due to a change in the direction of locomotor body undulations, from lateral to oblique.
Introduction
Authors: Brunette Gary W. , Nemhauser Jeffrey B.
Published: May 2019

Introduction to Travel Health & the CDC Yellow Book

Phyllis E. Kozarsky, Ronnie Henry

Travel Epidemiology

Allison Taylor Walker, Regina C. LaRocque, Mark J. Sotir

Why Guidelines Differ

David R. Shlim

The number of people traveling internationally continues to grow. According to the World Tourism Organization, there were 1.33 billion worldwide international tourist arrivals in 2017, an increase of 88% from 2015. International arrivals increased 6% in January–April 2018 compared to the same period in 2017. In 2017, US residents made nearly 88 million trips with at least 1 night outside the United States....
Popular Itineraries
Authors: Brunette Gary W. , Nemhauser Jeffrey B.
Published: May 2019

The Rationale for Popular Itineraries

Ronnie Henry

East Africa: Safaris

Karl Neumann

Saudi Arabia: Hajj/Umrah Pilgrimage

Salim Parker, Joanna Gaines

South Africa

Gary W. Brunette

Tanzania: Kilimanjaro

Kevin C. Kain

Brazil

Joanna Gaines, Ana Carolina Faria e Silva Santelli

Cuba

Andrea K. Boggild, Linda R. Taggart...
First Encounters
Authors: Hawkes Christopher H. , Sethi Kapil D. , Swift Thomas R.
Published: May 2019

This chapter describes disorders that can be diagnosed as the patient enters the consulting room by observing closely how he or she turns to close the door, walks toward you, and shakes your hand. Much information is gleaned by inspecting the face, clothes, fingernails, and jewelry or by listening to the voice or smelling the breath. From chronic conditions to congenital disorders to addictions, the competent neurologist will depend first on keen observation in the construction of a diagnosis. Neurological diagnosis requires good detective work; the good neurologists must play at being a “bedside Sherlock Holmes.”
Myopathy and Motor Neuron Disorders
Authors: Hawkes Christopher H. , Sethi Kapil D. , Swift Thomas R.
Published: May 2019

The first part of this chapter deals with the main varieties of muscular dystrophy and their differential diagnosis, many of which are instantly recognizable. Handles are given for the main neuromuscular junction disorders including, myasthenia gravis and Lambert-Eaton myasthenic syndrome. Inflammatory and dysthyroid myopathies are evaluated. Also appraised are periodic paralysis, McArdle’s syndrome, and mitochondrial, distal, and medication-induced myopathy. In the second section, motor neuron disorders are discussed, in particular the characteristic features of amyotrophic lateral sclerosis and its mimics as well as various forms of bulbar palsy. Hereditary spastic paraplegia and its variants are discussed and how they can simulate other diseases.
Spinal Lesions and Cerebrospinal Fluid
Authors: Hawkes Christopher H. , Sethi Kapil D. , Swift Thomas R.
Published: May 2019

This chapter explains the major lesions of the spinal cord with emphasis on myelopathies, Brown-Sequard syndrome and syringomyelia. Points from the history and examination that aid lesion localization are detailed. Handles for specific disorders are listed, such as spinal dural arteriovenous fistula and claudication. Detail is supplied on infectious myelopathies, in particular recurrent myelopathy and recurrent meningitis. Clues are given that would allow rapid interpretation of cerebrospinal fluid analysis and the causes of a dry spinal tap.
Overview: The Accelerating Movement of Partnerships for Health
Authors: Michener J. Lloyd , Castrucci Brian C. , Bradley Don W. , Hunter Edward L. , Thomas Craig W.
Published: May 2019

Chapter 1 provides an introduction to the history and background to a general desire to try to find ways to improve population health through primary care and public health. The first Practical Playbook derived from an internet-based initiative that sought to find, assemble, assess, and share stories of how communities and agencies across the United States were working together to improve health. This text is the second development from that, after the realization that a completely new text was needed that would build on the experiences of the broadening array of sites and sectors and provide a concise set of tools, methods, and examples that support multi-sector partnerships to improve population health. The chapter then outlines the coverage of the rest of the chapters.
On Health Equity
Authors: Martinez-Bianchi Viviana
Published: May 2019

Chapter 2 asks: what is health equality? It is the attainment of the highest level of health for all people. This so-called “high level” is determined by a mixture of personal responsibility, biology, and the options and possibilities for good health available to each individual. Health equality, the chapter argues, matters from many perspectives and the economic survival of an entire community is affected by health equality. The chapter goes on to look at the issues associated with attaining health equality and how to teach it. It argues for the benefits of having a passion for health for all and a desire to make a difference beyond the confines of health care walls.
Overview—Data: Finding and Using Information
Authors: Castrucci Brian C. , Bradley Don W.
Published: May 2019

This chapter looks at the broader picture of this section of the book which is the uses, issues, benefits, and pitfalls of data in the goal of improving community collaboration for public health benefits. This section of the book, the chapter explains, explores what is happening to build the trust and accountability necessary for partnerships in which data sharing is at the center. Data on the causes of death and disease are necessary to drive well-informed, impactful resource allocation and policy decisions. As maintaining health has become more complicated, so has the need for more complete data. Electronic health records has digitized patient encounters, creating an unprecedented volume of data on disease. But, these data alone do not provide the information needed to improve health.
Going Way Upstream: How One Foundation Redefined Its Work to Improve Population Health
Authors: Long Peter , Imwalle Brittany
Published: May 2019

This chapter presents a case study from the Blue Shield of California Foundation (BSCF) which in 2016 achieved considerable success in its work to expand access to high-quality health care and to end domestic violence in California. The case of BSCF demonstrates how to integrate disparate health care services, such as primary care and specialty care, and behavioral health and primary care, to improve access and quality while potentially lowering costs. BSCF created networks of established leaders within the health care and domestic violence safety nets in California and influenced safety net systems in California to think and act differently. However, despite these notable successes, BSCF struggled to sustain, scale, and spread these innovations to other organizations and systems or to embed them into policy changes. The chapter analyses why.
Case Study—Acting (and Funding) Locally: How One Virginia Foundation Is Changing the Way It Supports Communities
Authors: Mathews Patricia N.
Published: May 2019

This chapter presents a case study based on the experience of the Northern Virginia Health Foundation (NVHF). The NVHF was created twelve years ago and was created to improve the health and health care of the residents of Northern Virginia, with a particular emphasis on those of low income and the uninsured. The chapter shows how despite being a small foundation, over the years, NVHF has made significant investments in the health care safety net. However, despite this, low-income residents in the area continue to face considerable challenges. The chapter makes some general conclusions based on this experience: cross-sector collaboration is difficult and, in many instances, expensive. But the return on investment is potentially strong. The direction should be creative and focused.
The Impact of State and Territorial Public Health Policy: Interventions to Prevent Opioid Misuse and Addiction
Authors: Fraser Michael R. , Tucker Philicia , Butler Jay C.
Published: May 2019

This chapter outlines the powerful role of state health officials in the policy process, illustrated by the collaborative approach to the complex opioids epidemic. The opioid misuse and addiction epidemic has left no segment of the American population untouched. It is important to note that multiple factors have led to the explosive scale and spread of addiction to prescription and illicit opioids. The combination of tertiary, secondary, and primary prevention programs and the policies that support them are critical. No single policy will comprehensively address the complex issues involved in the current crisis, the chapter argues, but more work in the area of primary prevention is greatly needed. A comprehensive approach that utilizes evidence-based approaches to primary, secondary, and tertiary prevention are critical. The chapter concludes that the complexity of the opioid crisis requires strong clinical and community partnerships to scale and spread successful policy interventions. State and territorial public health officials are committed and well-positioned to lead such efforts in their jurisdictions.
Voices of the Next Generation
Authors: Corcoran Elizabeth , LaFave Sarah , Agana Denny Fe Garcia , Kampman Haleigh , Penner John C. , McCarthy Margaret L. , Mullins Katherine P. , Vu Michelle , Duncan Ashten
Published: May 2019

This chapter presents a number of personal perspectives on experiences and thoughts on collaborative population health projects that have taken place. It presents a number of essays that look at slightly different aspects of the topic. The first essay focuses on the team of professionals who are involved in such projects. The second essay looks at care for the elderly. The third essay gives a very personal account of hopes to make a difference in population health. The next essay looks at employment and public health. The fifth essay is about food insecurity. The essay that follows looks at the role of the pharmacist. The seventh essay considers interdisciplinary collaboration for improving health in the United States.
Conclusion: From the Edges Toward the Middle
Authors: Michener J. Lloyd , Castrucci Brian C. , Bradley Don W. , Thomas Craig W. , Hunter Edward L.
Published: May 2019

This chapter concludes the book and looks to the future. The teams and partnerships for health are clearly underway across the United States. From this point on, health care professionals and other agencies will all need to incorporate lessons learned and practices adopted into training programs, for all the health and related disciplines. Rather than learn what makes a difference in health, the aim should be to discover and then teach what makes a difference for some, and what works better for others. Training would be best carried out in teams, so the skills of teamwork and partnership are not just ideas, but practiced skills. The chapter concludes with this thought: health is something we can achieve together, but that no person or group can achieve alone.
Cognition
Authors: Ryle Cym Anthony
Published: May 2019

This chapter considers the fundamental characteristics of human cognition. It suggests that the capacity to make sense of the world involves a complex interaction between external realities and mental models. It considers that there are two complementary types of model—holistic representations, and models consisting of abstract componentsorganized in categories and hierarchies. It suggests that knowledge can be described as stable sets of models and their connections. It notes that reasoning is usually described as having two modes: Intuition operates rapidly and unconsciously; analysis requires sustained conscious effort. It argues that an absolute distinction between the two modes is artificial; intuition is usually the driving force, but effective reasoning depends on the synergy of both modes. It introduces the concept of bias and suggests that bias and intuition are inseparable.
Safeguards
Authors: Ryle Cym Anthony
Published: May 2019

This chapter refers to the 2015 report Improving Diagnosis in Health Care by the Institute of Medicine (IOM), which sets out the case for changes in healthcare organizations, professional education, and clinical practice. It notes that the insights in the IOM report are not new, but the pace of reform has been slow. It suggests that both the inertia of large organizations and professional and institutional resistance to change are implicated in this delay. It suggests that, despite methodological challenges, there is evidence that changes in clinical processes and professional reflective practice can improve diagnostic accuracy. It reiterates the importance of clinical skills, suggests modifications to medical record-keeping, proposes enhanced procedures for generating and verifying the differential diagnosis, and suggests that computerized diagnostic decision support has potential. It concludes that evidence and expert opinion support these changes, but acknowledges there will be a battle for hearts and minds.
Takotsubo syndrome
Authors: Lyon Alexander , Sweeney Mark , Omerovic Elmir
Published: May 2019

Takotsubo syndrome is an acute heart failure syndrome characterized by acute, reversible ventricular dysfunction, often in response to a physical or an emotional stressor. Takotsubo syndrome mimics acute myocardial infarction, presenting as chest pain or breathlessness, with electrocardiographic changes and troponin elevation, but with no explanatory coronary artery lesions on coronary angiography. It is increasingly commonly recognized in recent years as a cause of acute chest pain presentations. Although the majority of patients have a good prognosis following an episode of Takotsubo syndrome, it is becoming apparent that there is a significant burden of morbidity and mortality associated with this condition. The pathophysiology is likely to relate to an acute surge of catecholamines in response to stress, which results in multiple effects on the myocardium and vascular system. Currently, trial evidence is lacking, and management is based on clinical opinion, with optimal supportive care and avoidance of catecholamines as the mainstay of treatment in the acute phase. Non-catecholamine-related inotropes, such as levosimendan, have been reported in patients who require inotropic support, with anecdotal success. However, early consideration of referral to specialist centres for mechanical circulatory support is important in these severe cases. Evidence for medication to minimize recurrence is limited. Some observational data suggest angiotensin-converting enzyme inhibitors and beta-blockers may be beneficial in reducing mortality and preventing recurrence. However, there are no prospective data to inform treatment, and current management is guided by expert consensus.
Ventricular arrhythmias
Authors: Borggrefe Martin , Tülümen Erol , Brugada Josep
Published: May 2019

Ventricular arrhythmias are abnormal rhythms that originate from below the atrioventricular node. They include premature ventricular complexes, ventricular tachycardias, and ventricular fibrillation. Ventricular arrhythmias may occur in patients with structural heart disease (ischaemic heart disease, cardiomyopathies such as dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, etc.) or in patients with a structurally normal heart (genetic arrhythmia syndromes such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or as idiopathic ventricular tachycardias). Symptoms depend on the frequency, duration, and haemodynamic effects of the arrhythmia. They may be asymptomatic or may cause symptoms, such as palpitations, shortness of breath, chest discomfort, dizziness, or syncope, or may present with cardiac arrest. This chapter is focused on the role of antiarrhythmic drugs in the management of ventricular arrhythmias. The recommendations are based on the current guidelines of the European Society of Cardiology for the management of patients with ventricular arrhythmias.
Syncope
Authors: Ruiz-Granell Ricardo
Published: May 2019

Syncope results from sudden, transient, global cerebral hypoperfusion. Neurally mediated syncope, orthostatic hypotension, arrhythmic and cardiac syncope, and steal syndromes are the main pathophysiological forms of syncope. This chapter focuses on the treatment of neurally mediated syncope and orthostatic syncope, since other forms of syncope are reviewed elsewhere. In neurally mediated and orthostatic syncope, patient education and non-pharmacological measures are the mainstay of treatment, although benefits of pharmacological treatment are not so evident.
Liver disease
Authors: Hojs Nina , Ala Aftab , Banerjee Debasish
Published: May 2019

Cardiovascular disease in patients with liver disease, previously uncommon, is rising because of an increasing incidence of non-alcoholic fatty liver disease and better survival of patients with viral hepatitis, particularly hepatitis C. Liver dysfunction alters the pharmacokinetics and pharmacodynamics of many drugs, and hence careful use and dose adjustments are necessary. This chapter describes common cardiovascular conditions and the pharmacotherapy in patients with different liver diseases.
Genetics and genetic instability in cancer
Authors: Glaire Mark A. , Church David N.
Published: May 2019

"The Integrity"of the human genome is under continual threat from endogenous and exogenous mutagens, and as a result of errors introduced during DNA replication. As the lesions generated by these processes, if left uncorrected, may lead to deleterious mutations, cells employ several sophisticated mechanisms to both prevent and repair such genomic damage. Failure of these repair mechanisms, leading to genomic instability, is common in cancer, and has even been suggested to be a universal characteristic of malignancy. This chapter outlines these cellular processes and reviews the both the mechanisms and consequences of their dysregulation in human cancer. It also highlights the emerging evidence suggesting that genomic instability is an important determinant of tumour behaviour. Finally, it discusses the possibility that targeting genomic instability may benefit patients with genomically unstable tumours in the clinic.
Radiation as a carcinogen
Authors: Xiang Yan-Qun , Qian Chao-Nan
Published: May 2019

The data from animals, cell lines, and humans have led to the consensus of induction of carcinogenesis by ionizing radiation, especially at low-level doses, and that there is a dose–response relationship between radiation and cancer incidence. However, additional factors, including radiation type, dose rate, specific tissues, and animal species, also provide a contribution. The development of molecular biology research has helped explain the mechanism of radiation carcinogenesis, including pathway activation and chromosome alterations. Bystander effects and abscopal effects are additionally characteristics of radiation carcinogenesis. This chapter takes a look at how radiation, from both environment and industry, has contributed to cancer incidence over the past century.
Hormones and cancer
Authors: Abderrahman Balkees , Jordan V. Craig
Published: May 2019

Breast and prostate cancer cells are regulated by sex steroids through their nuclear receptors. These receptor-positive cells are a major component of both cancers. The discovery of sex-steroid receptor regulation in breast, uterine, and prostate cancer has provided the most important targets in cancer therapeutics. This targeted therapeutic approach resulted in the enhanced survival of millions of patients worldwide. The biology of sex-steroid receptor regulation is discussed and individual therapeutic strategies are described. The molecular biology of acquired drug resistance in breast and prostate cancer is compared. Information linking mutations of sex-steroid receptors with acquired drug resistance is noted, as this is influencing future drug discovery with selective oestrogen receptor downregulators (SERDs). Current clinical approaches to subvert acquired drug resistance in breast and prostate cancer are also summarized.
Cancer stem cells
Authors: Sweeney Connor , Quek Lynn , Gration Betty , Vyas Paresh
Published: May 2019

The concept of cancer stem cells (CSCs) emerged from our understanding of the way in which normal tissues are generated from multipotent stem cells. Regenerative tissues exhibit a cellular hierarchy of differentiation, which is maintained by stem cells. Evidence from experimental models has indicated that a similar hierarchy is seen in at least some cancers, where CSCs give rise to disordered and dysfunctional tissues, leading to disease. The CSC model proposes that tumours can be divided into at least two distinct populations. The stem cells are a specialized population of cancer cells with the unique property of long-term self-renewal that maintain the growth of the cancerous clone. These stem cells give rise to the second population of cells, which form the bulk of the tumour, and lack indefinite self-renewal. Recently, our understanding of CSCs has been refined through combining genetic, epigenetic, and functional models of tumorigenesis. Malignant transformation occurs as the result of sequential acquisition of genetic mutations. Capacity for self-renewal is essential for a clone to survive and progress to become cancerous. If an oncogenic mutation occurs in a cell that is incapable of self-renewal, the clone will become exhausted through differentiation. CSCs may survive anticancer chemotherapy and increasing evidence indicates their role in mediating treatment resistance and relapse. Therefore, strategies to eradicate cancers must effectively target the stem cells that maintain their growth. CSC-directed therapeutic strategies are currently being explored in experimental studies and clinical trials but reducing toxicity to normal tissue stem cells represents a significant challenge.
Cancer-associated stroma
Authors: Mesker Wilma , Tollenaar Rob
Published: May 2019

Tumorigenesis is a dynamic process. Research on cancer development and metastases focuses on the tumour ‘host’ interface, and in particular on the role of the stromal tissue. For a few decades now, it has been well established that the tumour-associated stroma affects cancer growth and progression. Fibroblasts of the stroma orchestrate the recruitment of immune cells to promote cancer growth. Moreover, the tumour stroma of each tumour is different in terms of quantity and of cellular composition. The tumour stroma has gained interest in the clinic with regard to patient prognosis and its potential to influence therapy response. Where cancer drug development traditionally focused on targeting the tumour cells, emphasis has now shifted towards the tumour microenvironment for the development of novel therapeutics.
Proteomics and metabolomics applications in cancer biology
Authors: Cutillas Pedro , Kessler Benedikt M.
Published: May 2019

Methodologies for proteomics and metabolomics are providing an unprecedented wealth of insights into cancer molecular biology. Although different techniques for proteomics and metabolomics exist, molecular snapshots in cancer metabolism and alterations in the proteome are mainly possible due to advancements in state-of-the-art mass spectrometry technologies. In this chapter, we describe examples of how proteo-metabolomic approaches are contributing to our understanding of the molecular biology of cancer progression, signalling, survival mechanisms, angiogenesis, and metastasis. We also provide an overview of the translational information (including biomarkers) and clinically relevant insights that proteomics and metabolomics strategies may be able to deliver, despite limitations and technical challenges that still exist. A better understanding of cancer progression and an improvement of clinical outcomes will benefit from precision medicine initiatives, in which appropriate application of proteo-metabolomic methods are key for their success.
Cancer biology through immunohistology
Authors: Pulford Karen , Gatter Kevin
Published: May 2019

Immunohistology is the microscopic study of cells and tissues using specific antibodies that bind to individual molecules expressed by the cellular and non-cellular components of the tissues. This branch of science is an essential link in the analysis and interpretation of data from high throughput genomic and proteomic technologies. Its use, both in the research and in the clinical arenas, has led to an increased understanding of cancer biology. This knowledge has also resulted in improvements in diagnosis, the provision of prognostic and predictive information, and highlighted the use of appropriate treatments. Furthermore, immunohistochemistry is a critical component in the search for personalized treatments. The ongoing advances in the availability of specific validated antibodies, continued improvements in staining and image analysis, and the integration of different technologies will ensure that immunohistochemistry becomes an even more essential tool in the study of cancer biology.
The clinical picture, creating diagnostic constructs, and causation
Authors: Huda Ahmed Samei
Published: May 2019

The clinical picture is the doctor’s interpretation based on what has happened to the patient and symptoms, signs, and results of investigations that are available to her. It is created by the interaction of causative factors as well as multiple cultural, interactive, and individual factors. The doctor matches the patient’s clinical picture with the diagnostic construct and the most common elements of an attached clinical picture. Diagnostic constructs based on similarity with the clinical picture may have clinical utility by accumulating information about likely outcomes and responses to treatments. Diagnostic constructs based on common mechanisms (such as changes in structure or processes) and/or causes have greater scientific validity and allow more reliable diagnostic investigations and better prospects of developing superior treatments. Most medical conditions are caused by a combination of causative factors. Proving a factor is causative is complex. One of the best known methods is Austen Hill’s framework. Conditions occur due to combinations of causes, characteristics, and contexts.
Early intervention for psychosis
Authors: Chen Eric Y.H. , Chan Sherry Kit-wa , Chang Wing-chung , Hui Christy Lai-ming , Lee Edwin Ho-ming , Lo Tak-lam , Chong Catherine Shiu-yin , Yeung Wai-song , Ng Roger Man-kin , Cheung Eric Fuk-chi , Chung Dicky Wai-sau , Poon Lap-tak
Published: May 2019

This chapter provides a comprehensive review of some of the key issues in early intervention for psychosis using the example of a population-based service in Hong Kong, for which a full range of data is available. The authors review a number of studies addressing: (i) the DUP and its associated factors in Hong Kong; (ii) whether DUP can be changed by public awareness programmes; (iii) the immediate outcome of a two-year early intervention programme; (iv) whether the improved outcome can be sustained after the programme, over ten years; and (v) whether receiving one more year of intervention could further improve the outcome. The results show that even in a low-resource setting in Hong Kong, significant improvements in functioning can be achieved, with reduced hospitalization and reduced suicide. A long-term follow-up study observed that these effects are sustainable over ten years. Further improvements can be attained by providing longer intervention to a group that responded less favourably. However, these enhancements proved more difficult to sustain. Together, these suggest a possible dose effect on the impact and sustainability of early intervention for psychosis. Future work should aim to clarify the role of increased intervention resources such as manpower and a more defined specific programme (e.g. coaching, exercise, cognitive interventions). More work is also required to investigate the culture of early psychosis services (such as a hope-centred culture), as well as how more personalized needs of individual patients can be met.
Where next for early intervention programmes?
Authors: Bhugra Dinesh , Ventriglio Antonio , Chen Eric Y.H.
Published: May 2019

Early intervention treatments and approaches are reaching across the globe. There is no doubt though that these services are a low priority, especially in countries where adequate resources are not available. The practice of psychiatry has, in the last 50 years, moved from asylums, to community mental-health teams, to home treatments and early intervention. There appears to be an increasing body of evidence to suggest that early interventions can work in reducing the duration of untreated illness and aiding better recovery, but this needs to be researched in conditions other than psychoses, for which evidence is strong. This chapter provides recommendations for researchers, clinicians, and policymakers. All these recommendations are based on the principle of equity between physical and mental illness, and better integration between psychiatric services and social care and between primary care and psychiatric services.
Assessment
Authors: Davies Andrew
Published: May 2019

Successful management of breakthrough pain depends on adequate assessment and adequate re-assessment. The assessment of pain primarily depends on basic clinical skills, that is, taking a detailed history and performing a thorough examination. Inadequate assessment may lead to ineffective or even inappropriate treatment. The objectives of assessment are to determine the aetiology and pathophysiology of the pain, and factors that indicate or contraindicate particular treatments. It is important to differentiate patients with uncontrolled background pain experiencing transient exacerbations of that pain, from patients with controlled background pain experiencing episodes of breakthrough pain. Inadequate reassessment may lead to the continuance of ineffective or inappropriate treatment. A number of different tools have been developed for the assessment of cancer-related pain. Those focusing on breakthrough pain include: the Breakthrough Pain Questionnaire, the Alberta Breakthrough Pain Assessment Tool, and the Breakthrough Pain Assessment Tool.
General principles of management
Authors: Davies Andrew
Published: May 2019

Breakthrough pain is not a single entity, but a spectrum of very different entities. In most cases, the underlying cause of the pain is a direct effect of the cancer. There is emerging evidence to suggest certain oncological treatments may be effective in managing certain types of breakthrough pain. Optimal treatment of breakthrough pain depends on a variety of pain-related factors. Optimal treatment of breakthrough pain depends on a variety of patient-related factors. Avoidance or treatment of precipitating factors should be considered in patients with incident-type breakthrough pain. Movement-related/incident pain, secondary to metastatic bone disease, is a common phenomenon. Modification of the background analgesic regimen has been shown to be a useful approach in managing breakthrough pain. Multimodal approaches are often required. The cornerstone of the management of breakthrough pain episodes is the use of so-called rescue medication. The management of end-of-dose failure involves modification of the background analgesic regimen. The use of rescue medication depends on the type of breakthrough pain and acceptance depends on factors such as the route of administration of medication.
Oral and parenteral opioids
Authors: Davies Andrew
Published: May 2019

Rescue medication is taken as required, rather than on a regular basis. Oral opioids have a defined role in the management of breakthrough pain, but will only be effective if it is an opioid-responsive pain. Although the oral route is generally effective in the management of background pain, it is often less effective in the management of breakthrough pain. The ‘correct’ dose of rescue medication is the dose that provides maximal analgesia with minimal side effects. The pharmacokinetic profile of many orally delivered drugs does not mirror the temporal characteristics of many breakthrough pain episodes. The rectal administration of opioids is well established, although is now uncommon in day-to-day clinical practice. The intravenous route of administration is primarily used in secondary care settings. Intravenous/subcutaneous opioids provide rapid onset of analgesia, but are generally not practical in outpatient settings.
Other therapeutic interventions
Authors: Davies Andrew
Published: May 2019

Breakthrough pain is a heterogeneous condition. Non-pharmacological interventions include: rubbing/massage, application of heat, application of cold, distraction techniques, relaxation techniques, hypnotherapy/hypnosis, transcutaneous electrical nerve stimulation (TENS), and acupuncture. But most of these have not been subject to rigorous study. Anaesthetic interventions are usually utilized in patients with uncontrolled background pain, but they are sometimes used in patients with uncontrolled breakthrough pain. A variety of different techniques are available. Peripheral (local anaesthetic) nerve blockade and neuraxial analgesia delivery may be used. Non-surgical stabilization, surgical stabilization, corticosteroid instillation, alcohol instillation, phenol instillation, cryoablation, radiofrequency ablation, laser ablation, cementoplasty/vertebroplasty, balloon kyphoplasty, and MR-guided focused ultrasound surgery are other strategies, most of which have not been subject to rigorous scientific investigation. Non-opioid analgesics are a diverse group of drugs. Non-opioid analgesics may have a role in the management of breakthrough pain. Data on the use of most non-opioid analgesics is limited.
On the relative bias of void tracers in the Dark Energy Survey
Authors: Pollina G , Hamaus N , Paech K , Dolag K , Weller J , Sánchez C , Rykoff E S , Jain B , Abbott T M C , Allam S , Avila S , Bernstein R A , Bertin E , Brooks D , Burke D L , Carnero Rosell A , Carrasco Kind M , Carretero J , Cunha C E , D’Andrea C B , da Costa L N , De Vicente J , DePoy D L , Desai S , Diehl H T , Doel P , Evrard A E , Flaugher B , Fosalba P , Frieman J , García-Bellido J , Gerdes D W , Giannantonio T , Gruen D , Gschwend J , Gutierrez G , Hartley W G , Hollowood D L , Honscheid K , Hoyle B , James D J , Jeltema T , Kuehn K , Kuropatkin N , Lima M , March M , Marshall J L , Melchior P , Menanteau F , Miquel R , Plazas A A , Romer A K , Sanchez E , Scarpine V , Schindler R , Schubnell M , Sevilla-Noarbe I , Smith M , Soares-Santos M , Sobreira F , Suchyta E , Tarle G , Walker A R , Wester W ,   (DES Collaboration)
Published: May 2019

Luminous tracers of large-scale structure are not entirely representative of the distribution of mass in our Universe. As they arise from the highest peaks in the matter density field, the spatial distribution of luminous objects is biased towards those peaks. On large scales, where density fluctuations are mild, this bias simply amounts to a constant offset in the clustering amplitude of the tracer, known as linear bias. In this work we focus on the relative bias between galaxies and galaxy clusters that are located inside and in the vicinity of cosmic voids, extended regions of relatively low density in the large-scale structure of the Universe. With the help of mock data we verify that the relation between galaxy and cluster overdensity around voids remains linear. Hence, the void-centric density profiles of different tracers can be linked by a single multiplicative constant. This amounts to the same value as the relative linear bias between tracers for the largest voids in the sample. For voids of small sizes, which typically arise in higher density regions, this constant has a higher value, possibly showing an environmental dependence similar to that observed for the linear bias itself. We confirm our findings by analysing data obtained during the first year of observations by the Dark Energy Survey. As a side product, we present the first catalogue of three-dimensional voids extracted from a photometric survey with a controlled photo-z uncertainty. Our results will be relevant in forthcoming analyses that attempt to use voids as cosmological probes.
Examining the radius valley: a machine-learning approach
Authors: MacDonald Mariah G
Published: May 2019

The ‘radius valley’ is a relative dearth of planets between two potential populations of exoplanets, super-Earths and mini-Neptunes. This feature appears in examining the distribution of planetary radii, but has only ever been characterized on small samples. The valley could be a result of photoevaporation, which has been predicted in numerous theoretical models, or a result of other processes. Here, we investigate the relationship between planetary radius and orbital period through two-dimensional kernel density estimator and various clustering methods, using all known super-Earths (R < 4.0RE). With our larger sample, we confirm the radius valley and characterize it as a power law. Using a variety of methods, we find a range of slopes that are consistent with each other and distinctly negative. We average over these results and find the slope to be $m=-0.319^{+0.088}_{-0.116}$. We repeat our analysis on samples from previous studies. For all methods we use, the resulting line has a negative slope, which is consistent with models of photoevaporation and core-powered mass-loss but inconsistent with planets forming in a gas-poor disc