The cellular events that contribute to tissue healing of non-sterile wounds to the skin and ischaemic injury to internal organs such as the heart share remarkable similarities despite the differences between these injury types and organs. In adult vertebrates, both injuries are characterised by a complex series of overlapping events involving multiple different cell types and cellular interactions. In adult mammals both tissue-healing processes ultimately lead to the permanent formation of a fibrotic, collagenous scar, which can have varying effects on tissue function depending on the site and magnitude of damage. Extensive scarring in the heart as a result of a severe myocardial infarction contributes to ventricular dysfunction and the progression of heart failure. Some vertebrates such as adult zebrafish, however, retain a more embryonic capacity for scar-free tissue regeneration in many tissues including the skin and heart. In this review, the similarities and differences between these different types of wound healing are discussed, with special attention on recent advances in regenerative, non-scarring vertebrate models such as the zebrafish. Wound healing in the skin, for example, can repair serious and extensive surgical and traumatic injuries even in a non-sterile environment. Similarly, serious ischaemic injury, where occlusion of blood vessels results in a region of tissue experiencing a transient loss of oxygen within internal organs such as the heart, can be effectively repaired. The long-term consequences of these effective healing regimes can, however, be further detrimental to the function of these tissues and has varying effects on organ function. Although our ability to repair serious tissue trauma remains relatively remarkable, mammals lose any significant ability to regenerate lost cells and tissues or to heal in a scar-free fashion during early post-natal periods.12 Due to the non-sterile nature of injuries to the skin, many critical coordinating roles have been suggested for inflammatory cells, which are crucial for fighting external pathogens (described below).The skin serves as the primary defence against external pathogen invasion and environmental extremes and regulates body homeostasis via control of the rate of water loss and temperature regulation; therefore, any breach of this primary defence must be rapidly repaired to re-establish this essential barrier function. Differing mechanisms of cutaneous wound healing exist between vertebrate species and between developmental and adult stages and these have been extensively studied allowing the complex interplay of events and cellular interactions that allow for tissue repair to take place to be established Figs. –3. Studi14 The wound healing response to ischaemic injury to internal organs follows a similar programme of cellular events to that of the skin and often results in fibrosis and scarring and a concomitant reduction in tissue function and this process is particularly detrimental to the function of the heart as a mechanical organ. Accordingly, cardiovascular disease remains the biggest killer globally and coronary artery disease accounts for a significant proportion of those deaths.14 On a positive note, however, advances in surgical interventions, rapid treatment regimens and increased public understanding have vastly reduced the mortality rate for patients suffering an acute MI.16 Despite these advances, the consequences of a severe MI can still include the formation of a permanent scar within the myocardium, limiting the contractility of the ventricle, leading to adverse ventricular remodelling, reducing the capacity to pump blood around the body and increased susceptibility to developing heart failure.17 Scar formation within the ventricular myocardium can also lead to progressive degeneration of the surrounding musculature, exacerbating the injury and ultimately leading to an inevitable progression to heart failure. Early heart failure can often be managed with combined medication to reduce blood pressure, relax vessels and reduce heart rate, but more severely affected patients can require more significant treatments including the implantation of a left ventricular assist device, and, for the most severe cases, there is still no curative treatment apart from complete heart transplant. Because of the worldwide prevalence of coronary heart disease and heart failure and the urgent need for improved treatments following extensive cellular damage due to ischaemic injury, therapeutic interventions to replace cardiomyocytes and modify the adverse cellular microenvironment of a scar are under intense investigation and could be of enormous clinical benefit.16By contrast, ischaemic injury to internal organs such as the heart occurs in a sterile environment, but elicits a similar programme of cellular events to that observed following skin injury, triggered primarily by myocardial cell death Fig. . Chronic20 In recent years, zebrafish have become an important model organism for studying human disease.21 This vertebrate model shares a high degree of genetic homology with humans, they are small, easily maintained, transparent allowing sophisticated live imaging, genetically tractable  and are regenerative in multiple organs including the skin and heart allowing detailed cellular level analysis of many disease states. The regenerative capacity of adult zebrafish was first described in the spinal cord and caudal fins with the latter involving cutaneous repair and regeneration alongside other tissues, for example, bone.23 A thorough understanding of the cellular basis for this regenerative capacity could, therefore, hold the key to improved tissue healing therapeutics of the future.Studying the remarkable ability of fish and amphibia to regenerate tissues following traumatic or ischaemic injuries, including replacement of multiple different cell types such as mature cardiomyocytes as well as resolution of interstitial scarring, may hold promise for providing new therapeutic avenues.25 By introducing multiple wounds, several biological replicates can be obtained from the same animal as well as control and test samples.26 Similarly, methods for introducing partial  and full-thickness skin injuries to the flank of adult zebrafish using a dermatological laser have been described  and other cell types at the site of injury Fig. .32 This ved Fig.  followin38 Additionally, ischaemic injury results in activation of the epicardium, endocardium and myocardium and induces the activation of numerous early response genes including c-fos, Hsp70, c-jun and Erg-1,42 many of which are also upregulated in response to cutaneous injury.45 These early response genes are thought to be protective and induce subsequent crucial wound healing responses, particularly the inflammatory response.41 Indeed, immune cells respond rapidly to injury signals and very early damage/recruitment signals for inflammatory cells, including hydrogen peroxide and calcium, have recently been identified in zebrafish and Drosophila.48By comparison, ischaemic injury in the heart does not result in excessive bleeding or the formation of a platelet-rich clot, although endothelial damage can still activate the coagulation cascade resulting in thrombin accumulation and fibrin deposition in the myocardium in rodents and zebrafish.7 Indeed, partial-thickness wounds, induced by removal of a single scale, are re-epithelialized within an hour  and transforming growth factor-β (TGFβ) signalling.7 Similarly, following fin resection the surrounding epidermis is mobilised and the epithelial gap is closed within hours.18 By contrast, the epithelial layer enveloping the entire heart, the epicardium, is not mobilised to recover the wounded area with epithelium for several days, even in adult zebrafish.49 This layer does, however, play several specialist and crucial roles in subsequent cardiac injury responses (see below)In mammalian cutaneous wound healing, the process of re-epithelialization is considered a relatively late phase of the repair response only commencing after a fibrin clot has formed and the subsequent phases of healing have begun , suggesting additional complexity for the balance of neutrophil function or tissue-specific neutrophil behaviours that have not yet been fully deciphered. Recent reports have also indicated roles for different neutrophil polarisation phenotypes in the response to MI, although the true roles of these different subsets are less well established than for macrophages (see below).70 Resolution of activated neutrophils is thought to be a critical stage of successful healing. For many years, the dogma has been that neutrophils undergo apoptosis at the site of injury and are cleared by phagocytic macrophages.73 However, more recent reports, especially using the live imaging advantages of zebrafish, have demonstrated that neutrophils can also survive the early inflammatory phase of an injury and then undergo reverse migration from the injured tissue back into the peripheral blood and that this is an important inflammation resolution mechanism.77 Further studies will be required to determine the functional and phenotypic effects this reverse migration process has on the surviving neutrophils and zebrafish would be an advantageous model in which to decipher this.76Supporting potential predominant negative effects of neutrophils on tissue repair, in the heart studies in adult mice that reduce the number of neutrophils responding to models of MI, demonstrate a reduction in the extent of myocardial injury.80 but other immune cells including mast cells and dendritic cells of the innate immune system and B and T cells of the adaptive immune system are also present in these tissues during homeostasis.80 These tissue-resident cells can act as early responders as they are already present in the injured tissue and can respond rapidly, although additional cells are often recruited from the peripheral blood . Precise and important roles are just starting to be assigned for these resident populations. For example, reduced number of activated (degranulating) mast cells is linked to decreased scarring and improved collagen distribution following wounding in mice,84 partly through reduced accumulation of myofibroblasts.85 Mast cells are present in regenerative models such as zebrafish,86 but their role and the roles of other tissue-resident populations in tissue regeneration has not yet been determined.Whereas neutrophils exist as a patrolling cell type in the bloodstream and are recruited to the site of injury, other innate immune cell types exist as permanently tissue-resident cells. Macrophages (discussed below) make up the largest proportion of tissue-resident cells in the skin and heart,89 Macrophages exist either as tissue-resident cells, both within the skin and heart, or as a population of circulating monocytes in the blood.90 Arguably, tissue-resident macrophages could be considered as early responders as they respond to local injury very quickly; however, in adult mammals, it is recruited circulating monocytes that are thought to be the major effectors of downstream tissue injury responses including the induction of scar formation.92 Indeed, two different origins have been proposed for macrophages, either embryonically derived, which tissue-resident cells are enriched for, or adult bone marrow derived, which mainly contribute to the circulating monocyte population.94 Resident cardiac macrophages have been shown to be a self-maintaining population via local proliferation with a turnover of approximately 1 month during homeostasis.93 However, these cells rapidly die or migrate to hematopoietic organs following models of MI93 and are then replaced by circulating monocytes, which, again, become self-maintaining once the heart has returned to steady-state after injury.93The main innate immune cell type attributed to crucial wound healing functions is the macrophage. A huge array of studies have described a plethora of different macrophage phenotypic states that can have varying roles during homeostasis, tissue repair and disease.95 These findings extend those of previous findings in spontaneous liver regeneration in rodents.96 Macrophages are also required for cardiac and fin regeneration in zebrafish with loss of this cell type resulting in reduced regenerative cell proliferation.100 Most recently, it has been shown that differences in macrophage expression profiles may contribute to zebrafish regenerative potential.100 Interestingly, recent reports suggest that macrophage origin can determine the regenerative capacity of these cells with embryonic-derived macrophages (i.e. tissue-resident) being more anti-inflammatory and pro-angiogenic and so playing more regenerative roles than their adult bone marrow-derived monocyte counterparts, which are more pro-inflammatory in the heart.92 This may impact on regenerative ability as inflammation following injury is mediated predominantly by monocytes.92 However, subsequent findings suggest that this may be too simplistic and that more pro-inflammatory as well as pro-regenerative macrophage subsets may exist and that differentiation of these is governed by their local microenvironment.101 It is becoming clear that macrophage subtypes have vital and somewhat contradictory roles during tissue repair and that the careful balance of these different phenotypic states will be crucial for allowing full tissue regeneration.104 Macrophage subsets have recently been identified in zebrafish105 and suggested to contribute to aspects of larval fin regeneration and wound angiogenesis (see section 'Re-vascularisation' below),107 but further investigation will be required to determine the origin of these different subtypes and if pro-regenerative populations are enriched following skin or cardiac injury in fish, contributing to the regenerative capacity of these organs.Studies in neonatal mice, which are also capable of full cardiac regeneration for a limited time period, have recently shown that macrophages are crucial for allowing this regenerative potential.113 and these cells may influence macrophage phenotype.109 In particular, Foxp3+ regulatory T cells (Treg) have been proposed to promote alternative activation of macrophages post MI and that this process is crucial for correct mammalian cardiac repair.109 Multiple different T cell subtypes have been shown to contribute to mammalian tissue injury, but adaptive immunity has been relatively under-studied in regenerative models such as zebrafish. Recent reports have indicated evolutionary conserved roles for Foxp3 as a master regulator of Treg differentiation114 and verified the presence of different T cell populations in zebrafish.115 Indeed, very recent work has demonstrated a requirement for zebrafish Treg cells in promoting regeneration in a number of organs including the heart via secretion of organ-specific regenerative factors, namely Ntf3 in the spinal cord, Nrg1 in the heart and Igf1 in the retina in a Foxp3-dependent manner.116 Further work will be required to fully decipher the cellular differences between mammalian and zebrafish T cells that govern regenerative capacity.T cell populations have recently been suggested to play a role in the response to cardiac and cutaneous tissue injury during later stage responsesinterleukin 1 beta (il1b) expression, terminating the early pro-inflammatory response and allowing regenerative blastemal cells to survive following fin amputation.104 Changes in macrophage phenotype have been linked to inflammation resolution during tissue injury in mammals,109 but this fails to induce regeneration. The identification of pro-regenerative factors in macrophages of regenerative species such as zebrafish could provide areas of further investigation and therapeutic development.As discussed above, macrophages can exist as a spectrum of different activation states including as anti-inflammatory/pro-resolution mediators. Indeed, studies in zebrafish have shown that macrophages are crucial for regulating inflammatory 119 In adult zebrafish, rapid re-vascularisation following cryoinjury to the heart is required for cardiac regeneration and VEGF-A is critical for this process.120 Indeed, a recent report suggests that rapid administration of synthetic VEGF-A to the ischaemic heart improved cardiac function and long-term survival in a mouse model of MI.121 In both adult mammals and adult zebrafish, it is the epicardium of the heart that is thought to provide these pro-angiogenic factors.122 Indeed, activation of the epicardium has been shown to be crucial for regeneration to take place, dedifferentiating and contributing to new cell types including perivascular cells . Interestingly, a recent report suggests a vital role for pro-inflammatory macrophages in mediating wound angiogenesis in a larval zebrafish wound model via control of anti-angiogenic neutrophils and delivery of VEGF-A,107 further supporting the critical role of macrophage subtypes and inflammatory control on disparate aspects of the tissue healing response. Another recent report also suggests a direct role for vegfaa in driving adult zebrafish heart regeneration by enhancing cardiomyocyte proliferation as well as inducing neo-vascularisation.123Damage signals released at the site of tissue injury also induce the formation of new blood vessels and this is a crucial response to both cutaneous wounds and ischaemic injury to the heart, restoring an oxygenated blood supply and providing nutrients for growth. Multiple growth factors are known to be critical for inducing neo-angiogenesis from existing ECs including vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor.125 In zebrafish and neonatal mouse hearts, cholinergic neurons are required for regeneration following ischaemic and surgical resection of the ventricle with pharmacological and mechanical removal of these neurons resulting in significantly reduced cardiomyocyte proliferation and increased scarring.124 In adult mice, lineage tracing identifies peripheral glial-derived cells present in the granulation tissue of cutaneous wounds.125 These glial-derived cells are capable of de-differentiation and proliferation and secrete paracrine factors such as TGF-β to induce myofibroblast formation and wound closure.125 Studies such as these demonstrate the importance of other cell types in the wound microenvironment for promoting correct cardiac muscle and dermal replacement.Recent reports have characterised the re-establishment of neuronal networks following cutaneous and cardiac injury and identified crucial roles for this process in driving wound healing and regeneration.10 Fibroblasts, and subsequent differentiated myofibroblasts, are considered to be the major cell type contributing to the production of extracellular scar material in adult mammals.127 In adult zebrafish, fibroblasts accumulate beneath a full-thickness skin wound to form a granulation tissue similar to what is observed in mammals  results in the activation of interstitial fibroblasts inducing proliferation, collagen production and differentiation into myofibroblasts in mammals and zebrafish  occurs after partial or complete ablation during skin wounding (Fig. 6 Interestingly, a requirement for cells residing in hair follicles in adult mice and between scales in adult zebrafish has been described to allow for correct and timely re-epithelialisation.138In adult mammals, there is limited regenerative response to either acute skin injury or ischaemia and both generally result in the formation of a permanent collagenous scar. Furthermore, full-thickness skin wounds in adult mammals are characterised by a failure in appendage regeneration, for example, hair follicles and sebaceous glands, although a recent study has demonstrated a role for macrophages in inducing hair follicle neogenesis after wounding.ing Fig. .6 Intere139 This study suggests that a common, genetically controlled programme can contribute to cellular plasticity and regenerative potential in diverse tissues providing the exciting possibility to uncover genetic pathways that could drive regeneration in any affected organ.139Intriguingly, a recent report has demonstrated a regulatory genetic element activated by TGFβ/Activin-β activity, which is transiently activated following both fin resection and cardiac ischaemic injury in adult zebrafish.The tissue injury response to acute cutaneous damage or to ischaemic injury to internal organs such as the heart elicit similar programmes of cellular events ultimately leading to fibrosis and scarring in adult mammals. Alternative vertebrate models such as adult zebrafish also exhibit similar injury responses, but are ultimately capable of complete regeneration of these damaged tissue sites. A thorough understanding of the similarities and differences between these regenerative and non-regenerative species can only aid the drive to induce endogenous regenerative potential in adult mammals. Additionally, the identification of common regenerative programmes between tissues and injury types could lead to universal therapeutics in the future, which could drive regeneration in any damaged tissue.


Mechanisms by which acute and chronic exercise promote cardiometabolic health presents some of the latest ideas, arguments, and evidence from investigations at the molecular level to macroscopic observations on whole animals including humans.Exercise promotes cardiometabolic wellness and is effective in the prevention and treatment of cardiovascular disease, diabetes, and obesity-related conditions. Despite unequivocal evidence of the cardiovascular benefits conferred by exercise, the mechanisms by which the cardiovascular system adapts to exercise remain poorly understood. This Research Topic on Nystoriak and Bhatnagar which highlights the classic observations of decreased cardiovascular mortality and risk of developing cardiovascular disease in physically active individuals. These epidemiological observations are supported by robust physiology data on exercising individuals having lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile—all of which are mechanistically supported by animal models of exercise. The authors continue with a “more is not always better” opinion where even though moderate levels of exercise have been found to be consistently associated with a reduction in cardiovascular disease risk, there is evidence to suggest that continuously high levels of exercise, such as marathon running, could have detrimental effects on cardiovascular health. Certainly, continued work is needed to identify the specific dose response relationship between the extent and duration of exercise and the reduction in cardiovascular disease risk and mortality.We begin our compilation with a comprehensive review of the cardiovascular effects and benefits of exercise by Pinckard et al. on how exercise enhances inter-organ communication through the release of myokines and their role in exercise-mediated adaptation. Myokines are chemical messengers that function in an autocrine, paracrine, or endocrine manner to influence crosstalk between different organs including skeletal muscle, liver, and adipose tissue. They are of great interest with regards to cardiovascular health because the well-known protective actions of exercise on cardiovascular function are at least partially mediated by increased secretion of myokines. The myokines reviewed include interleukin-6, myonectin, follistatin-like 1, and neuron-derived neurotrophic factor and how recent work has focused on potential therapies using exercise-induced myokines as a therapeutic strategy to improve cardiovascular function in patients who are unable or unwilling to exercise.The collection continues with a review by Zakari et al. where the authors distinguish between the inherent capacity to perform, as compared to adaptive responses to active exercise training in relation to cardiovascular health and peripheral artery disease. The position of “exercise as medicine” has been advocated in the broad context as general medical care, but also in the specific context as a therapeutic, to be considered in much the same way as other drugs. As there are non-responders to many medications, there also are non-responders to exercise; individuals who participate but do not demonstrate appreciable improvement/benefit. In this review, the authors highlight the settings where the stress induced by exercise may aggravate an underlying condition, rather than attenuate chronic disease.Certainly, there is ample evidence that regular exercise and increased physical activity are critical for health but are there limitations to exercise benefits in disease states such as peripheral artery disease? A compelling perspective is offered by Chuong et al. ask the important question of whether or not changes in innate immunity underlie the cardiovascular benefits of exercise? Despite the immunoregulatory effects of exercise, the underlying cellular mechanisms and signaling pathways that promote cardiovascular health remain unknown. Identifying key determinants by which exercise modulates inflammatory responses will likely offer new therapeutic targets for the treatment of cardiovascular disease. Given that the innate immune system is responsible for initiating most inflammatory responses and causally contributes to cardiac pathology and repair, the opinion is presented that neutrophils and macrophages are critical in mediating the cardioprotective effects afforded by exercise.Although exercise promotes numerous salutary effects on the cardiovascular system, several human studies have concluded that the beneficial effects of regular exercise are attributable to a decrease in chronic inflammation and inflammatory mediator production. These clinical findings are complemented by animal studies that report regular moderate intensity exercise decreases the risk for chronic disease development through modification of the immune system. Given this backdrop, Fulghum and Hill discuss how exercise affects cardiac structure and function and how exercise-induced changes in metabolism regulate cardiac adaptation. They review the latest evidence on how exercise elicits an adaptive, beneficial form of cardiac remodeling that involves cardiomyocyte growth and proliferation. Conversely, the authors highlight how chronic levels of extreme exercise may increase the risk for pathological cardiac remodeling or sudden cardiac death. The mechanistic underpinnings of how acute and chronic cardiac adaptations to exercise involve the concept of metabolic periodicity, which appears important for regulating mitochondrial quality and function, for stimulating metabolism-mediated exercise gene programs and hypertrophic kinase activity, and for coordinating biosynthetic pathway activity.While the periodic metabolic stress imposed by regular exercise appears fundamental in driving cardiovascular tissue adaptation, it remains to be fully elucidated as to how different types, intensities, or durations of exercise elicit different levels of metabolic stress and promote tissue remodeling. Shanmugam et al. tested the hypothesis that exercise-based activation of Nrf2, and its transcriptional regulation of antioxidants, protects the heart from isoproterenol-induced myocardial damage and dysfunction in mice. Isoproterenol is a beta-adrenergic receptor agonist and has been widely accepted as an inducer of pathologic cardiac remodeling in experimental animals by generation of excessive ROS, leading to alterations in cardiac metabolism and progressive myocardial injury. These data provide evidence for exercise-mediated enhancement of Nrf2 activity and the prevention oxidative stress mediated myocardial injury.Nuclear factor erythroid 2 like 2 (Nrf2) is the major stress response transcriptional regulator for antioxidant genes. Declined Nrf2-antioxidant signaling leads to accumulation of reactive oxygen/nitrogen species (ROS/RNS) and oxidative stress, which is either causally linked or associated with numerous health problems including diabetes and cardiovascular disease. Thus, targeting endogenous antioxidant defense mechanisms such as Nrf2 to enhance cytoprotection may be efficacious. Importantly, sustained physical activity or routine exercise training upregulates Nrf2-dependent cytoprotective targets in human skeletal muscle and mouse heart and provides a non-pharmacological strategy for combatting ROS/RNS at the cellular level. In this collection's only original research article, Mey and Haus continue the series with a mini review on the phenomenon of dicarbonyl stress and glyoxalase-1 downregulation and they ask what implications reduced GLO1 may have for insulin resistance, type 2 diabetes (T2D) and cardiovascular disease. The authors also emphasize the therapeutic potential for exercise intervention in restoring healthy GLO1 expression. Glyoxalase-1 (GLO1) is a ubiquitously expressed cytosolic protein which detoxifies reactive dicarbonyl metabolites and thus a consequence of reduced GLO1 protein expression is accumulation of carbonyl-modified proteins or dicarbonyl stress, which is elevated in obesity, insulin resistance and T2D. Recent work has identified the therapeutic potential of novel natural agents as a GLO1 inducer, which resulted in improved whole-body metabolism in obese adults. Given skeletal muscle is a major contributor to whole-body glucose, lipid, and protein metabolism, such GLO1 inducers may act, in part, through mechanisms in skeletal muscle. Current investigations examining the specificity of dicarbonyl stress and GLO1 biology in human skeletal muscle are lacking and this minireview summarizes the existing human literature examining skeletal muscle GLO1 and highlights the emerging therapeutic concepts for GLO1 gain-of-function in conditions such as insulin resistance and cardiometabolic disease.As mentioned above, Nrf2 is a transcriptional regulator for antioxidant genes. One such gene, GLO1 , when downregulated, has been implicated in the pathology of complications associated with diabetes and perhaps a novel mechanism responsible for the development of insulin resistance. Solomon et al. conclude the series with a compelling argument that interrupting sitting time in the postprandial period is a desirable strategy to optimize blood glucose control and maximize cardiometabolic health. Experimental evidence demonstrates that interrupting inactivity (sitting time) with physical activity breaks is a successful approach for managing blood glucose levels but recommendations concerning the optimal time to interrupt sitting do not yet exist. Since postprandial hyperglycemia is an independent cardiovascular risk factor and since we spend many hours each day in a postprandial state, timing the interruption of sitting with physical activity to minimize postprandial fluctuations in blood glucose is a sensible approach to maximize cardiometabolic health. Approaches such as this will help curb the increasing incidence of diabetes and thereby improve cardiovascular health, longevity, and quality of life for the increasingly inactive global population.It is not a new message that physical activity helps optimize blood glucose control, improve cardiovascular health, and reduce cardiovascular-related mortality, but increased awareness of the dangers of inactivity and refinement of physical activity advice is essential. While the benefits of increased physical activity are clear, what kind of exercise is best and when is the right time to move? To fully test our understanding of exercise dose on mitigating hyperglycemia, detailed studies of differential exercise time and intensity are needed. It is our sincere hope that this Research Topic will not only provide readers with new insights and viewpoints on the issue of exercise and cardiometabolic health, but will also stimulate novel ideas, experiments, and further advances in this research field.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dreams and psychosis share several important features regarding symptoms and underlying neurobiology, which is helpful in constructing a testable model of, for example, schizophrenia and delirium. The purpose of the present communication is to discuss two major concepts in dreaming and psychosis that have received much attention in the recent literature: insight and dissociation. Both phenomena are considered functions of higher order consciousness because they involve metacognition in the form of reflective thought and attempted control of negative emotional impact. Insight in dreams is a core criterion for lucid dreams. Lucid dreams are usually accompanied by attempts to control the dream plot and dissociative elements akin to depersonalization and derealization. These concepts are also relevant in psychotic illness. Whereas insightfulness can be considered innocuous in lucid dreaming and even advantageous in psychosis, the concept of dissociation is still unresolved. The present review compares correlates and functions of insight and dissociation in lucid dreaming and psychosis. This is helpful in understanding the two concepts with regard to psychological function as well as neurophysiology. SeveralBy contrast, emotionality in normal REM sleep dreams resembles what is known as “unconscious affect” , referriIn normal REM sleep dreams, the VPFC is down-regulated, allowing for unconscious affect to prevail . By cont3. This method has previously been successfully used to induce lucidity in dreams of healthy young adults  recently tried to apply gamma frequency band electrical stimulation of the fronto-temporal parts of the brain in an acute psychotic patient with acoustic hallucinationsg adults , resultiWhile this particular case study must not be over-generalized, it shows that (1) insight can indeed be triggered via mechanisms akin to lucid dreaming and (2) that increased insight and dissociative thought may not automatically effect positive emotionality. Whereas in non-psychotic patients, insight and dissociative are linked with reduced negative emotions, the opposite may apply to psychotic patients see also .In our study of EEG tracings during lucid dreaming, the most striking finding was that lucidity was accompanied by an increased activation of the frontal lobes of the brain . Example 1: Intentional properties such as directing awareness and performing plot control are significantly enhanced in lucid dreaming as compared to either non-lucid dreaming or psychosis Table .In dreams and psychosis alike, internally generated stimuli that rise to consciousness are interpreted as external signals generated by the environment. Weakening of abstract thinking and loss of metacognitive thought  appear to determine impaired reality testing in both conditions, suggesting a crucial role for the frontal lobes. In lucidity, reactivation of these cerebral regions during REM sleep can explain insight into the hallucinatory nature of one’s experience. Intriguingly, frontal lobe processing is known to play a critical role within the complex neural circuitry underlying lack of insight in psychotic disorders . DisruptRegarding maturational influences, clinically relevant symptoms of the so-called major psychoses are known to emerge during adolescence or early adult life. Neurodevelopmental hypotheses converge on abnormal pruning or apoptosis of prefrontal synapses and fibers as a possible pathogenetic mechanism for the complex alterations in higher functions found in these disorders .Given this type of experimental evidence, it has been speculated that dream lucidity might prove beneficial in fostering insight in psychotic patients see . Indeed,per se seems to be more complex. Our experimental data indicate that frontal lobe activation in consciousness-relevant fast frequencies may be responsible for the perceived changes in dream perception, such as awareness of awareness and dream plot control. Regarding dissociation, we look forward to future research on its physiological correlates and its modulating function in lucid dreams as well as in psychosis.In conclusion, it appears that while lucid dreaming bears high similarity to insightful psychosis, lucid dreaming All authors were involved in the preparation of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Stress is commonplace to modern society and can be a major factor negatively influencing a balanced lifestyle which is crucial to maintain a healthy aging process. While acute stress can be beneficial for dealing with unexpected situations, prolonged stress has been shown to have adverse consequences on many organ systems as well as negative impacts on behavioural and physiological responses including feeding behaviour and energy homeostasis. In humans, stress affects individuals differently with regards to feeding; some decrease food intake and lose weight during or after stress, while most others increase their food intake during stress. Importantly, however, independent of hypo- or hyperphagia, people often report that they prefer highly palatable food during periods of prolonged stress, rich in both sugar and fat, which significantly contributes to the development of obesity. Similarly, when rodents have a choice of highly palatable diet, stress also increases the intake of such calorie dense foods . DespiteCentral control of energy homeostasis is known to be orchestrated by a complex neuronal network with neuropeptide Y (NPY)-ergic pathways being one of the most prominent. NPY is a 36-amino acid neuropeptide that is highly expressed in the arcuate nucleus of the hypothalamus (Arc), a brain region critical in the regulation of energy homeostasis. However, recent study also points to an important role of NPY in aging and lifespan determination, with lack of NPY in mice leading to loss of the beneficial effects under calorie restriction which would otherwise confer on lifespan extension . NegativNpy-expressing neurons, consistent with our finding that insulin infusion into the CeA shows a dosage-dependent inhibition of Npy levels [Npy by insulin on CeA neurons was lost under chronic stress combined with HFD condition. We further showed that ablation of the InsR specifically only in CeA-NPY neurons recapitulated the hyperphagic and exacerbated obese phenotype in mice, similarly to that observed in those with CeA-NPY overproduction when under stress combined with HFD condition, suggesting that the loss of responsiveness of CeA-NPY neurons to insulin signalling is the primary cause for the food over-consummatory behaviour in these mice [Circulating hormones are known to signal information on peripheral energy status either via vagal connections or directly by accessing their respective receptors via various circumventricular organs to the brain . Two of y levels . Importaese mice .Htr2a)-expressing CeA neuron activation promotes intrinsic food consummatory behaviour through a positive-valence mechanism [In addition to the NPY circuit, other orexigenic neuron populations also exist in the CeA. For instance, GABAergic serotonin receptor 2a (echanism . Similarechanism . Whetherechanism . Importa


Hendra virus (HeV) infection is endemic in Australian flying-fox populations. Habitat loss has increased the peri-urban presence of flying-foxes, increasing the risk of contact and therefore viral ‘spillovers’ into horse and human populations. An equine vaccine is available and horse-husbandry practices that minimize HeV exposure are encouraged, but their adoption is suboptimal. Ecological approaches–such as habitat creation and conservation–could complement vaccination and behavioural strategies by reducing spillover risks, but these are controversial.We convened three community juries  to elicit the views of well-informed citizens on the acceptability of adding ecological approaches to current interventions for HeV risk. Thirty-one participants of diverse backgrounds, mixed genders and ages were recruited using random-digit-dialling. Each jury was presented with balanced factual evidence, given time to ask questions of expert presenters and, after deliberation, come to well-reasoned conclusions.All juries voted unanimously that ecological strategies should be included in HeV risk management strategies but concluded that current interventions–including vaccination and changing horse-husbandry practices–must remain the priority. The key reasons given for adopting ecological approaches were: (i) they address underlying drivers of disease emergence, (ii) the potential to prevent spillover of other bat-borne pathogens, and (iii) there would be broader community benefits. Juries differed regarding the best mechanism to create/conserve flying-fox habitat: participants in regional centres favoured direct government action, whereas the metropolitan jury preferred to place the burden on landholders.Informed citizens acknowledge the value of addressing the drivers of bat-borne infectious risks but differ substantially as to the best implementation strategies. Ecological approaches to securing bat habitat could find broad social support in Australia, but disagreement about how best to achieve them indicates the need for negotiation with affected communities to co-develop fair, effective and locally appropriate policies. Pteropus conspicillatus) and black flying-fox  are considered the most likely sources of equine HeV infections [Hendra virus (HeV) infection is endemic in Australian flying-fox populations. Of the four flying-fox species native to Australia, the spectacled flying-fox  species have long been a protected species under state or national legislation, although enforcement was not well resourced or prioritised until the emergence of HeV [Ecological approaches could usefully complement HeV vaccination and changing horse husbandry practices, such that flying-fox habitat conservation could be an effective public health intervention . Spectace of HeV , 35. Come of HeV . Despitee of HeV . Experiee of HeV , 38. Rate of HeV . Roost de of HeV , 41. Yete of HeV . Land ore of HeV . Habitate of HeV , 44. Howe of HeV  and histe of HeV , 36, 45.e of HeV , 47.We report on three community juries convened to consider dilemmas raised by increased contact between humans and flying-foxes and the emergence of HeV as a threat to human and equine health. Our aim was to elicit the views of well-informed members of the Australian public regarding the acceptability and perceived legitimacy of adding ecological approaches to current interventions that mitigate the risk of HeV spillover. Gaining some understanding of the public acceptability (or otherwise) of ecological approaches is important because the adoption of these types of interventions for HeV risks requires substantial reform of land use policy. Previous research shows that a lack of consistency and public trust in Australian government planning decision-making have led to anti-government attitudes among many regional landholders , 49. MorThis study was approved by the Human Research Ethics Committee at The University of Sydney and supported by a project grant (APP1083079) from the Australian National Health and Medical Research Council. The funding organization had no role in the design, conduct, analyses or reporting of this study.A community jury is a group of citizens brought together to receive detailed evidence about–and deliberate on–a specific issue . Unlike A group of citizens is convened for 1–3 days;They are asked to consider a specific issue;They hear (sometimes opposing) evidence from experts, and are given an opportunity to ask them questions;They are given time for deliberation, and to come to a conclusion, which is documented.We convened three community juries: one in Rockhampton , one in Lismore (Northern NSW) and one in Sydney (NSW). All were held over two days between October 2017 and March 2018. Rockhampton and Lismore are both small cities in rural areas on the eastern seaboard of Australia; both have been affected by local HeV outbreaks. The capital of NSW, Sydney is a coastal metropolis located further south than the other study settings. Home to a large racing and recreational horse population, Sydney has at least a dozen permanent flying-fox camps located across the metropolitan region . Sydney We contracted an independent professional research service to recruit the jury participants, who lived in each of the study sites, from randomly generated list-based samples, based on representative socio-demographic characteristics (including gender and age) using random-digit-dialling. When first contacted by the recruitment company, potential participants were told that the study was about flying-foxes, horses and how best to manage infectious disease risks. The jurors were then selected purposively from the pool of people who indicated they were interested in taking part, with the final composition of each jury determined by individual availability and eligibility (satisfy exclusion and inclusion criteria). Each jury was stratified to ensure that people who owned or interacted with horses and people who had no interaction with horses were represented, and that there was socioeconomic and cultural diversity within each jury , 61. ThiClearly a jury of 10–14 people cannot possibly represent a statistically characterized sample of ‘the general public’. But it is possible to derive a sense of what an informed public would advise from a smaller group who are given factual information and time to deliberate , 62. RatFirst, we asked each jury to consider the legitimacy and appropriateness of adding ecological approaches to current HeV control interventions . To valiEach jury commenced with an orientation session to introduce the process, the questions for consideration and obtain consent. Jury Day 1 focused on understanding: basic HeV biology; the socio-economic impact of HeV emergence; different interventions to manage infection risks; common clinical and practical issues associated with these strategies and with management of potentially HeV-infected horses; and the epidemiological evidence for the drivers of HeV emergence . TestimoFor the first hour of Jury Day 2, jurors reflected on, discussed and debated the evidence, aided by a researcher acting as facilitator. Juries then deliberated for an hour, without researchers being present, to reach a verdict on the questions posed. The verdicts, underpinning reasoning and dissenting views, were reported to the research team in a final facilitated feedback session. Our research and reporting processes for these Community juries were cross-checked against the CJChecklist protocol .The three deliberative groups (juries) are the units of analysis in this study. All jury deliberations (facilitated and un-facilitated) and expert question and answer sessions were audio-recorded and transcribed. To track changes in the positions held by individual jurors, participants completed an anonymous ballot at 3 time-points during jury proceedings . Jurors also completed an Exit Survey for the purposes of process evaluation at the conclusion of each final jury session. During the final session a researcher recorded the verdict and reasons on a flipchart. Each point was reviewed by the jury to ensure accuracy. Transcripts were subsequently reviewed to identify and clarify key reasons why jurors supported or rejected the presented options. In what follows we have summarized jurors’ own descriptions of the rationale and reasoning that underpinned their responses to the questions asked of them. The verdict of the juries in response to the question  Part B rThe juries in all three settings reported an unanimous verdict, namely that ecological strategies should be part of the approach taken to mitigate the risk of HeV spillovers in Australia. However, the balance of the vote changed during the course of each of the three juries before a final consensus was reached: at different time-points during proceedings some participants expressed the view that ecological approaches should not be actively pursued . The keyEcological changes have created this problem … So, you’ve got to go back to trying to remedy some of these ecological issues hand-in-hand with addressing the public health issues as well. This is going to be an ever-present risk. It’s not going to go away. (CJ2 - #9)However, support for the adoption of ecological approaches was conditional. When asked to prioritise six different approaches to HeV risk mitigation, the further promotion of current measures such as equine vaccination and the adoption of safer horse-husbandry practices by owners were ranked as highest by all three juries . Jurors So far there has not been a HeV spillover event in the Greater Sydney region. Notably, in their final rankings the jury in Sydney gave equal priority to measures that protect remaining flying-fox habitat and measures that promote vaccine uptake/risk reducing horse husbandry practices. They held that the adoption of at least one ecological measure should be prioritised because it would be a first step towards longer term measures to support ecological health. In contrast, in Rockhampton and Lismore the jurors’ endorsement of ecological approaches entirely depended upon sufficient resources being allocated to promote the vaccination of horses against HeV and the uptake of less risky husbandry practices among horse owners. They argued that equine vaccination provided effective and rapid protection against HeV transmission, and that measures to promote higher vaccination rates could be implemented immediately and were relatively cheap compared to financial and welfare costs associated with managing sick, unvaccinated, and potentially HeV infected horses. This final ranking was agreed to by all jury participants at both regional settings, noting that a minority of jurors at Lismore also believed that at least one of the ecological measures should be given the highest priority, but compromised during deliberations because the final outcome still distributed benefits and burdens between flying-fox populations, horse owners and landholders in a manner that they believed was appropriate.Most jurors in all three study settings acknowledged that relying on owners to voluntarily vaccinate their horses was unlikely to be an effective stand-alone strategy. They noted that some owners were resistant to vaccination, others lacked the resources to prioritise this form of protection, and many would remain complacent unless a HeV spillover event occurred in their local area. A minority of participants on each of the three juries raised the possibility of making HeV vaccination mandatory, but this additional step was ultimately rejected by each of the deliberative groups for a range of reasons but primarily because of the economic and social costs of enforcement.Different ecological approaches to mitigate the risks of HeV spillover events from flying-foxes were favoured in different settings . The jur… there’s a lot of restrictions already. And if you’re going to put more restrictions on farmers they are going to be a lot less inclined to go along with anything. … And as we have all been saying, they are not following existing restrictions anyway (CJ1 - #7).The Rockhampton jury saw an important role for government in providing funds to acquire flying-fox habitat. This jury was resistant to restrictive or coercive measures that impacted on individuals. In contrast, the Sydney jury preferred incentives and regulations to encourage individuals to take responsibility for avoiding exposure of themselves and others to HeV risks. A minority of jurors felt that additional measures would not be needed, if everyone vaccinated their horses and flying-fox habitat was protected by restricting land clearing. After considering other juror’s views, these participants eventually supported adoption of measures to generate ecological benefits, but only if they had broader environmental benefits than HeV risk mitigation alone; in common with the jurors in Rockhampton, they believed that flying-fox populations were already well protected and not necessarily endangered. Sydney jurors also rejected proposals for government to acquire land for flying-fox habitat; they felt that private land-holders should be expected to manage their land in ecologically sustainable ways, broadly defined. About this, a juror in Sydney noted:… this seems to be a problem of getting landowners or land users to do the right thing. … Why should my tax money go into acquiring land for flying-fox habitat—the building the fences around trees, increasing restrictions on clearing so you're not taking away existing habitats, those measures I think are sufficient. (CJ3 - #10)The Lismore jury ranked provision of more resources for vaccination and safer horse husbandry practices more highly than their Rockhampton and Sydney counterparts. However, a minority thought that ecological measures should be given equal priority because current approaches did not address the cause of the problem. They suggested combining increased protection of flying-foxes and their habitat  with incentives for landholders to create and maintain habitat on their properties, to stop deterioration in the short term and help reverse it in future. Like the Rockhampton jurors, most of those in Lismore felt it important that measures to encourage farmers to introduce mitigation strategies should be voluntary rather coercive. Notably, further restriction on private land clearing engendered heated debate and polarisation among jurors, in this setting: while some thought it vitally important, the majority felt there was already sufficient regulation and any escalation would require substantial buy-in from farmers and lead to controversy and further politicisation of the issue. Two of six jurors in Lismore who voted this way argued that further restrictions to land clearing should not be implemented under any circumstances. Of the remaining options, the least preferred was for the government to additional acquire land. The main objection was that governments already had substantial land holdings and the emphasis should be on identifying those considered to be suitable flying-fox habitat and improving their management, rather than adding more.Recent research on the influence of flying-fox ecology and population dynamics on HeV spillovers suggests the possibility of landscape management as an effective public health intervention against this zoonotic risk , 28, 30.Jurors were surprised at the moderate uptake of HeV vaccination among horse owners. Research with horse owners suggests that drivers of HeV vaccine refusal are similar to those of vaccine refusal and hesitancy among parents. These include: distrust of scientific authority; different conceptualisations of how to act responsibly; and prioritisation of other values in decision-making around these issues , 22. PubThe different responses of each deliberative group to the prioritisation task were highly informative. Successful implementation of ecological approaches to HeV would also depend on navigating longstanding tensions in Australia about how best to manage and distribute the benefits and burdens of land use between privately-owned primary industries and taxpayers , 83. In Our study has significant implications for those advocating landscape management to mitigate the risks of HeV spillover. Informed citizens in areas affected by HeV risks support the current emphasis on raising rates of equine HeV vaccination , 21. MovCommunity juries are a deliberative method that involves a process of iterative two-way exchange of information between members of the public and experts. By providing extensive information from a range of experts, and ensuring conditions for reasonable and extended debate, community juries elicit more considered judgements than other social research methods such as surveys or focus groups. A possible limitation is that the sample size was small, but this is an unavoidable characteristic of community jury methods and is necessary for high-quality deliberation. It is also possible that each jury was comprised of participants who are more interested in issues surrounding flying-fox management than most Australia citizens, by self-selecting during otherwise random recruitment processes. The number of jurors in urban Sydney who own or regularly interact with horses was proportionally smaller than among regional juries, but was consistent with the socio-demographic characteristics of their respective populations. A strength of this study was the quality and reputation of the experts who gave testimony, and the process by which they moderated one another’s presentations until all experts could accept that all views presented could be argued from the evidence.Habitat sparing and wildlife-friendly farming have been proposed as measures that could promote ecological benefits for agricultural landscapes . Researc


Sport-related concussion is an important condition that can affect collegiate and professional athletes. Expert consensus guidelines currently suggest that all athletes who sustain acute concussion be managed with a conservative approach consisting of relative rest and gradual resumption of school and sport activities with active intervention reserved for those with persistent post-concussion symptoms lasting >10–14 days for adults. Unfortunately, these recommendations place little emphasis on the rapid physical deconditioning that occurs in athletes within days of exercise cessation or the pathophysiological processes responsible for acute concussion symptoms that can be successfully targeted by evidence-based rehabilitation strategies. Based on our evolving approach to patients with persistent post-concussion symptoms, we now present an updated physiological approach to the initial medical assessment, rehabilitation, and multi-disciplinary management of collegiate and professional athletes with acute concussion. Utilizing the results of a careful clinical history, comprehensive physical examination and graded aerobic exercise testing, we outline how team physicians, and athletic training staff can partner with multi-disciplinary experts in traumatic brain injury to develop individually tailored rehabilitation programs that target the main physiological causes of acute concussion symptoms  while maintaining the athlete's physical fitness during the recovery period. Considerations for multi-disciplinary medical clearance of collegiate and professional athletes as well as the application of this approach to non-elite athletes are also discussed. Concussion is a form of traumatic brain injury (TBI) that has become an increasingly recognized condition among collegiate and professional athletes participating in contact and collision sports. Clinical research indicates that the majority of adult athletes achieve a complete neurological and neurocognitive recovery within 10–14 days of injury, with ~10–15% experiencing symptoms that persist beyond this timeframe . HistoriBased on the principles of our rapidly evolving physiological approach to management of patients with persistent post-concussion symptoms (PPCS) –13, we nBasic science research suggests that acute concussion is characterized by a metabolic energy crisis that arises as a consequence of a mismatch between cellular energy demands and impairments in energy substrate delivery. Animal model studies suggest that biomechanical forces applied to the brain result in a cascade of cellular events including acute alterations in neuronal depolarization, excitatory neurotransmitter release, cellular ion homeostasis, glycolysis, and oxidative functioning as well as disturbances in cerebral blood flow regulation –16. In hPatients with acute concussion present with a wide spectrum of neurological symptoms that reflect these global alterations in brain physiology. Symptoms commonly reported during the acute phase of injury include headache, nausea, dizziness, light and sound sensitivity, fatigue, drowsiness, sleep disturbance, and difficulty with memory and concentration. As a consequence of the metabolic energy crisis that characterizes this injury, patients with acute concussion often experience worsening of their symptoms during periods of increased physical and cognitive exertion. Patients with acute concussion can present with an elevated resting heart rate and evidence of orthostatic hypotension while graded aerobic exercise testing often reveals evidence of early exercise intolerance .In addition to the generalized symptoms and exercise intolerance observed among patients with acute concussion, abnormal biomechanical forces transmitted to the head and neck can also lead to physiological disturbances in vestibulo-ocular and cervical spine functioning that can result in a unique constellation of symptoms and objective physical examination findings. Impairments in vision, oculomotor, and vestibular functioning can occur as a result of structural or functional injury to the brain or peripheral visual or vestibular sensory organs –42. PatiTaken together, there is emerging evidence that acute concussion can result in a wide spectrum of clinical symptoms and examination findings that are reflective of heterogeneous and often overlapping physiological processes that have an important impact on patient recovery. While conservative management with physical and cognitive rest will lead to symptom resolution in the vast majority of acute concussion patients, this approach is associated with its own negative effects on physiological functioning, especially when applied to collegiate and professional athletes.Regular exposure to physical exercise through training, practice, and game play leads to a number of physiological adaptations that help optimize physical fitness and performance among athletes. However, abrupt cessation of physical exercise, such as during injury, illness, or due to other factors, can lead to rapid declines in cardiorespiratory and metabolic functioning and pronounced performance loss . ExperimDespite ongoing scientific advances in concussion and sport physiology over the past three decades, published expert guidelines continue to advocate for a uniform and largely conservative approach to management of acute concussion in athletes. Historically, experts have held the view that acute concussion is a condition characterized by non-specific neurological symptoms that follow a sequential course to spontaneous resolution and are reflective of temporary global alterations in brain functioning. Consistent with this understanding, consensus guidelines published up to 2013 by numerous groups have uniformly recommended that all athletes with acute sport-related concussion be managed with strict physical and cognitive rest until all symptoms completely resolved followed by structured re-exposure to physical exercise and sport-specific activities . FollowiIn addition to these published guidelines, other authors have proposed alternative approaches to concussion management. For instance, authors from the University of Pittsburgh have presented a comprehensive targeted approach to the clinical care of sport-related concussion in athletes. Relying largely on symptom inventories and abbreviated vestibular/oculomotor and computerized neurocognitive screening tools, the authors suggest that athletes with sport-related concussion can be classified into symptom-based trajectories or profiles , 70. UnfThe initial medical assessment of all collegiate and professional athletes with suspected acute concussion must achieve three important objectives: 1) provide a definitive medical diagnosis of acute concussion; (2) identify the clinico-pathophysiological features that may place the athlete at risk of prolonged recovery; and (3) inform the development of an individually tailored rehabilitation program that targets the pathophysiological causes of concussion symptoms while maintaining the athlete's physical fitness level during the recovery process  as well as any video footage of the injury should also be obtained and reviewed. Clinical research and systematic reviews suggest that a number of pre-injury and non-modifiable risk factors may place athletes at an elevated risk of prolonged recovery following concussion . InformaAs part of the clinical history, assessment of the patient's symptoms should be undertaken both with the use of a validated symptom inventory, such as the Post-Concussion Symptom Scale that is included as part of the Sport Concussion Assessment Tool-5 (SCAT5) , as wellFollowing the clinical history all patients with suspected head and spine trauma should undergo a comprehensive physical examination. Although abbreviated tools, such as the SCAT5 , King-DeAlthough the medical diagnosis of acute sport-related concussion can often be made based on the findings of a comprehensive clinical history and physical examination alone, there are instances where the use of supplemental tests are indicated. Given that neuroimaging studies are normal in the vast majority of sport-related concussion patients , 81, phyIn very rare instances when the treating physician cannot confidently confirm the medical diagnosis of acute concussion based on clinical history and physical examination findings alone, consideration should be given to referral to the team neuropsychologist for neuropsychological testing. This testing should be especially considered in patients who report transient and non-specific symptoms following head and neck trauma, such as fatigue or fogginess or those who experience the onset of migraine headaches in the setting of contact sport activities. In circumstances when neuropsychological testing does not reveal results consistent with acute concussion, the definitive diagnosis of acute concussion should remain one of collaborative clinical judgment and is best made by a team of multi-disciplinary TBI experts. Student-athletes with a diagnosed acute concussion should be provided individualized Return-to-School guidance and accommodations as needed.In order to develop an individually tailored rehabilitation program that mitigates the effects of aerobic deconditioning in athletes with acute concussion it is essential to conduct a standardized assessment of exercise tolerance. Over the past decade, the Buffalo Concussion Treadmill Test (BCTT) has emerged as a safe, reliable, valid, and clinically useful tool to measure exercise tolerance in children and adults with acute concussion and PPCS , 85–90. In our clinical practice, the timing of graded aerobic exercise testing depends on a number of factors including the severity of the patient's symptoms, the time since injury, the need for additional supplemental testing, and physician judgment. In collegiate and professional athletes who undergo initial evaluation < 24 h post-injury and who present with a high burden of symptoms, we usually recommend a period of sub-symptom threshold physical and cognitive rest for 24–48 h prior to performing graded aerobic exercise testing. However, in those who present with a lower burden of symptoms < 48 h post-injury and those that present >48 h post-injury we perform graded aerobic exercise testing during the initial medical assessment.The goals of an individually tailored rehabilitation program are to initiate evidence-based rehabilitation strategies that target the clinico-pathophysiological features responsible for acute concussion symptoms and help maintain the athlete's physical fitness level. The three key pathophysiological processes that are most frequently targeted following acute concussion are: 1) autonomic dysfunction and exercise intolerance; (2) vestibulo-ocular dysfunction; and (3) cervical spine dysfunction . These physicians typically serve as team physicians or consultants, have access to other multi-disciplinary experts in TBI, including neuropsychologists, exercise scientists, physiotherapists, neuro-ophthalmologists, and psychiatrists and work directly with the athlete's team medical and athletic therapy staff. In order to consider active rehabilitation of the pathophysiological manifestations of acute concussion, it is critically important that a definitive medical diagnosis of concussion is confirmed by a physician and that further diagnostic testing  and rehabilitation strategies be carried out by the healthcare professionals that are optimally trained and licensed to provide these individual services. The authors are well-aware that over the past decade, there has been an explosion in the number of “concussion clinics” and “certified providers” who are advertising concussion-related services, many of which are doing so without direct on-site access to experienced physicians and healthcare professionals that have competency-based training in TBI related sub-disciplines , 142. ItSport-related concussion is a common injury sustained among athletes that produces clinical manifestations that result from several unique and overlapping pathophysiological processes. This novel approach to the assessment and rehabilitation of acute concussion builds on our evolving physiological approach to patients with PPCS to offer a comprehensive, evidence-based framework that guides the initial medical assessment and multi-disciplinary management of collegiate and professional athletes with acute concussion. Combining the results of a comprehensive clinical history, physical examination, and graded aerobic exercise testing, this approach allows clinicians to work together to develop an individually-tailored program that promotes the active rehabilitation of acute concussion while minimizing physiological deconditioning. This approach will undoubtedly require further refinement as novel insights into the pathophysiology and evidence-based management of concussion become available in the future.ME, JL, DC, and BW: conception and design of the work, drafting the work and revising it critically for intellectual content, final approval of the version to be published, and agreement to be accountable for all aspects of the work ensuring that questions related to the accuracy and integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The traditional diagnostic gold standard for inflammatory skin lesions of unclear etiology is dermato-histopathology. As this approach requires an invasive skin biopsy, biopsy processing and analysis by specialized histologists, it is a resource intensive approach requiring trained healthcare professionals. In many health care settings access to this diagnostic approach can be difficult and outside emergency cases will usually take several weeks. This scenario leads to delayed or inappropriate treatment given to patients. With dramatically increased sensitivity of a range of analysis systems including mass spectrometry, high sensitivity, multiplex ELISA based systems and PCR approaches we are now able to “measure” samples with unprecedented sensitivity and accuracy. Other important developments include the long-term monitoring of parameters using microneedle approaches and the improvement in imaging systems such as optical coherence tomography. In this review we will focus on recent achievements regarding measurements from non-invasive sampling, in particular from plucked hair and skin tape-strips which seem well suited for the diagnosis of lupus erythematosus and psoriatic inflammation, respectively. While these approaches will not replace clinical observation—they can contribute to improved subgroup diagnosis, stratified therapeutic approaches and have great potential for providing molecular and mechanistic insight in to inflammatory skin diseases. Traditionally, the diagnosis of autoimmune and inflammatory skin diseases relies on the visual assessment by experienced dermatologists as well as dermato-histopathology. Descriptive diagnosis of skin biopsies is normally based on conventional histological staining but may also include direct immunofluorescence for the detection of antibody and complement deposits. Depending on the underlying disease, blood results in particular regarding circulating auto-antibodies directed against structural epidermal components  or anti-nuclear antibodies can give certainty regarding the underlying disease. However, as blood focused diagnostics can often be negative for cutaneous disease manifesting, key information must often be derived from analysis of skin tissue itself.So why are changes or additions to the established diagnostic approach for inflammatory skin disease required? There are a number of reasons. Firstly, due to the non-systemic nature of many skin diseases, reliable serum biomarkers may simply be non-existent or unreliable. Secondly, the use of skin biopsies as a diagnostic tool is an invasive procedure and not always readily available in many health systems or local situations. Skin biopsies require specialized, trained health care professionals, laboratory and histology staff (dermatohistopathologists) and the time to perform biopsies in addition to the wait for result reporting, can in clinical reality often be weeks. Furthermore, as many primary health care settings lack access to specialist dermatology care, approaches suitable for general practitioners (GP) would be very welcome to support diagnostic pathways.Apart from costs, time and staff availability, an important issue comes from the recognized need and ambition to move forward in the field of stratified medicine . This approach aims to recognize sub-types of diseases outside the traditional morphology based categories, allowing optimized treatment choices and thus preventing the current “trial and error” approach to identify which treatment actually works best for which patient. For this to become a reality for a wide range of patients, researchers, and clinicians need to start thinking of alternatives to conventional approaches and embrace new molecular analysis tools, parameters not traditionally included in dermatology diagnosis, and easy, non-invasive approaches. Ideally, these approaches would not require highly-trained specialists to perform and analyse results, results would be available within the first presentation of the patient (“point-of-care” diagnostic) and would allow repeated diagnostic assessment over time.While confirming the diagnosis of cutaneous lupus erythematosus (LE) can be challenging due to the wide variety of possible lesion morphologies, the diagnosis of psoriasis is usually directed by pathognomonic clinical presentation. So why is there a need to additional approaches regarding psoriatic inflammation? Diagnostic challenges occur for lesions which do not fall into the typical plaque type psoriasis or display minimal pathology; however, they are important to diagnose due to the existence of co-morbidities such as psoriatic arthritis and cardiovascular disease. Lesions in certain anatomical locations such as palmoplantar, retro-auricular, outer ear canal and scalp can also be challenging for both GP and trained dermatologists, and in particular skin fold lesions can often be misdiagnosed as fungal infection and treated without success with anti-fungals.In this review we endeavor to give an overview of existing non-invasive techniques and highlight major recent advances demonstrating their potential as next generation diagnostics and as powerful tools to provide cellular and molecular insights in to inflammatory skin diseases.Recent developments in imaging and imagining analysis techniques have added to our ability to assess real time changes in the skin. The most widely used imaging technique in standard care dermatology for suspicious and/or pigmented lesions is dermatoscopy. Dermatoscopy standards are developed by the international dermatoscopy society (dermoscopy-ids.org) and the approach has also been successfully used to support diagnosis of inflammatory skin conditions [for review: –3]. DermWhile this review does not specifically focus on imaging techniques, the following innovative approaches have to be mentioned, although they do require significant financial investments. A recent development, not yet introduced into clinical settings is Raster Scanning Optoacoustic Mesoscopy (RSOM) 4). This technique also termend photoacoustic mesoscopy is based on ultra-broadband (10–180 MHz) detection, achieves tissue resolution of 4 μm axially and 20 μm laterally and importantly can visualize vascular patterns in dermal skin compartments. A number of studies have collected images from human skin including eczema, psoriasis and nail fold changes in scleroderma capillaries . This te. This imBy contrast, optical coherence tomography (OCT), which can deliver similar morphology information [detailed comparison of OCT vs. RSOM is given in ], has beIn psoriasis, OCT can detect all common psoriasis nail changes including leukonychia/white spots, pitting/localized surface irregularities, diffuse surface waving, onycholysis, and subungual hyperkeratosis . StudiesIn cutaneous LE, OCT has been shown to correlate with histological features of disease including hyperkeratosis, epidermal atrophy, and edema . More reUnfortunately, at present, costly hardware, expertise and time required to analyzed skin lesions is likely to limit the use of OCT to the research setting and specialist clinics.Microcirculatory abnormalities are found in many inflammatory skin diseases. High Resolution Laser Doppler imaging (LDI) is a single-probe, non-invasive imaging method that can quantify total local microcirculatory blood perfusion, including capillaries, arterioles, venules, and shunting vessels. Similarly to ultrasound, it is based on the Doppler effect. Briefly, when low-level light is directed onto the skin, a fraction of this light penetrates the skin and interacts with both the static tissue and the moving red blood cells (RBCs). The light that is reflected from this static tissue remains unchanged in wavelength. The light that is scattered from the moving RBCs undergoes a change in wavelength. This backscattered light is then collected by the photodetector of LDI system to provide a signal or reading that is proportional to the speed and density of the moving RBCs . Alterat2). In addition to resting TEWL, epidermal function can be assessed by measuring TEWL recovery over time following barrier disruption by repeated tape stripping  is a validated measure of skin epidermal permeability barrier function, measured with a non-invasive Tewameter® probe , 21. Evatripping .Although atopic eczema is best recognized for its barrier defects clinical and molecular evidence suggest that barrier defects play a role in psoriatic disease pathogenesis –25. FurtSeveral small clinical studies have employed TEWL as a measure of treatment efficacy in psoriasis –40. HoweTEWL is mainly examined in diseases with epidermal involvement. Thus, LE which shows inflammatory activity around the basement membrane area may not show significant changes in TEWL but this is currently unexplored.Skin elasticity is typically measured by a non-invasive Cutometer® probe (or similar method) which utilizes negative pressure to aspirate a small section of skin. The distance the skin travels is affected by its elastic properties and this is recorded as a series of parameters . This haA limited number of studies have assessed changes in skin elasticity in psoriasis. Differences in total elastic and plastic deformation were found between psoriasis, dermatitis, and lichen planus patients and within patient groups compared to uninvolved sites, with psoriasis exhibiting the greatest superficial stiffness . This coAs with TEWL, changes in elasticity were also detected between uninvolved sites in patients with psoriasis and skin from healthy volunteers .Skin elasticity in LE has not been studied in detail but reports indicate differential elastic fiber staining compared to lichen planopilaris which is challenging to distinguish clinically in the later stages , suggestHowever, the lack of molecular information obtained through this method and variability caused by factors such as age, sun-exposure, anatomical location, and ethnicity are likely to prevent this method being widely used for personalized diagnostics.Non-invasive sampling of skin epithelium via tape stripping uses adhesive tapes to “strip” the superficial layers of the skin, peeling of layers tape by tape. This method has been widely used over the last decade in research settings; however with increased sensitivity of detection methods and the given ease of sampling—this approach becomes more interesting for clinical diagnostic pathways.2). It has been shown that due to the stronger adhesion of corneocytes toward the stratum granulosum, the protein content of tapes decreases in parallel with the increase of tape number/depth of penetration , and synthetic rubber-based tapes  but other tapes, such as Barrier  and cellophane tapes  are also utilized. Tapes are placed on the skin with gentle pressure for 2–10 s, and then removed with a quick movement. D-squame pressure applicator (Monaderm) can be used to standardize pressure . In contrast to biopsies, which are not a preferred option in pediatric settings and at certain anatomical sites due to their invasiveness and potential for scar formation, tape stripping can be repeatedly performed at any anatomical site, independent of age and location –58.A potential disadvantage of tape stripping lies in the difficulty of sampling standardization. Quantity and quality of sampled skin may differ not only between individuals, but also intra-individually due to differences in epidermal thickness, skin hydration and intercellular adherence , 59–62. Healthy skin sampling is limited to the stratum corneum (SC), however this is often not the case in pathologically involved skin, where inflammation influences not only the morphology [hyperproliferative epidermis with thickened SC in psoriasis vs. reduced SC thickness with increased corneocyte cohesion in acute eczema compared to healthy and non-lesional skin ], but alStudies focusing on transcriptomic profiling of lesional and non-lesional skin material obtained by non-invasive tape stripping are limited in number. In an early study Morhenn et al. used 20 subsequent acrylic based tapes describing distinct RNA cytokine profiles in allergic and irritant contact dermatitis using ribonuclease protection assay . Follow However, overall there are noteworthy limitations for the use of skin tape-strip sampling for transcriptomic analysis as the quantity and quality of RNA obtained is suboptimal. This is due to the skin surface being particularly rich in RNAases and due to the fact that RNA degradation is a natural process of skin differentiation as cells mature into corneocytes. This makes the method prone to false negative results. A recent study by Dyjack et al.  reportedRecent evidence suggests that protein sampling of the epidermis via tape stripping is a surprisingly efficient method to detect and study a range of mediators, from structural proteins to antimicrobial peptides, chemokines, and cytokines contributing to disease pathomechanisms, using traditional ELISA, western blot and Multiplex bead-based technologies where available. Furthermore, studies analyzing protein extracts from tape stripping with highly sensitive mass spectrometry (MS) techniques are emerging as an unbiased approach to examine disease entities not only from the perspective of disease subtype diagnosis, but importantly the detection of differentially expressed proteins can also provide potential mechanistic insight into the initiation and maintenance of these inflammatory diseases.One of the most comprehensive tape stripping studies focusing on healthy vs. psoriatic skin identified 140 proteins expressed in lesional psoriatic skin by combining tape sampling and MS analysis . Compare+ IL-17 producing leukocytes  and TSLP in tape harvested material with correlations to disease severity , 87. HowWe have recently  comparedLesional psoriatic skin is well described to overexpress antimicrobial peptides (AMPs) in the outermost layers of the skin. Thus, non-invasive surface sampling is ideally suited study their expression in different conditions. AMPs measured via tape stripping , 93 but All skin diseases showing epidermal inflammation present with some degree of pruritus, which is well recognized to be a complex phenomenon. Neuropeptides which can impact on release of histamine, vasoactive mediators and pro-inflammatory cytokines and play a role in itch. Keratinocytes are the main source of the neurotrophic nerve growth factor (NGF), a regulator of sensory nerves innervating the skin and which can induce lymphocyte activation and keratinocyte proliferation , 99. NGFMetabolomics is an exciting newly emerging field. Recent data using skin and serum samples suggest that perturbations in the glycolysis and amino acid metabolic pathways may play an important role in the pathogenesis of psoriasis , 104. Soin vivo secretion of AMP  for diagnostic or research purposes and are also happy for repeated sampling e.g., to ascertain therapeutic responses. In addition, hair follicle collection does not require specialist training.The need to include analysis of tissue specific responses in precision medicine approaches has been recognized. As highlighted in this review, novel imaging techniques have great potential to allow non-invasive diagnostic by visualizing changes in the epidermal down to the vessel compartment. Access to imaging devices such as OCT and RSOM are however limited to specialized centers due to high costs.By contrast, epidermal sampling by tape stripping and for the scalp by hair follicle plucking do not need specific training, are easy and fast to perform, suitable for point of care approaches and can give molecular information beyond morphology changes. This could significantly help with disease subgroup identification and importantly provide a molecular understanding of the inflammatory processes behind these diseases and highlight novel targets for future therapeutics. Thus, protein biomarkers detectable with non-invasive epidermal/hair follicle sampling has the potential to direct treatment pathways, follow up disease progression and therapeutic response.It remains to be demonstrated in well planned prospective studies which compare standard of care diagnostic with the here discussed non-invasive diagnostic approaches if suitable protein biomarker algorithm can be developed with high enough sensitivity and specificity for a range of inflammatory skin conditions to replace current biopsy approaches. Another previously discussed  outcome All authors contributed to writing the manuscript. AB performed the optical coherence tomography imaging shown in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Impacts of climate warming on freshwater ecosystems have been documented recently for a variety of sites around the globe. Here we provide a review of studies that report long-term  effects of warming trends on thermal properties and plankton dynamics in northern hemispheric lakes. We show that higher lake temperatures, shorter periods with ice cover, and shorter stagnation periods were common trends for lakes across the hemisphere in response to the warmer conditions. Only for shallow dimictic lakes was it observed that deep-water temperatures decreased. Moreover, it became evident that phytoplankton dynamics and primary productivity altered in conjunction with changes in lake physics. Algal spring blooms developed early and were more pronounced in several European lakes after mild winters with short ice cover periods, and primary productivity increased in North American lakes. Effects of elevated temperatures on zooplankton communities were seen in an early development of various species and groups, as is documented for cladocerans, copepods, and rotifers in European lakes. Furthermore, thermophile species reached higher abundance in warmer years.Obviously, the nature of responses is species specific, and depends on the detailed seasonal patterning of warming. Complex responses such as effects propagating across trophic levels are likely, indicating that observed climate—ecosystem relationships are not generally applicable. Nonetheless, the picture emerges that climate-driven changes in freshwater ecosystems may be synchronised to a certain extent among lakes even over great distances if climatic influences are not masked by anthropogenic impacts or differences in lake morphology. Macro-scale climatic fluctuations — such as the North Atlantic Oscillation or the El Niño-Southern Oscillation — were identified as the most important candidates responsible for such coherence, with the former predominating in Europe and the latter in North America. We emphasise, however, that the driving mechanisms and the future behaviour of these oscillations are rather uncertain, which complicates extrapolation of observed effects into the future. Thus, it is necessary to quantify the most important climate—ecosystem relationships in models of appropriate complexity. Such models will help elucidate the multiple pathways climate affects freshwater ecosystems, and will indicate possible adverse effects of a warmer future climate.