Neural basis of social learning, social deciding, and other-regarding preferences cover a large part of current debate in, and expand our knowledge of, social behaviors from the perspectives of neural networks and neuromodulators involved, as well as unique behavioral strategies engaged. This collection addresses outstanding questions in the neurobiology of human and non-human animal social behaviors in the form of original research articles, reviews, and perspective-type papers.What makes us do things like cooperate with others, perform altruistic behaviors, or be empathetic toward others? What neural circuits compute, and how hormones modulate, social behaviors? Our brains were evolved to function in complex social environments, demanding us to naturally tune our behaviors to social information Wilson, . Social Lee and Harris sets the stage by reviewing useful ways to effectively combine the knowledge gained from the tradition of social psychology research and more recently emerged research in neuroeconomics, in order to better understand social behaviors and their neural correlates  and valence displayed (happy vs. sad faces) from the images of infants, indicating that positive or negative values associated with infant face are processed in strikingly different ways depending on social context (Strathearn and Kim, Facial expression serves as a key source of social information in human and non-human primates. In a perspective article, Gothard reviews how distributed networks of sensory, motor, affective, as well as motivational systems coordinate to generate facial expression, focusing particularly on the pathways between the amygdala and the midcingulate areas for transforming emotion-related signals into facial motor signals Gothard, . It is wRecently, there has been much interest in testing how neurons sensitive to primary reinforcement and action monitoring respond to socially-rewarding events and socially-relevant actions (Izuma et al., The papers appearing in the E-Book collectively highlight new advances and emerging interests in the field of social neuroscience. The field is rapidly growing, providing many interesting insights into the neural underpinnings of social behavior. However, many challenges lie ahead. How does the brain know when to enhance social processing? What are some fundamental computational principles in the shared neural circuits across social and non-social behaviors? How do different parts of the brain or distinct subpopulations of neurons orchestrate social computation? These are just some of the interesting questions and challenges that remain before us.Steve W. C. Chang and Masaki Isoda wrote the current paper and served as the editors of this Research Topic E-Book.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.


Economic and social transitions in the era of globalization warrant a fresh look at the neurological risks associated with environmental change. These are driven by industrial expansion, transfer and mobility of goods, climate change and population growth. In these contexts, risk of both infectious and non-infectious diseases are shared across geographical boundaries. In low- and middle-income countries, the risk of environmentally mediated brain disease is augmented several-fold by lack of infrastructure, poor health and safety regulations, and limited measures for environmental protection. Neurological disorders may occur as a result of direct exposure to chemical and/or non-chemical stressors such as ultrafine particulate matters. Individual susceptibilities to exposure-related diseases are modified by genetic, epigenetic and metagenomic factors. The existence of several uniquely exposed populations, including those in the areas surrounding the Niger Delta or north western Amazon oil operations; those working in poorly regulated environments, such as artisanal mining industries; or those, mostly in sub-Saharan Africa, relying on cassava as a staple food, offers invaluable opportunities to advance the current understanding of brain responses to environmental challenges. Increased awareness of the brain disorders that are prevalent in low- and middle-income countries and investments in capacity for further environmental health-related research are positive steps towards improving human health. However, the impact of such signatures on both brain health and region or global disability-adjusted life years (DALYs) remains unknown and needs to be added to the agenda of global environmental health research. As for high-income countries, environmental health research programmes in LMICs must primarily focus on elucidating the entire range and source of exposures to define the human ‘exposome’  in LMICs. The research agenda should include mechanistic and translational research, as well as capacity building to foster a new generation of environmental health scientists.Reports from the World Health Organization (WHO) indicate that the global burden of disease is determined by patterns of disease and disability in low- and middle-income countries (LMICs), which, predictably, have their own environmental signatures (http://data.worldbank.org/about/country-and-lending-groups). An iterative search of the literature was conducted using PubMed to retrieve information related to environmental determinants and mechanisms of brain disease in LMICs. Additional opinion was obtained from interviews with leading environmental scientists and neuroscientists, as well as programme officers at the US National Institutes of Health and US National Institute of Environmental Health Sciences (NIEHS), and Fogarty International Center. This Review integrates the goals and approaches to environmental health research as per the NIEHS 2012–2017 strategic plan (https://www.niehs.nih.gov/about/strategicplan/).In this Review, we focus on environmental risk factors for brain diseases and conditions in LMICs  have created conditions that exacerbated the risk of environmental exposure and brain disease10. Flawed regulations compounded by a lack of infrastructure set the stage for environmental degradation and pollution to pose serious threats — of a chemical or non-chemical nature — to human health. The degradation of local ecosystems leads to the creation of ‘microenvironments’ that have a high risk of harmful exposures, often resulting in unique challenges and increased risk of human disease , the grass pea Lathyrus sativus or the seeds from the cycad plants, which are all known to be associated with a high-burden of neurodisabilities at a population level22. Populations with unique exposures and risks include those living in the tropical cassava belt of Angola, the Central African Republic, Cameroon, Democratic Republic of the Congo, Tanzania, Uganda, Nigeria and Mozambique30; those reliant on L. sativus as a staple food in Ethiopia, Eritrea, India and Bangladesh33; and the people of the Pacific island Guam or the Japanese Kii Peninsula where the rates of environmentally linked syndromes such as amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS/PDC) have been declining for reasons that have yet to be uncovered35.Microenvironments in which the population has a higher susceptibility to exposure-related diseases have also been created by extreme poverty and natural disasters, including drought and flooding that can degrade soils, plants and farming operations. The burden of conventional neurodevelopmental stressors  on children is exacerbated by unique environmental challenges, including malnutrition and enteric infections15. This vicious cycle establishes what is called environmental enteropathy, a mostly subclinical condition (even without diarrhoea) caused by various degrees of intestinal barrier dysfunction, luminal-to-blood intestinal bacterial translocation, low-grade local and systemic inflammation, and poor innate intestinal immune responses that may affect growth36 and cognition37 and possibly lead to neurodegeneration as well as liver, and metabolic diseases later in life39.The impact of early childhood diseases that lead to a vicious cycle of enteric infections and malnutrition has been underestimated and neglected, especially in areas that lack acceptable levels of hygiene and sanitation and that have reduced accessibility to vaccines and antimicrobials. This has caused clinically silent, chronic-illness-related effects, which jeopardize the child’s full cognitive development41. In this context, adolescent workers are at risk of exposure to agrochemicals such as pesticides43. Other work-related threats include exposure to organic solvents in work that involves painting and manufacture, to toxic metals and fine particulate matters in artisanal mining, and to heat and ambient air pollution while working long hours and outside41. Exposure to industrial solvents such as n-hexane, for example, may occur because of poor safety regulations or recreational glue sniffing. This may result in headache, acute encephalopathy or sensorimotor neuropathies that are reversible on cessation44.Adolescents in LMICs experience a higher burden of exposures (in contrast with those in high-income countries), primarily because of the childhood labour crisis. Although there are regulations and international agreements restricting child labour, often there are exceptions for certain industries, notably the growing agricultural industry, one of the most hazardous industries worldwide46. In certain circumstances, women of childbearing age are particularly vulnerable because they are more susceptible to the toxicity of cassava cyanogens for reasons that have not been elucidated, although may be linked to hormonal influences and poor nutrition47.Adults in LMICs may be at a particularly high risk of environmental exposure and related brain diseases compared with those in high-income countries. In general, adults experience a higher burden of disease owing to a lifetime of cumulative exposures and co-morbidities that are highly prevalent in LMICs. The latter include malaria, nutritional deficiencies and neurotropic infections such as those caused by human T-cell lymphotropic virus (HTLV). For example, it was reported that endemic foci of HTLV-I-associated myelopathy coexist with outbreaks of konzo, which causes spastic paraparesis and is linked to the toxicity of cassava cyanogens within some areas of the Democratic Republic of the CongoExposure-related brain damage may result from chemical and/or non-chemical stressors. Damage to the nervous system often leads to a range of bilateral and symmetrical motor and/or sensory symptoms. Behavioural problems, cognition deficits and psychiatric illness may also occur. Non-chemical stressors include, but are not limited to, psychological stress, heat, noise, fine and ultrafine particulate matter (FUPM), and waterborne, airborne or foodborne pathogens that may occur under the conceptual framework shown in Brain damage linked to chemical exposure may result from chemicals interfering with neurotransmission through molecular mimicry or reacting with crucial biomolecules and causing incorrect function . For both chemical and non-chemical exposures, the mechanisms of brain damage may include injury to the vascular system , systemic dyshomeostasis  and hormonal imbalance  and by local traffic-related air pollution  revealed significant multiplicative interaction between the risk genotype and the air pollution exposure56.It is increasingly acknowledged that genetic and epigenetic factors, including the effect of maternal stress on brain function, influence the effect of environmental exposure58. Many studies suggest that the genetic and environmental causes of late onset diseases act in parallel and share common molecular mechanisms59. A number of studies have supported the concept that early-life exposure to pollutants reprograms global gene expression in old age through epigenetic mechanisms63. Variation in exposure response, even among individuals exposed to the same environment could be due not only to early-life exposures, but also to differences in genetic make up66. The extent and nature of exposures and related brain diseases in LMICs provide opportunities to explore and overcome the long reach that childhood exposure has into adulthood, as well as provide us with new advances in environmental health sciences67.Our knowledge of the pathways that lead to late onset of exposure-related neurological disease is still sparse69 (Exposure-related neurological deficits in LMICs range from peripheral neuropathies to a large number of acute, subacute or chronic central nervous system diseases. Deficits may occur prenatally, or during childhood or adolescence, and may be carried through to old age. Clinical implications include, but are not limited to, neural tube defects, learning disabilities, behavioural problems, psychiatric disorders, cognitive decline and the occurrence of distinct entities such as neurolathyrism, tropical ataxic neuropathy, ALS/PDC and konzo69 .70, the metabolism of food-borne neurotoxicants such as cassava cyanogens18, and the outcome of enteric diseases in early life, including the child’s neurodevelopmental potential73.The human microbiome may be of particular interest to the mechanistic understanding of exposure-related diseases in LMICs because it may influence the burden of heavy metalsRecent advances in environmental health sciences have elucidated the myriad risk factors and mechanisms of brain damage that are associated with environmental exposures. The existence of uniquely exposed populations in LMICs offers invaluable opportunities to advance our current understanding of brain responses to environmental threats. In some instances, well-characterized neurotoxicants may be used as chemical probes to dissect the pathophysiology of the nervous system. Challenges at the population level still remain, including setting exposure limits and developing metrics and methodologies to assess the long-term impact of environmental exposures on disease burden in LMICs and, therefore, globally. Climate change and mining of rare elements, which may include radioactive materials, present unpredictable risks, and should be added to the environmental health research agenda. The toll of such exposures on the global burden of disease may be efficiently addressed only through competent partnerships and alliances established on a global scale and focused on key areas and priorities . Althoug74. Addressing environmental threats and risks for incapacitating diseases will therefore require a serious commitment to trans-disciplinary work, vigilance and capacity building on a global scale75Environmental degradation and contamination, changes in climate and ecosystems, and vector-born pathogens or neurotoxicants are the primary environmental threats to human life and intellectual performance. Humans, plants and animals adapt to environmental challenges, but some may overcome their adaptive capabilities and create imminent risks for all


Rapid progress in biotechnology has introduced a host of pressing ethical and policy issues pertaining to stem cell research. In this review, we provide an overview of the most significant issues with which the stem cell research community should be familiar. We draw on a sample of the bioethics and scientific literatures to address issues that are specific to stem cell research and therapy, as well as issues that are important for stem cell research and therapy but also for translational research in related fields, and issues that apply to all clinical research and therapy. Although debate about the moral status of the embryo in human embryonic stem cell research continues to have relevance, the discovery of other highly multipotent stem cell types and alternative methods of isolating and creating highly multipotent stem cells has raised new questions and concerns. Induced pluripotent stem cells hold great promise, but care is needed to ensure their safety in translational clinical trials, despite the temptation to move quickly from bench to bedside. A variety of highly multipotent stem cells - such as mesenchymal stem/stromal cells and stem cells derived from amniotic fluid, umbilical cord blood, adipose tissue, or urine - present the opportunity for widespread biobanking and increased access. With these increased opportunities, however, come pressing policy issues of consent, control, and justice. The imperatives to minimize risks of harm, obtain informed consent, reduce the likelihood of the therapeutic misconception, and facilitate sound translation from bench to bedside are not unique to stem cell research; their application to stem cell research and therapy nonetheless merits particular attention. Because stem cell research is both scientifically promising and ethically challenging, both the application of existing ethical frameworks and careful consideration of new ethical implications are necessary as this broad and diverse field moves forward. As every reader of this journal knows, ‘stem cell research’ is a category of enormous breadth and complexity. Current and potential therapeutic applications for stem cells are numerous. Stem cell researchers may be engaged in many different endeavors, including but not limited to seeking new sources of highly multipotent stem cells and methods of perpetuating them; creating induced pluripotent stem cell (iPSC) lines to study genetic disorders or explore pharmacogenomics; conducting animal or early-phase human studies of experimental stem cell interventions; or working with stem cells and biomaterials to develop organoids and other products for use in regenerative medicine, to name only a few possibilities.In this review of selected major ethical issues in stem cell research and therapy, we briefly describe and discuss the most significant ethical implications of this wide-ranging and fast-moving field. Our discussion addresses research oversight in the historical context of human embryonic stem cell (hESC) research; clinical translation and uncertainty; the profound tension between the desire for clinical progress and the need for scientific caution; and issues of consent, control, commercialization, and justice arising from stem cell banking, disease modeling, and drug discovery. We seek to make stem cell scientists more aware of the need for clarity of discussion and to improve professional and public understanding of the ethical and policy issues affecting this important but early research. A review this brief is necessarily general; our hope is that researchers can use this discussion as a starting point for more in-depth identification and analysis of issues pertinent to specific translational research projects -3.The basic system of regulation and review of research involving humans and animals as subjects ,5 is famIn this respect, stem cell research is not unique; stem cell researchers should ask themselves the same questions about the trajectory of their translational research as would any other biomedical researcher . OversigThe ethical issues that all researchers face during clinical translation begin with the need to ask a meaningful question, the answer to which has both scientific and social value and can be reached by the study as designed when properly conducted ,15. The Stem cell research may give rise to heightened concern in several of these areas. One such concern is clarity of language. The term ‘stem cell’ by itself is broad and non-specific enough to be confusing; it can refer to hESCs, to iPSCs, to other types of multipotent and highly multipotent stem cells , or to determined or adult stem cells like hematopoietic stem cells (HSCs), which have long been used in standard therapies. Patients, science reporters, and the public, on hearing the term ‘stem cell’, may thus find it difficult to distinguish between experimental stem cell interventions and proven stem cell therapies of long standing, such as treatments involving autologous or allogeneic HSC transplantation. The commercial availability worldwide of unproven ‘stem cell therapies’ that have not been studied in translational research adds to this confusion -26,28,29Hopes that the ethical controversy surrounding hESCs would become irrelevant when new sources of highly multipotent stem cells became available have proven somewhat premature. hESCs remain scientifically promising and continue to have important uses, even as research with iPSCs and other highly multipotent stem cells gains momentum -32. A brThe first hESC line was derived in 1998, ushering in one of the most public, spirited, and intractable debates in research ethics: the moral status of the embryo from which hESCs are derived. To harvest hESCs, it is first necessary to destroy the 5-day-old preimplantation embryo. Opponents of hESC research argue that because the embryo is capable of developing into a human being, it has significant moral standing; therefore, its destruction is unethical. Some proponents of hESC research deny that the embryo has any moral status; others grant it limited moral status but argue that the value of this limited status is far outweighed by the potential benefits that can result from hESC research ,33.Guidelines for Human Embryonic Stem Cell Research, most recently amended in 2010 [The ethical implications of hESC research in the US have been reflected in federal funding policy and in research oversight. In 2003, the National Academy of Sciences (NAS) established a committee to develop guidelines for institutions and investigators conducting hESC research . The NAS in 2010 , comprehMany research institutions have created ESCROs or ‘SCROs’ to review hESC and iPSC research; others rely on their institutional review boards or their animal care and use committees or both. As stem cell research diversifies, its ethical oversight also becomes more diverse, and questions have been raised regarding the ongoing need for specialized committees like ESCROs and SCROs ,10. The Controversy about the derivation and use of hESCs led investigators to seek less ethically fraught but maximally useful types of stem cells . The hisIn research with iPSCs as well as with other types of stem cells, it is essential that preclinical studies in animal models and other media be sufficient to justify the progression to clinical trials. Toxicity and the risk of tumorigenicity must be assessed for all stem cell-based products, especially when genetically modified, in order to minimize the risks of harm as far as feasible before moving to humans ,17,26,40Concern about the research use of animals - especially non-human primates - in preclinical research, including iPSC research, is growing and must be addressed; at the same time, researchers are increasingly aware that good animal models are often unavailable or inadequate to predict effects in humans. Thus, considerable uncertainty continues to surround first-in-human trials and other early-phase studies using stem cells, even as the rapid pace and apparently improving safety of iPSC creation tempt the field to move rapidly into clinical research and even therapeutic applications ,25,41.Clinical trials of iPSCs and other highly pluripotent stem cell interventions generally enroll patients as subjects at all trial stages, as using healthy volunteers may raise safety concerns or compromise the value of the data. All clinical trials must, of course, be carefully designed, rigorously justified, and properly conducted in order to protect the rights, interests, and welfare of trial subjects and contribute to generalizable knowledge ,26,35,40The Geron trial provides just one instructive example. In late January 2009, the FDA approved the first clinical trial of an hESC-based experimental intervention for spinal cord injury. The product, oligodendrocyte progenitor cells (OPCs), is thought to remyelinate spinal cord axons. The trial was to enroll a small number of patient-subjects with recent serious spinal cord lesions. It was placed on hold once by the FDA to ensure the purity and safety of the OPCs and ultimately was halted by the sponsor, Geron Corporation , for reasons of cost, after only four patient-subjects had received the intervention.Both the trial’s design and its ultimate discontinuation were controversial. Its design caused controversy because the subjects were enrolled very soon after a serious injury, making understanding and consent challenging in this first-in-human trial and in addition making it potentially difficult to distinguish between spontaneous recovery of function and remyelination attributable to the intervention. Patients with older lesions, though very probably in a better position to make decisions about trial participation, have scar tissue that makes remyelination unlikely or impossible. The sponsor’s premature discontinuation of the trial was problematic because data insufficiency renders worthless not only its own investment but also those made by patient-subjects and investigators. The outcome had the potential to discourage pioneering stem cell research in the future ,43,44. NDisclosure and discussion of uncertainty with potential subjects in stem cell trials are essential in order to reduce the incidence of therapeutic misconception, whereby research subjects and also investigators and oversight bodies view research as a treatment modality or significantly overestimate the likelihood of direct benefit or both -22,41. TMany types of multipotent and highly multipotent stem cells have been identified as potentially suitable for clinical applications. Some of the most significant challenges faced in clinical application include how quickly to move forward in the face of great promise, great uncertainty, and great clinical need; how to regard research with investigational interventions that are difficult to standardize and impossible to undo; and how to define and describe these uncertainties in the consent process. A growing number of prestigious academics from both science and bioethics are calling attention to these challenges ,24,26,42One prominent scientist commentator compares the current state of stem cell research with the histories of HSC transplantation and gene transfer research, citing several principles: risks of harm should be commensurate with the severity of the condition under study, preclinical animal models remain critically important, and gaining insight into therapeutic mechanisms is essential to the success of a line of clinical research. He advocates ‘a conservative approach to clinical translation of stem cell therapies’ at present, not because of risks of harm, ‘but rather because our understanding of the mechanisms by which stem cells might prove useful, and in which diseases, remains primitive’ . Similarex vivo organoids), are essential components of disease modeling and drug discovery. ‘Body-on-a-chip’ types of three-dimensional organoid arrays hold great promise for improving drug development, disease modeling, and pharmacogenomic research, by lowering costs, speeding results, and increasing the safety and potential efficacy signaling of first-in-human trials, and considerable research is under way [Some applications of stem cell research, such as disease modeling, drug discovery and testing, cell line banking, and commercialization of stem cell therapies, also give rise to ethical considerations specific to the field -26,28,29nder way . That prnder way ,26,47-50As potentially therapeutic applications proliferate for different highly multipotent stem cell types and as technical barriers to the collection and perpetuation of cell lines continue to fall, proposed research and treatment uses abound for both autologous and allogeneic stem cells. In particular, the development of public and other broadly accessible biobanking models for stem cells derived from umbilical cord blood, amniotic fluid and placental tissue, urine, and adipose tissue holds promise for easy collection of good allograft matches for a large percentage of the population but also requires attention to ethical and policy issues ,51.Justice is a necessary but neglected consideration in all scientific research. Like many novel biotechnologies, gene- and cell-based and regenerative medicine interventions and products can be extraordinarily costly and time- and labor-intensive to develop and use. Justice thus requires attention to the costs of developing stem cell therapies and making them available, with the goal of reducing unfair disparities in access. Cost is a standard distributive justice concern. Less commonly discussed is the effect of research funding decisions on health disparities - both priority-setting within research and priority between research funding and funding for medical care, public health, and other public goods -21.Justice considerations are addressed in stem cell research and therapy in several ways. The first is biobanking policy and practice. The rationale for public stem cell banking is to provide a resource for transplantation of blood-forming HSCs to virtually anyone. Ideally, large-scale banking efforts could store enough different lines of broadly multipotent and pluripotent stem cells, suitable for use in regenerative medicine applications, to provide good matches for nearly the entire population of the US. Comprehensive systems for the collection, storage, and use of stem cells of different types are, however, still in the early stages of technological and policy development. Scientific, practical, and ethical challenges include ensuring broad availability of matches for those in need, determining access for both research and therapy, refining consent forms and processes, and protecting confidentiality in labeling and information linkage ,26,51,52The second justice-promoting feature of stem cell research and therapy has some similarities. Attempts to standardize and streamline production are more prevalent in stem cell-related research than elsewhere - especially in development of cell-based products and in regenerative medicine. In other new technologies like gene transfer, standardization, the development of platform technologies, and attempts at large-scale, cost-reducing production are in their infancy. This production perspective is an important step in reducing time, labor, and costs and thus increasing access, but it could also have interesting ethical implications. Autologous or individually ‘compounded’ cell-based interventions will certainly be more costly and less readily available - and will take more time to produce - than allogeneic and other ‘mass-produced’ cell-based interventions, which may provide a less-than-perfect match or fit for a given patient. Such differences could have efficacy implications that must be monitored and balanced against cost savings and access gains .A final justice consideration that is heightened in the stem cell context is the simple reality that important work dedicated to improving the health of the public takes place in a market system with its attendant pressures of competition and commercialization. The attempt to ensure that hope does not become hype and that hype does not become fraud is a matter of justice. Thus, sound practice in clinical translation, careful discussion in the media, and even seeking balance between scientific transparency and data-sharing and the intellectual property interests of industry all have important justice implications -29,42,53Individual researchers may at first regard justice considerations as somewhat removed from their daily work at bench or bedside. The goals of advancing knowledge and, ultimately, improving human health are nonetheless social goals, not merely scientific goals. Researchers make vital contributions to societal views about the value of - and best directions for - scientific progress. For this reason alone, it is worthwhile for researchers to keep in mind the population-level applications of stem cell research as well as the effects of stem cell therapy on individual health.As our discussion has shown, many of the ethical and policy issues that are most significant for stem cell research and therapy are similar to those arising in other novel biotechnologies. Consideration of these issues in both scientific and bioethics literatures addresses many common themes: the minimization of risks of harm; the importance of information disclosure and informed consent; the potential for overpromising, overexpectations, and the therapeutic misconception; and the pressure from disease constituencies and commercial entities to move quickly into the clinic, too often at the expense of understanding basic mechanisms. In the realm of clinical translation, trial-specific examinations of ethical issues continue to provide important guidance, not only with regard to the trials specifically considered but also as models for investigators starting down new translational pathways.Although the creation and use of hESCs have long been the unique focus of stem cell ethics, more current controversies include the creation, for research use, of human embryos, human-animal chimeras, and gametes. Yet these marquee controversies are, in the long run, less important for the field as a whole than are more mundane, justice-oriented concerns like the creation and use of stem cell banks for research and therapy, facilitation of ‘off-the-shelf’ stem cell applications that could be less costly though perhaps less than perfect, and questions of consent, provenance, and policy. Finally, moving forward with the right blend of creativity and caution is essential, in the interest of both science and patients. In all areas of stem cell research and therapy, nuanced consideration and discussion of the best translational pathways, as viewed by ethics as well as science, will play a vital role in balancing hope and hype now and in the future, as the field continues its rapid progress.ESCRO: embryonic stem cell research oversight (committee); FDA: US Food and Drug Administration; hESC: human embryonic stem cell; HSC: hematopoietic stem cell; iPSC: induced pluripotent stem cell; NAS: National Academy of Sciences; OPC: oligodendrocyte progenitor cell; SCRO: stem cell research oversight (committee).The authors declare that they have no competing interests.


Falls and fall-induced injuries are major global public health problems. Balance and gait disorders have been the second leading cause of falls. Inertial motion sensors and force sensors have been widely used to monitor both static and dynamic balance performance. Based on the detected performance, instant visual, auditory, electrotactile and vibrotactile biofeedback could be provided to augment the somatosensory input and enhance balance control. This review aims to synthesize the research examining the effect of biofeedback systems, with wearable inertial motion sensors and force sensors, on balance performance. Randomized and non-randomized clinical trials were included in this review. All studies were evaluated based on the methodological quality. Sample characteristics, device design and study characteristics were summarized. Most previous studies suggested that biofeedback devices were effective in enhancing static and dynamic balance in healthy young and older adults, and patients with balance and gait disorders. Attention should be paid to the choice of appropriate types of sensors and biofeedback for different intended purposes. Maximizing the computing capacity of the micro-processer, while minimizing the size of the electronic components, appears to be the future direction of optimizing the devices. Wearable balance-improving devices have their potential of serving as balance aids in daily life, which can be used indoors and outdoors. Falls and fall-induced injuries are major global public health problems ,2,3. AppSince poor balance during standing and walking is the leading cause of falls, some researchers have used state-of-the-art technology to monitor balance performance and provide instant feedback reminding on the necessary postural adjustments in an attempt to improve balance. Floor-mounted force plates ,17,18,19To make the overall system portable, some other devices using wearable sensors to monitor the balance performance were developed ,30,31,32All those wearable inertial motion and force sensors were connected to computers/smartphones, which analyzed postures by interpreting the body motion and plantar force signals. To provide biofeedback, control signals were then sent to a display  ,57,58,59et al. reviewed recent wearable foot plantar pressure measurement systems [et al. reviewed the effects of smartphones on detecting falling risks and preventing falls [et al. summarized the advantages of using body-worn movement monitoring technology for balance and gait rehabilitation [There are a growing number of wearable devices aimed at improving static and dynamic balance in patients or aged population, and several relevant reviews have been conducted. Razak  systems . They ma systems , and conng falls . They colitation . Based oThis paper extends previous efforts by reviewing various biofeedback systems with plantar force and inertial motion sensors that are wearable. A better understanding of the effective design of previous devices can shed new lights on future design of wearable biofeedback devices to improve balance and reduce falls. The objectives of this study were: (1) to review the underlying wearable sensing mechanisms and commonly employed balance assessment methods; (2) to summarize the key design concepts of biofeedback systems using wearable motion sensors; (3) to examine the effectiveness of biofeedback systems with wearable sensors on improving balance performance; and (4) to suggest future design directions of wearable biofeedback systems that could potentially make them sustainably viable.Inertial motion and plantar force sensors are the most commonly used sensors to objectively evaluate body motion. Their small size allows them to be wearable. Inertial motion sensors can detect the postural sway by measuring the linear acceleration, angular velocity, and direction of body movements. Plantar force sensors can detect the postural sway and gait variability by measuring the COP trajectory at plantar surface of foot and stance/swing time during walking, respectively. The range, average, and standard deviation of these quantities are used to evaluate the degrees of postural sway and gait variability. Generally, increases in postural sway and gait variability are interpreted as a deterioration of balance performance ,27,73. AState-of-the-art inertial measurement units (IMU), based on microelectromechanical systems (MEMS), can incorporate up to all nine axes of sensing in a single integrated circuit package. The units consist of a tri-axial accelerometer, a tri-axial gyroscope, and a tri-axial magnetometer ,74, measThe tri-axial accelerometers could detect the acceleration of X, Y, and Z movements in a three dimensional space. The underlying mechanisms are that the accelerometers independently measure the respective acceleration in each of the three directions, or the so-called “g-force”, as a vector quantity. The output of an accelerometer is normally expressed as in Equation (1):te frame .Based on the detected changes of magnitude and direction of g-force, the direction of linear movements of an object could be obtained . This ism represents the mass, The gyroscopes could measure the extent and rate of rotation in a three dimensional space  . They ared force .The gyroscope involves a spinning disc in which the axis of rotation is free to assume any orientation. The orientation of this axis is not affected by instantaneous tilting or rotation of the mounting object according to the conservation of angular momentum, which allows the gyroscopes to detect more accurate movement within a three-dimensional space than using accelerometers only in a relative short time period .The magnetometers could provide the direction information or the absolute angular measurements relative to the Earth’s magnetic field . The detEither a tri-axial accelerometer or a tri-axial gyroscope can already provide orientation information of an object. However, the accelerometer only measures linear acceleration along one or several axes, and the signal measured by an accelerometer is biased by gravity . It alsoP is the pressure at plantar surface of each foot, p(x), p(y) is the pressure depends on the distance x, y from a reference line, ∫dx, ∫dy is the integration of a continuous function.In addition to the inertial motion sensors that measure the body inclination directly, the force sensors located at plantar surface of foot measured the plantar force/pressure information, which could be further analyzed to assess balance performance. Plantar foot surface is 3-dimensional, with the presence of foot arches. The degrees of freedom of these plantar pressure measurements are determined by the number and positions of the sensors being used. The common balance indicators derived from plantar force sensors include COP trajectory and variability of spatial-temporal gait parameters. The force sensor’s location at insoles and the force measured by multiple force sensors could be used to calculate the location and trajectory of center-of-pressure (COP) (Equation (3)):The parameters calculated based on the trajectory of COP during standing  and walkIn addition to the COP variability, gait variability could also be determined based on the variation of stance and swing time, and weight-bearing asymmetry measured by the force sensors put under the left and right feet . Some syTo evaluate the clinical values of biofeedback systems with wearable sensors, balance assessments have to be conducted comparing the differences between with and without the use of the systems.Assessment of balance control is important to evaluate risk of falling and can be grouped into two categories: static and dynamic ,84. StatInstrumented and non-instrumented tests have been adopted to evaluate static and dynamic balance. Instrumented tests commonly measure the movement of COP during standing using a floor-mounted force plate, or movement of COM during standing/walking using inertial motion sensors integrated in a smartphone or infrared cameras and reflective markers adhering to the body bony landmarks. Non-instrumented tests mainly consist of some clinical tests, balance assessing scales and questionnaires. They are widely applied in clinical practice, as these tests do not rely on bulky electronic instruments and are easy to administer. Only simple objects, e.g., stopwatch, pencil, and paper, are used to do the recording. Sometimes, both instrumented and non-instrumented approaches are used to obtain a better picture of balance performance.While maintaining the COP within the base of support is the key to maintain balance , balanceM is the total body mass, im is the mass of the ith segment, iCOM is the coordinate of the ith segment, and N is the number of segments defining the body COM [The COM is defined as the point that equivalent of the total body mass in a global reference system and is the weighted average of the COM of each body segment in a three dimensional space . Measurebody COM . Generalbody COM .l being leg length and g the acceleration of gravity [XcoM is the extrapolated center of mass, x is the projection of the COM position on the ground, xv is the velocity of COM, l is the leg length, and g is the acceleration of gravity [Some researchers also proposed the use of extrapolated COM (XcoM), based on the inverted pendulum theory, to evaluate the postural stability in dynamic situations. The extrapolated center of mass is defined as the center of mass position plus the center of mass velocity multiplied by a parameter related to the subject's leg length. The XcoM usually moves away from the COP, and the COM ultimately follows the XcoM. To maintain balance, the position  of the COM plus its velocity times a factor  gravity ,92. The  gravity ,92. Larg gravity ,92.In addition to conventional static and dynamic balance assessments, the balance control would be more challenging by adding some perturbations . The common interventions include requiring the subjects to stand/walk on a foam pad ,94 or moCommon static balance tests include the Romberg test, which compares postural stability between the eyes-open and eyes-closed states during standing with feet together, upper limbs crossed over and hands rested on the opposite shoulders . It evalThe so-called Tandem Standing Test is the “sharpened” or “challenging” Romberg test and asks the subjects to stand in the tandem position, which is to stand with the heel of front foot touching the toe of back foot. In this standing condition, the proprioceptive input from the ankle joints would become more discordant compared with the vestibular and visual inputs, which makes the test more sensitive to dysfunctions of proprioceptive sensory systems .Evaluation of LOS requires the subjects to stand quietly first, then lean their trunk forward as far as possible while maintaining the maximum leaning position without loss of balance . The subThe SEBT has been a widely adopted dynamic balance test to assess presence of pathological conditions and effectiveness of interventions, with high level of reliability and validity to identify dynamic balance deficits . It requThe tandem gait is the walking pattern with the heel of front foot touching the toe of back foot at each walking step ,102. GenThe BBS is a balance assessment questionnaire that measures subjective perceived balance ability while performing each of the 14 daily activities, including transferring, standing unsupported, rising from a sitting to standing position, tandem standing, turning 360° and single-leg standing ,104. TheThe Timed Up and Go test (TUG) is commonly employed to detect dynamic balance deficits in patients and elderly people . When peThis review considered studies that included healthy adults, as well as patients with balance disorders, including stroke, neuropathy, lower-limb amputation, vestibular diseases, cerebral palsy, spinal cord injury, and Parkinson’s disease. Studies were included in this review only if the participants were adults aged 18 years or over.This review considered studies that used wearable sensors to detect balance and provided instant biofeedback based on the detected information. The sensors included wearable inertial motion sensors  and force sensors placed at plantar surface of foot. Studies that provided visual, auditory, electrotactile or vibrotactile biofeedback were included in this review.This review considered studies that included the following intervention outcome measures: (1) instrumented measurements, including displacement of COP, COM, spatial-temporal and kinematic gait parameters; and (2) non-instrumented measurements, including standard clinical assessments, questionnaires, and verbal reports. Instrumented measurements were conducted using either the wearable sensors integrated in the biofeedback systems or extra sensors that were not part of the biofeedback system. Non-instrumented tests were conducted based on the examiner’s subjective observation, and the results of questionnaires and verbal reports.This review considered experimental study designs, including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies, and analytical cross sectional studies for inclusion. This review also considered descriptive epidemiological study designs, including case series, individual case reports, and descriptive cross sectional studies for inclusion.Published studies were searched following the guidelines of the standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). A three-step search strategy was employed. An initial search at MEDLINE only was undertaken to analyze the words contained in the titles and the abstracts, and the index terms that were used to describe the articles. The aim of this search was to identify appropriate keywords (Step 1). A second search was then undertaken to use all identified keywords and index terms to search across all included databases to identify all papers suitable for this review (Step 2). Thirdly, the reference lists of all identified reports and articles were also searched for more relevant studies (Step 3). Studies published in English and published from 1995 to 2015 were included in this review. The searching results are shown in the following flow chart, a total of 379 publications were found . The keyQuantitative papers selected for retrieval were assessed for methodological validity prior to inclusion in the review, following the instructions of JBI-MAStARI. Two reviewers, who were not blinded to the authors and journals of the publications, independently assessed the quality of each included study in terms of grade of recommendation and level of evidence using the scoring protocol developed by the Oxford Centre for Evidence-based Medicine . This scThe highest level of evidence is systematic review (with homogeneity) of randomized controlled trials, and the lowest is expert opinion without explicit critical appraisal. A Downs and Black quality list was adopted to assess the reporting quality, methodological design, external validity and internal validity, and statistical power of all included randomized and non-randomized studies following the standard procedures as specified in  Table 4Table 4. Qualitative data were extracted from papers and included in the review using the standardized data extraction tool from JBI-MAStARI. The data extracted included specific details about the interventions, populations, study methods, and outcomes of significance to the review question and specific objectives.Studies were then summarized according to the following characteristics: methodological quality and level of evidence; study design; sample size; sample characteristics (age and gender); key characteristics of the device; follow-up time; outcome measures ; and results. The summary of these study characteristics were demonstrated using figures and tables in the following sections. Data synthesis using a meta-analysis was not possible due to the variety of study designs, methodologies, and outcome measures.Seventeen publications were included in this review . In termAs shown in Force sensors were attached to the plantar surface of foot to measure the ground-reaction-force information, which were processed and used to estimate the weight bearing asymmetry between affected and sound sides ,49,50; eDifferent kinds of biofeedback have been provided . Single The outcome measures of balance performance incorporated in these studies varied with respect to assessment specificity . Of all Both instrumented tests and non-instrumented tests were used for balance evaluation. The studies used self-contained wearable sensors only ,49,64,89There was one study reporting only four out of 10 subjects showed balance improvements upon using the biofeedback system integrated with inertial motion sensors . HoweverA total of eleven reviewed studies evaluated the effects of the use of inertial motion sensors on static balance. Among them, except one study found positive effects in only four out of 10 patients with bilateral vestibular issues , while aNone of the involved study aimed to enhance dynamic balance with inertial motion sensors only.One study tested if a visual biofeedback system with both plantar force sensors and inertial motion sensors enhanced dynamic balance of suhjects with balance and gait disorders . A pair One study evaluated the static balance effects of using a vibroactile biofeedback system with force sensors put at the plantar surface of the foot . Four viA total of four studies evaluated the dynamic balance effects of biofeedback systems with plantar force sensors. The force sensors were put at the heel and forefoot to detect the onset of heel-strike, flat foot and toe-off, and stance time during walking. Clues about the occurrence of heel strike and toe-off, as detected by force sensors, were provided to users via auditory , visual-This investigation of the literatures about biofeedback systems incorporated with wearable sensors demonstrates the potential of applying wearable sensors and biofeedback to enhance static and dynamic balance performance in patients and aged population. Furthermore, this systematic review also builds on the previous research by examining specific design of biofeedback devices that may influence the efficacy of improving balance.Overall, evidence supports the effectiveness of biofeedback systems in enhancing static and dynamic balance among healthy adults and patients with balance disorders. The three studies with high level of evidence and high level of recommendation strongly supported the effectiveness of inertial motion sensors and force sensors in enhancing static and dynamic balance ,47,50. TThe wearable characteristics of the sensors would enable them to provide augmented feedback in indoor and outdoor conditions. Significantly reduced postural sway, weight bearing asymmetry, and gait variability were achieved upon using them. Wearable sensors enable objective assessment of balance and gait abnormalities compared with assessments based on clinician/researcher’s subjective perception ,113,114.The wearable sensors that appeared in the publications reviewed in this paper could be divided into two categories: (1) inertial motion sensors, including accelerometers, gyroscopes, and magnetometers; and (2) plantar force/pressure sensors. Information about the body tilt, joint coordination, weight bearing asymmetry, plantar force distribution, and gait variability were detected based on these sensors.It can be seen that inertial motion sensors were applied mainly in detecting body sway at static conditions. When it comes to dynamic situations, plantar force sensors were needed . One majWhile some previous studies have suggested that wearable sensors could monitor the body motion outside laboratory environment accurately and reliably ,45,48,69This review highlights several issues that merit further exploration. Firstly, most early studies only focused on enhancing static balance or postural stability during standing ,110,111.Secondly, although the existing research provides evidence for the ability to improve balance performance by providing biofeedback based on body motion measured by wearable sensors, it is not clear what effects of these improvements have on function in daily life or risk of falls. Outcome measurements could be expanded to include functional measures of balance performance relevant to daily life, including ascending and descending stairs, walking on slopes, or some dual-task conditions. Future studies should also incorporate the prospective long-term effect of these devices on simple and more functional balance assessments.Thirdly, the decision-making of choosing appropriate sensors could be made after thorough evaluations and be further utilized based on the user’s condition in the future. Combined inertial motion and force sensors should be superior for the development of new wearable device, as they could compensate each other’s function . There aFourthly, the biofeedback devices could be developed more wearable and more appropriate for outdoor uses in the future. Some of the previous biofeedback devices were connected physically to computers for analyzing signals and sending feedback ,39,40,41Fifthly, most of the wearable devices have not been fully utilized for balance enhancement in commercial market yet. Attempts have been made to turn commercially available smartphones into wearable balance-improving biofeedback devices. Researchers used built-in inertial motion sensors to monitor postural balance ,89, and Finally, in order to strengthen the evidence base of enhancing static and dynamic balance performance through wearable biofeedback systems, future studies could recruit larger, more representative samples, and apply a standard set of assessment methods to allow possible cross-study comparison and meta-analysis. Randomized controlled trials should also be conducted.Seventeen clinical trials evaluated the effectiveness of biofeedback systems based on wearable sensor measurements in a total of 282 subjects were reviewed. Due to heterogeneous outcome measures, the quantitative synthesis and meta-analysis were excluded unfortunately. Furthermore, the quality of evidence in this review was mixed, with a risk of bias, as some studies did not adopt randomization.Studies incorporated a variety of experimental protocols and different outcomes to assess the effectiveness of the devices. This led to the difficulty of identifying the optimal device design and providing specific recommendations. The lack of long-term follow-up period also made it difficult to determine the existence of retained effect of these devices.A synthesis of research examining the effect of biofeedback on static and dynamic balance performance based on body motion information measured by wearable sensors suggests that most of these devices are effective. Inertial motion sensors and plantar force sensors have been adopted to capture the body motion in static and dynamic conditions, including head/trunk tilt, lower-limb joint co-ordination, weight bearing asymmetry, and spatial-temporal gait variability. A variety of feedbacks  were delivered to the users. The design of these devices could be further optimized by applying some state-of-the-art technologies to make the devices more lightweight, with more powerful processing capacities, smaller size, and higher usability. Some smart products could be integrated/connected with wearable sensors wirelessly to compute body balance and provide various biofeedback information. These devices have a good potential to be used as laboratory- and home-based rehabilitation training devices, as well as balance aids in daily life. Numerous various populations could be benefit from these devices in the future.


Chronic excessive alcohol consumption induces cognitive impairments mainly affecting executive functions, episodic memory, and visuospatial capacities related to multiple brain lesions. These cognitive impairments not only determine everyday management of these patients, but also impact on the efficacy of management and may compromise the abstinence prognosis. Maintenance of lasting abstinence is associated with cognitive recovery in these patients, but some impairments may persist and interfere with the good conduct and the efficacy of management. It therefore appears essential to clearly define neuropsychological management designed to identify and evaluate the type and severity of alcohol-related cognitive impairments. It is also essential to develop cognitive remediation therapy so that the patient can fully benefit from the management proposed in addiction medicine units. Alcoholism causes a multitude of social and health problems with negative impact on quality of life and secondary costs to society –3. EvideFrom a neurobiological perspective, alcohol-dependence is a chronic disorder, which implies the dopaminergic system. As seen in other drugs abuses, alcohol consumption acutely stimulates dopamine (DA) release from the major terminal area of the mesolimbic DA system, nucleus accumbens (NAC). Enhanced DA transmission in the NAC plays a critical role in the positive rewarding aspects of drugs abuses and the initiation of addictive process. Chronic administration is associated with functional alterations of this important part of the brain reward system. Globally, dysregulation of the dopaminergic system caused by chronic alcohol consumption produces drug dependence reinforcement and is most likely involved in the development of drug addiction –18.The harmful effects of chronic alcohol consumption on the brain and cognitive functioning have been well described in the literature over recent decades . CognitiNeuroanatomical alterations can account for cognitive impairments affecting various functions, primarily executive functions . Fifty tIhara et al.  defined The characteristic profile of alteration of episodic memory in alcohol-dependent patients comprises limited learning capacities, impairments of encoding, and recollection processes, difficulties recalling the temporospatial context and deficits of autonoetic consciousness, while information storage is preserved , 30. AltFinally, visuospatial functions are also predominantly affected, as several studies have demonstrated impaired performances on visuospatial processing, memory and visual learning, visuospatial organization, and visuoconstruction tasks , 32.Three main hypotheses have been proposed in the literature to account for the characteristic cognitive profile observed in alcohol-dependent patients [see Ref.  for a deThe first hypothesis is based on the pervasiveness and impaired recovery after withdrawal of visuospatial cognitive functions that are attributed to the non-dominant hemisphere. The right hemisphere would therefore be more susceptible to the neurotoxic effects of alcohol . HoweverChronic excessive alcohol consumption induces global brain atrophy characterized by reduction of brain volume and enlargement of the ventricles and sulci . The sevMore precisely, Kril et al.  estimateAlcohol-related brain damage also concerns the limbic system and particularly the hippocampus, regions involved in episodic memory –44. The Finally, the cerebellum is also affected in these patients, with a reduction of the white matter volume in the vermis and cerebellar hemispheres . A studyIn this context, the detection of cognitive impairments in alcohol-dependent patients is therefore essential and should be systematic. The Montreal Cognitive Assessment (MoCA) Test appears to be the most appropriate screening test for detection of cognitive impairments in these patients , as thisIn the alcohol-dependent population, the most susceptible executive processes to be evaluated are working memory, mental flexibility, inhibition, processing speed, concept formation, planning, and problem-solving capacities. Evaluation of verbal and visual memory must focus on encoding, recall, storage, learning, and recognition capacities, while assessment of visuospatial functions must focus on visuospatial organization and visuoconstruction capacities.The study of the implicit mechanisms involved in addictive behavior has been considerably developed over recent years. The addictive problem of alcohol-dependence results from a conflict between an urge to drink and the desire to limit alcohol intake. Dual-process models can explain this conflict by the fact that drinking behavior involves two cognitive systems: an impulsive system and a reflexive system . The impThe interaction between the two systems has been clearly documented in the field of alcohol-dependence . AccordiThe study of alcohol-dependent patients also constitutes a model of brain plasticity, as an increase of brain volume characterized by increased white matter and gray matter volumes and a reduction of the size of sulci and ventricles is observed right from the first months of abstinence –60. The In parallel, it has been shown that new brain regions can be recruited by recently weaned alcohol-dependent patients to compensate for alcohol-related brain damage , 67. NeuHowever, although abstinence allows an improvement of cognitive functions, this is only achieved after a period of several months. A recent meta-analysis showed that, despite studies showing early cognitive recovery, a global deficit was still present several months after installation of abstinence and the cognitive profile tended to become normal only after 1 year of abstinence, while certain residual cognitive impairments may persist. For example, the presence of visuospatial function deficits may be observed after several years of abstinence, related to the decreased volume of the right parietal cortex .Appropriate management of alcohol withdrawal is mandatory to prevent severe complications like delirium tremens or epileptic seizure. Prevention of Wernicke’s encephalopathy relies on thiamine prescription. If benzodiazepines usage and appropriate rehydration are codified, the dose and duration of thiamine treatment remains unclear . NeverthThe presence of cognitive impairments therefore requires adaptation of the management of alcohol-dependent patients. CBT has been demonstrated to be effective in the management of alcohol-dependence , but it The efficacy of CBT would therefore depend on the integrity of certain brain regions of interest. For example, it has been shown in schizophrenic patients that the volume of gray matter in the frontal, temporal (including hippocampus), parietal, and cerebellar regions, brain regions that are also damaged in alcohol-dependent patients, is predictive of the efficacy of management . SimilarCognitive behavioral therapy in addiction medicine also requires elaborate cognitive capacities such as episodic, semantic and procedural memories, and executive functions , 73–77. Cognitive impairment can also influence the expression of individual and environmental factors involved in management, such as self-efficacy, readiness to change, active participation in group therapy, or treatment compliance, as the initial cognitive impairment is predictive of poorer treatment compliance and a decreased self-efficacy. Patients with severe cognitive impairments are also less able to use their own resources during management, in which case the prognosis depends more on the role of external factors such as group therapy or the family support network .Finally, Le Berre et al.  demonstrThe presence of cognitive impairments on admission and during the first months of abstinence therefore influences management at various levels by determining the efficacy of treatment and the prognosis for lasting abstinence. Addiction medicine management must therefore be adapted to alcohol-dependent patients with cognitive impairments.In the light of these findings, it appears essential to propose management based on programs ranging from cognitive remediation to optimal use of the remaining capacities. However, very few addiction medicine units propose cognitive remediation therapy and very few studies have investigated this problem in alcohol-dependent patients. The majority of studies in the field are now relatively old , 79 and Studies of the implicit mechanisms involved in addictive behavior also constitute a field of predilection for cognitive remediation. A series of such studies has shown that training working memory and inhibition can lessen the impact of these implicit process on drinking behavior , 86, 87.Data published in the literature suggest that it is essential to take into account the cognitive dimension of alcohol-dependent patients in order to adapt their treatment and to palliate their difficulties in activities of daily living. The brain changes and the profile of cognitive impairments presented by patients with chronic excessive alcohol consumption have now been very extensively documented in the literature. The role of these changes on drinking behavior, especially via the cognitive processes involved in the mechanisms of addiction, also constitutes a rapidly growing new field of research. Finally, the impact of these impairments on the modalities and efficacy of the proposed management is a clinical problem systematically raised in research. The last domain to be developed in the field of management of alcohol-dependent patients is therefore that of cognitive remediation, which can establish the link between the various problems related to cognitive deficits in the clinical management of these patients in order to propose specific targeted follow-up in a remediation therapy program devoted to these impairments.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.


Glucocorticoids play a pivotal role in the management of many inflammatory rheumatic diseases. The therapeutic effects range from pain relief in arthritides, to disease-modifying effects in early rheumatoid arthritis, and to strong immunosuppressive actions in vasculitides and systemic lupus erythematosus. There are multiple indications that adverse effects are more frequent with the longer use of glucocorticoids and use of higher dosages, but high-quality data on the occurrence of adverse effects are scarce especially for dosages above 10 mg prednisone daily. The underlying rheumatic disease, disease activity, risk factors and individual responsiveness of the patient should guide treatment decisions. Monitoring for adverse effects should also be tailored to the patient. Continuously balancing the benefits and risks of glucocorticoid therapy is recommended. There is an ongoing quest for new drugs with glucocorticoid actions without the potential to cause harmful effects, such as selective glucocorticoid receptor agonists, but the application of a new compound in clinical practice will probably not occur within the next few years. In the meantime, basic research on glucocorticoid effects and detailed reports on therapeutic efficacy and occurrence of adverse effects will be valuable in weighing benefits and risks in clinical practice. The value of glucocorticoid therapy was discovered 65 years ago. In 1949, Philip Hench reported the dramatic effect of compound E on rheumatoid arthritis (RA) -7. GlucoGlucocorticoids are very effective anti-inflammatory and immunosuppressive drugs, but their use is restrained by fear for and occurrence of adverse effects Figure .The effects of glucocorticoids are thought to be mediated by different mechanisms -19. ClasThe repressive, anti-inflammatory effects of glucocorticoids were believed until recently to be based mainly on transrepression , whereasIn very high-dose therapy, nongenomic mechanisms also occur, effects of which are evident within minutes . These nThe size of genomic effects of glucocorticoid preparations defines their dose equivalence. Dexamethasone and betamethasone are the most potent preparations, followed by methylprednisolone, predniso(lo)ne, cortisol and cortisone . DosagesGlucocorticoid use  depends on the diagnosis, indications for glucocorticoid therapy, and the goal of treatment . Furthermore, in the case of (transient) acute visual loss, pulse therapy is applied.In the treatment of polymyalgia rheumatica and giant cell arteritis, other immunomodulatory drugs are sometimes added to glucocorticoids as glucocorticoid-sparing agents to decrease the dose or duration of glucocorticoid therapy. However, the results of research into the glucocorticoid-sparing properties of other immunosuppressive medication - that is, use of other agents to decrease the cumulative glucocorticoid dose - are not convincing. Outcomes of randomized controlled trials in polymyalgia rheumatica on the glucocorticoid-sparing effects of methotrexate -27, azatAcute episodes or particularly severe forms of rheumatic diseases and specific complications are indications for pulse therapy. In collagen disorders, pulse therapy is applied for disease induction or treatment of flares. In RA, pulse therapy is used to treat serious complications of the disease and to induce remission in active disease. In the latter, it makes sense to simultaneously start a new second-line antirheumatic treatment aiming at stabilizing the remission induced by pulse therapy, since the beneficial effects generally last about 6 weeks . There aIn systemic vasculitis, high-dose glucocorticoids are the cornerstone of induction therapy and the therapy of flares. Usually, other immunosuppressive drugs are applied simultaneously. In this chronic treatment, the dosages  are gradually reduced in weeks to months to a maintenance therapy of low to medium dose.Another application of high-dose glucocorticoids is intermittent treatment; for example, in gout to treat attacks. In a gout attack, treatment with 35 mg prednisone during 5 days improved pain scores, as did treatment with naproxen . GlucocoChronic glucocorticoid therapy in RA is often started and maintained at a low dose, mostly in addition to other disease-modifying antirheumatic drugs. Glucocorticoid therapy is highly effective for relieving symptoms in patients with active RA in the short and medium term ,40. ImprRecent studies have (re)established the disease-modifying potential of low-dose glucocorticoids in early RA and have renewed the debate on benefits and risks of this treatment -52. BeneAnother type of use is local application of glucocorticoids. In persisting nonbacterial arthritis of a joint, intra-articular glucocorticoid injection can be considered. The effect depends on several factors, such as the treated joint , the activity of arthritis and the volume of synovial fluid in the treated joint, the application of arthrocentesis  before injection, the choice and dose of the glucocorticoid preparation, the injection technique, and application of rest to the injected joint .Among the injectable glucocorticoids, triamcinolone hexacetonide is the least soluble preparation and showed the longest effect . In a raAn alternative to glucocorticoid therapy for intra-articular use has not yet been recognized.There is no doubt that glucocorticoids have a high potential for frequent and serious adverse events. Compared with other antirheumatic agents, glucocorticoids have a low incidence of short-term symptomatic toxicity and patients uncommonly discontinue therapy for this reason. There are multiple indications that adverse effects are more frequent with longer use of glucocorticoids and use of higher dosages ,65, but Therefore, despite over 60 years of use, robust data on toxicities of long-term glucocorticoid therapy are sorely lacking -70. FortIn the following paragraphs, several notorious adverse effects of glucocorticoid therapy are discussed. These paragraphs will give an overview of frequently reported adverse effects in literature. Additionally, we will discuss the influence of disease and treatment scheme on the occurrence of adverse effects.Chronic oral treatment with more than 5 mg prednisone daily can lead to a reduction in bone mineral density and an increase in the risk of fracture . HoweverBone mineral density changes may develop in RA in the absence of glucocorticoid therapy. Previous findings suggest that bone loss in RA patients not on glucocorticoid therapy mainly occurs during the first months of disease ,73. CorrFor adverse effects on bone other than osteoporosis, a major limitation is that trials have not been powered or designed to assess toxicity or long-term effects, and therefore uncertainty of the true incidence and relevance of these adverse effects still remains. In general, osteonecrosis does not occur frequently. The frequency of occurrence clearly depends on the dose of glucocorticoid therapy and the underlying disease. Regarding pulse therapy, osteonecrosis seems to be a more frequent side effect in patients with SLE compared with patients with RA . Both thIn the case of long-term endogenous or exogenous glucocorticoid excess, patients can experience increased appetite. As a consequence, this may contribute to increased body and trunk fat, finally leading to a cushingoid appearance with centripetal fat accumulation and thin extremities with atrophic skin and contusions. A recent trial in RA with 10 mg prednisone daily showed a small but significant gain in weight over 2 years, with a mean of 2.9 kg in the methotrexate-based strategy group treated with prednisone compared with 1.3 kg in the methotrexate-based strategy group treated with placebo-prednisone . AdditioThe incidence of iatrogenic Cushing's syndrome is dependent on dose and duration of therapy. Development of a moon face is uncommon in therapy with sub-physiologic dosages.Many doctors and patients are afraid of the development of diabetes during glucocorticoid therapy , and of In RA and SLE, markers of inflammation correlate with impaired insulin sensitivity and impaired beta-cell function -90. DeteAdministration of glucocorticoids leads to negative feedback on the hypothalamus and pituitary glands, resulting in less secretion of corticotropin-releasing hormone and adrenocorticotropic hormone, respectively. As a result, the cortisol secretory capacity of the fasciculate-reticularis zone of the adrenal cortex may decrease, since this inner cortical zone of cortisol production is dependent on adrenocorticotropic hormone for structure and function.Prediction of the suppression of the hypothalamic-pituitary-adrenal axis and tertiary adrenal insufficiency is not reliable, but their prevalence appears to depend on both the dose and duration of glucocorticoid treatment. In the case of long-term glucocorticoid therapy of up to 10 mg prednisone or equivalent daily, the risk of symptomatic adrenal failure is not high, but also not negligible. In clinical practice, it seems appropriate to anticipate potential adrenal insufficiency in patients who received 7.5 mg prednisone or equivalent for at least 3 weeks. Acute cessation of therapy could lead to problems. Gradual tapering of the glucocorticoid dose is therefore usually applied. In the case of suspected adrenal insufficiency, adrenocorticotropic hormone stimulation testing can help in evaluating the adrenal response . FurtherRandomized clinical trials with glucocorticoids often report a not increased risk of infection ,52,94,95Pneumocystis jiroveci have been reported for dosages from 16 mg prednisone equivalent daily during 8 weeks [Both typical and atypical microorganisms can cause infections. Clinicians should realize that glucocorticoids may blunt classical clinical features of infection, and thereby delay the recognition of the infection and the start of treatment. Opportunistic infections with  8 weeks .The performance of screening tests for infections, such as the tuberculin skin test and interferon gamma release assays, are suppressed by glucocorticoid therapy . FurtherThe risk of upper gastrointestinal tract bleeding or perforation increases about twofold with use of oral glucocorticoids or low-dose aspirin, and increases around fourfold with use of other NSAIDs . This reCases of bowel perforation and pancreatitis have been reported in the context of glucocorticoid use. However, causality between the glucocorticoid therapy and these events is unsure; other factors such as the inflammatory disease might also play a role.Slight increases in sense of well-being are frequently reported by patients starting glucocorticoid therapy. Symptoms of acathisia, insomnia and depression have also been recorded. Similar to the risk of osteonecrosis, the risk of psychosis seems to be a more frequent side effect of pulse therapy in SLE patients compared with patients with RA . WhetherEasy bruising, ecchymoses, skin atrophy, striae, disturbed wound healing, acne and increased hair growth  are undesirable dermatologic effects that occur with glucocorticoid therapy . The phyPosterior subcapsular cataract is a well-described complication of prolonged glucocorticoid use . This tyGlucocorticoid-treated patients may develop mild increased intra-ocular pressure, which can lead to minor visual disturbances. The development of frank glaucoma, threatening eye sight, is rare for low-dose therapy, and tends to appear in patients who are otherwise pre-disposed to the condition. A higher risk for glaucoma with glucocorticoids tends to occur more frequently if other risk factors are present, such as a family history of glaucoma, high myopia and diabetes . In thesSafe glucocorticoid therapy is glucocorticoid treatment with optimal therapeutic effects and with minimal adverse effects. To facilitate safe use, recommendations for the management of glucocorticoid therapy in rheumatic diseases have been developed and have been published in recent years -70. AdveFirst, patients should be informed of what to expect from this therapy. Nowadays, patients are more articulate and stand up for themselves. They should be actively informed about the expectations on both positive and negative effects of treatment with glucocorticoids. This information should be given over time, in small steps. Ideally, this should be supported by written information. Hopefully, this will lead to neutralizing of unfounded fears, earlier recognition of true adverse effects, and patient compliance.Patients with or at risk of glucocorticoid-induced osteoporosis should receive appropriate preventive and/ or therapeutic interventions. In general, all patients starting glucocorticoid therapy at medium to high dose are at risk of developing osteoporosis. Calcium, (active) vitamin D and bisphosphonates have been proven effective in preventing and treating glucocorticoid-induced osteoporosis -115. Pre® fracture risk assessment [Several algorithms have been developed to refine the estimate of the risk of fractures for individual patients, such as the Fracture Risk in Glucocorticoid-induced Osteoporosis score, which includes the glucocorticoid dosage taken, and FRAXsessment -119, forsessment ,121. TheThe initial dose, dose reduction and long-term dosing depend on the underlying rheumatic disease, disease activity, risk factors and individual responsiveness of the patient . Except Optimal choices regarding the use of glucocorticoids in rheumatic diseases are patient specific. The underlying disease, the presence of co-morbidity, the response to initial treatment, and the development of adverse effects should influence treatment decisions. Monitoring for adverse effects should also be tailored to the patient: specific aspects of individual patients may warrant a higher frequency of monitoring or a more comprehensive set of adverse effects to be monitored. Continuously balancing the benefits and risks of glucocorticoid therapy is recommended.The fetus is protected from maternal glucocorticoids since glucocorticoids bound to proteins cannot pass the placenta, and the enzyme 11β-hydroxysteroid dehydrogenase in the placenta converts cortisol and prednisolone into the inactive 11-dehydro-prohormones. The prednisolone maternal-to-fetal blood concentration ratio is therefore about 10:1. The risk of adverse effects of antenatal exposure to glucocorticoids such as reduced intrauterine growth and birth weight, neurocognitive adverse effects and oral cleft seems dependent on the dose, preparation, duration of therapy and stage of pregnancy . AvoidinNew biological therapies have not replaced glucocorticoids, and probably will not replace them in the near future, as anchor drugs in therapeutic strategies for rheumatic diseases. Future research should therefore stay focused on the mechanisms causing beneficial and harmful effects and on predictive factors for the effects of glucocorticoids. Ultimately, response to glucocorticoids should preferably be predictable for the individual patient; studies on genomics and proteomics are being performed currently to this aim.Apart from prediction of the treatment effects, there is an ongoing quest for new glucocorticoids without potential to cause harmful effects. Optimized glucocorticoids, such as selective glucocorticoid receptor agonists, are being developed to minimize the adverse effects many patients experience, especially if glucocorticoids are given at higher dosages over longer periods of time . The mosIn some decades to come, we will hopefully be able to prescribe new drugs with glucocorticoid actions with an improved risk-benefit ratio. Moreover, it might be possible to adjust the use of glucocorticoids and other medication to specific individual patients' needs, characteristics and prognostic factors: personalized medicine. This would lead to a more effective inhibition of the inflammatory diseases with less adverse effects. While this has not been achieved, basic research on glucocorticoid effects and detailed reports on therapeutic efficacy and occurrence of adverse effects will be valuable in weighing benefits and risks in clinical practice.Glucocorticoids are very effective anti-inflammatory and immunosuppressive drugs, but their use is restrained by fear for and occurrence of adverse effects. Many of the adverse effects can be avoided or dealt with when glucocorticoids are used prudently. Optimal choices regarding the use of glucocorticoids in rheumatic diseases are patient specific, as is monitoring for adverse effects. There is an ongoing quest for new glucocorticoids without the potential to cause harmful effects, such as selective glucocorticoid receptor agonists, but the application of a new compound in clinical practice will probably not occur within the next few years.NSAID: nonsteroidal anti-inflammatory drug; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus.The authors declare that they have no competing interests.The authors participated in the design of and helped to draft the manuscript. All authors read and approved the final manuscript.


Listeria monocytogenes is a Gram-positive pathogen responsible for the manifestation of human listeriosis, an opportunistic foodborne disease with an associated high mortality rate. The key to the pathogenesis of listeriosis is the capacity of this bacterium to trigger its internalization by non-phagocytic cells and to survive and even replicate within phagocytes. The arsenal of virulence proteins deployed by L. monocytogenes to successfully promote the invasion and infection of host cells has been progressively unveiled over the past decades. A large majority of them is located at the cell envelope, which provides an interface for the establishment of close interactions between these bacterial factors and their host targets. Along the multistep pathways carrying these virulence proteins from the inner side of the cytoplasmic membrane to their cell envelope destination, a multiplicity of auxiliary proteins must act on the immature polypeptides to ensure that they not only maturate into fully functional effectors but also are placed or guided to their correct position in the bacterial surface. As the major scaffold for surface proteins, the cell wall and its metabolism are critical elements in listerial virulence. Conversely, the crucial physical support and protection provided by this structure make it an ideal target for the host immune system. Therefore, mechanisms involving fine modifications of cell envelope components are activated by L. monocytogenes to render it less recognizable by the innate immunity sensors or more resistant to the activity of antimicrobial effectors. This review provides a state-of-the-art compilation of the mechanisms used by L. monocytogenes to organize its surface for virulence, with special focus on those proteins that work “behind the frontline”, either supporting virulence effectors or ensuring the survival of the bacterium within its host. Listeria monocytogenes is a ubiquitous Gram-positive bacillus and the causative agent of human listeriosis, a rare foodborne infectious disease with a high and particularly severe incidence in immunocompromised individuals and other risk groups, such as pregnant women and neonates. In these hosts, the invasive form of the illness can be symptomatically manifested as septicemia and meningoencephalitis, or abortions and neonatal infections, which contribute to an estimated mortality rate of 20–30% of clinical cases   system, the flagellar export apparatus (FEA), the Esx-1/Wss system and prophage holins  across the cytoplasmic membrane, to be either associated with the cell surface or further released into the extracellular environment. This multimeric system has been thoroughly characterized in Listeria spp.  and MurA (or NamA)  were also identified as SecA2 substrates  remain integrated within the plasma membrane or (ii) be released to either interact with cell envelope structures or diffuse to the extracellular milieu. The latter situation requires the enzymatic cleavage of the N-terminal signal peptide by a specific family of membrane-bound serine proteases, called signal peptidases (SPases)   and substrate sensing systems , which catalyzes the covalent linkage of a phospholipid-derived diacylglycerol moiety to the sulfhydryl group of a cysteine residue located in a lipobox motif, at the end of the signal peptide .To become stably associated with the Gram-positive cell wall, surface protein precursors have to be processed by an enzyme called sortase A. This trans-cytoplasmic, membrane-bound transpeptidase recognizes polypeptides with a C-terminal sorting signal sequence containing a signature LPXTG motif . In addition, proteins may also be tethered to the plasma membrane by a lipid anchor or completely span the bilayer, provided that they contain adequate stretches of hydrophobic residues to act as transmembrane regions  and the C-terminal threonine carboxyl group of the surface protein   an LPXTG pentapeptide motif, (ii) a hydrophobic domain, and (iii) a short positively charged tail , but only the latter is necessary for surface anchoring -tryptophan (W) dipeptide. This cell wall association motif was first discovered in Lactococcus lactis and Enterococcus faecalis autolysins  as the peptidoglycan moiety bound by LysM  was recently characterized as one of two novel listerial resuscitation-promoting factors, i.e., muralytic enzymes important for jump-starting the growth in dormant bacteria  domains are encountered in proteins from a broad variety of organisms, such as plants, fungi, bacteria, and viruses   family of proteases is one of the most conserved in all living organisms and the most predominant group of bacterial extracytoplasmic proteases Figure . Some HtThe cell envelope is a fundamental and defining structure of prokaryotes. In Gram-positive bacteria, it comprises the plasma membrane and a cell wall, which provides physical support and protection against external aggression. Its mesh-like constituent, the peptidoglycan, also acts as a biological scaffold for the surface positioning of proteins and other glycopolymers with relevant physiological roles. The remodeling of the cell wall is vital for bacterial growth and division, and requires a dynamic balance between peptidoglycan assembly and turnover. Coordination between these processes is mandatory to prevent morphological malformations and concomitant functional defects, such as the mislocalization of surface molecules.From an immunological view, the cell wall is a particularly relevant structure. Cell wall turnover events can generate fragments that are specifically recognized by and activate the host innate immune system. In turn, innate immunity effectors, such as lysozyme and cationic peptides, target the cell wall to promote bacterial lysis. The introduction of specific modifications in components of the cell envelope is a strategy developed by bacteria to render them undetectable to both immune recognition and to the bacteriolytic activity of host defense enzymes and peptides -N-acetylmuramic acid (MurNAc) glycan strands. LWM PBPs perform roles linked to peptidoglycan maturation and recycling  and N-acetylmuramidases (NAMases) cleave the glycosidic bond between glycan chain residues GlcNAc and MurNAc, respectively, after GlcNAc and MurNAc; N-acetylmuramyl-L-alanine amidases (or simply amidases) separate the stem peptide from the sugar strand by breaking the bond between MurNAc and L-alanine; finally, endo- and carboxypeptidases hydrolyse the amide bonds within and between stem peptides . Although none of the NAMases have been deeply characterized in a virulence-oriented perspective, two were recently shown to possess lysozyme-like activity in the presence of cell wall substrate and to be required for stimulating the replication of quiescent bacteria, possibly through their impact in cell wall reshaping and thus in cell growth and division  superfamily. Interestingly, most NlpC/p60 proteins are found in the genus O-linked  acetyl groups to the peptidoglycan residues GlcNAc and MurNAc was shown to confer resistance to lysozyme and reduce the activation of the host immune response , but it is a more predominant event, having been detected in numerous Gram-negative and Gram-positive species  or to the plasma membrane , via a linkage unit connected to MurNAc residues or phospholipids, respectively. The abundance of phosphate groups confers strong anionic properties to teichoic acids, which increase the net negative charge of the bacterial surface . Similarly to what was observed in S. aureus  mutants were screened in a mouse model for virulence attenuation  from the membrane  and PrfA   operon  . In addition, nearly 160 other L. monocytogenes genes were shown to have their expression directly or indirectly dependent on PrfA. Among these genes, several encode virulence factors involved in Listeria cell envelope architecture, composition, and modification   predicted to function in stress tolerance, carbohydrate metabolism, transport, and also in cell envelope processes and virulence . Interestingly, a significant subset of these genes is co-regulated by PrfA . PrfA and σB were shown to jointly contribute to processes such as intracellular growth and virulence . The fact that VirR regulates the expression of both dltABCD and mprF genes suggests that the VirR/VirS system plays a role in the modulation of L. monocytogenes resistance against host cationic peptides and constitutes another important virulence regulon involved in Listeria surface adaptation and pathogenesis.VirR is the response regulator element of the VirR/VirS two-component system. VirR was shown to be required for efficient mouse liver colonization and to positively control the transcription of 17 genes  are covalently attached to the peptidoglycan (see Sortases). Recently, the three-dimensional localization of InlA, InlH, InlJ, and SvpA in the cell envelope of L. monocytogenes surface is required for actin-based motility and successful infection (see Hydrophobic Tail) and appears to be a consequence of different cell wall growth rates along the bacterium, of the relative rates of protein secretion and degradation, and of bacterial growth (Rafelski and Theriot, The polar distribution of ActA on the L. monocytogenes. It not only affects Listeria cell separation, but also biofilm formation, host cell invasion and virulence. DivIVA was shown to influence the activity of the Sec system alternative ATPase SecA2, resulting in reduced extracellular levels of the autolysins p60 and MurA and inducing a pronounced chaining phenotype (Halbedel et al., DivIVA is a crucial topological factor required for completion of cell division in Listeria developed a complex regulatory network that links cell growth, cell wall dynamics, cell wall protein anchoring and response to environmental conditions, and coordinates the spatiotemporal expression and activity of surface-associated virulence factors.All these observations clearly demonstrate how 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.