Age-related macular degeneration (AMD) is a well-characterized and extensively studied disease. It is currently considered the leading cause of visual disability among patients over 60 years. The hallmark of early AMD is the formation of drusen, pigmentary changes at the macula, and mild to moderate vision loss. There are two forms of AMD: the “dry” and the “wet” form that is less frequent but is responsible for 90% of acute blindness due to AMD. Risk factors have been associated with AMD progression, and they are taking relevance to understand how AMD develops: (1) advanced age and the exposition to environmental factors inducing high levels of oxidative stress damaging the macula and (2) this damage, which causes inflammation inducing a vicious cycle, altogether causing central vision loss. There is neither a cure nor treatment to prevent AMD. However, there are some treatments available for the wet form of AMD. This article will review some molecular and cellular mechanisms associated with the onset of AMD focusing on feasible treatments for each related factor in the development of this pathology such as vascular endothelial growth factor, oxidative stress, failure of the clearance of proteins and organelles, and glial cell dysfunction in AMD. The hallmark of early AMD is the formation of drusen, pigmentary changes at the macula, and mild to moderate vision loss . There aThe treatment of the wet form had a major breakthrough due to the introduction of antiangiogenic drugs; suddenly, the functional prognosis changed from almost-certain blindness to more than 90% chance of three-line visual improvement after two years of treatment , 4. NeveThere are three main drugs that provide indirect antiangiogenesis by blocking vascular endothelial growth factor (VEGF) in the retina. Ranibizumab  was approved by the Food and Drug Administration (FDA) in 2006 for the treatment of neovascular AMD . It is aThe antiangiogenic treatment is aimed at treating the consequences of long-lasting cellular damage  production) but adds nothing to the prevention and prophylaxis of AMD development. In reality, this therapy is not modifying the course of the disease at all but merely resisting its impact through time and delaying its progression. Moreover, there is no proven treatment available for the dry form of AMD. This is in part because until now, the results of research on AMD are just beginning to unravel the intricate relationship between genetic predisposition, environmental factors, and the normal aging process that take place as part of the disease mechanisms. A better understanding of these relationships will help us to identify better potential treatment targets for both wet and dry forms of AMD.Therefore, the aim of the current manuscript is to review some of the principal molecular mechanisms associated with the pathogenesis of AMD such as the principal mechanism associated with neovascularization through VEGF signaling, oxidative stress, dysregulation of the mechanisms of clearance of proteins and organelles in AMD (autophagy), the pathophysiology of glial cells in the retina on AMD, and closing each subject of this review explaining some of the new potential treatment alternatives for AMD. We have divided the review into two big major subjects: molecular mechanisms and cellular mechanisms, for a better understanding of this work.The AMD process starts with atrophic formation, called dry AMD, characterized by decreased vision principally caused by retinal dysfunction, subsequently, developing to a wet condition. The latter occurs when abnormal blood vessels behind the retina start to grow under the macula; these new blood vessels are very fragile and often have blood and fluid leaks , 6. The The most studied factor related to ocular neovascularization is the vascular endothelial growth factor (VEGF) . VEGF waMembers of the VEGF family ) are proteins of approximately 40 kDa. The VEGF-A's biological activity is dependent on proteolytic processes; the products obtained from this degradation interact differentially with VEGF-R1 and VEGF-R2 receptors .Within this group of proteins, it has been reported that the VEGF-A protein induces vascular proliferation and migration of endothelial cells and is essential for both physiological and pathological angiogeneses.In several diseases, such as rheumatoid arthritis, cardiac ischemia, psoriasis, growth tumor, and diabetic retinopathy, as well as in AMD, the activity of the VEGF-A protein plays an important role. However, the VEGF released in these diseases is due to different factors. The best-studied mechanism of VEGF-A release is associated with the lack of available oxygen; thus, the production of VEGF can be induced in hypoxic cells. When cells are in a low-oxygen microenvironment, they produce the transcription of the hypoxia-inducible factor 1 (HIF-1) inducing the release of VEGF-A . VEGF-A γ) triggering the intracellular calcium release, promoting prostaglandin production, and increasing vascular permeability. The three pathways promote angiogenesis . T. T123]. patients .Based on the preclinical data reported, the initial clinical trials, evaluating the performance of the transplantation of hESC-derived RPE cells to subretinal space, were phase I trials designed to test the safety and tolerability of grafted hESC-derived RPE cells in patients with either dry AMD or Stargardt's macular dystrophy . The firConversely, stem cell generation may present challenges as well. Abnormal gene expression has been reported in some iPSCs, in which the T-cell-mediated immune response can be elicited even in syngeneic hosts . In addiStem cell-based therapies have been the object of an extensive research, and great advances have recently been made towards the generation of stem cell transplantation techniques for the functional replacement of RPE cells and photoreceptors. However, it is crucial to assess the long-term safety and efficacy of the current hESC- or iPSC-based RPE transplantation approach in human patients. Adverse events related to the surgery have to be further studied, and large numbers of patients with microperimetry assessments in conjunction with optical coherence tomography (OCT) and autofluorescence estimation should be evaluated to provide more rigorous structure-function correlations.Recent promising developments in the functional replacement of retinal RPE cells give rise to the expectation that clinical replacement of damaged retinal cells may be able to improve the outcomes of patients with retinal degenerative disease in the near future.As we have seen, there are many factors that influence the origin and progression of AMD and the more relevant pathways associated with chronic retinal degeneration. This opens new windows to provide multiple therapeutic targets for disease treatment. However, the design of new treatments must be very carefully done because most of the altered pathways in AMD are broadly redundant and may induce negative effects. Therefore, the new treatments should be carefully designed to cover different altered mechanisms at the same time. Looking towards the future of AMD therapy, there is an emerging paradigm that diverges from the normal approach of preventing retinal dysfunction and death. We should try to recover retinal health in spite of injury, rather than avoid and eliminate numerous overlapping insults. This kind of research should not be discarded in order to improve AMD prevention and treatment. Some experimental ideas are already being performed in our laboratory.Finally, it is totally necessary to consider the financial burden that AMD represents due to its progressive nature, for example, loss of productivity, and related expenses like nursing homes, caretakers, and comorbidities, and currently available treatment is a significant challenge to any health system. Currently, it represents an excessive direct annual medical cost and, as the incidence raises with the passing of time, the annual cost will increase; for this reason, the finding of a new functional treatment for AMD becomes totally needful.


In addition to thrombus formation, alterations in platelet function are frequently observed in cancer patients. Importantly, both thrombus and tumor formation are influenced by age, although the mechanisms through which physiological aging modulates these processes remain poorly understood. In this context, the potential effects of senescent cells on platelet function represent pathophysiological mechanisms that deserve further exploration. Cellular senescence has traditionally been viewed as a barrier to tumorigenesis. However, far from being passive bystanders, senescent cells are metabolically active and able to secrete a variety of soluble and insoluble factors. This feature, known as the senescence-associated secretory phenotype (SASP), may provide senescent cells with the capacity to modify the tissue environment and, paradoxically, promote proliferation and neoplastic transformation of neighboring cells. In fact, the SASP-dependent ability of senescent cells to enhance tumorigenesis has been confirmed in cellular systems involving epithelial cells and fibroblasts, leaving open the question as to whether similar interactions can be extended to other cellular contexts. In this review, we discuss the diverse functions of platelets in tumorigenesis and suggest the possibility that senescent cells might also influence tumorigenesis through their ability to modulate the functional status of platelets through the SASP. Platelets are key blood components that are continuously generated in the bone marrow through fragmentation of the edges of megakaryocytes . In addiThe functional connection between cancer and platelets has been recognized since the late nineteenth century, when an association between the occurrence of certain solid tumors and the development of venous thrombosis and blood hypercoagulability was first described . Accordivia P-selectin), which in turn is required to stimulate NETosis and a hyper-coagulation/pro-thrombotic state  by allowing the survival of tumor cells in the circulation [circulating tumor cells (CTCs)] . Under nPlatelets may also facilitate the adhesion of tumor cells to the endothelium, generating a locally protected tumor microenvironment that promotes migration of tumor cells. The establishment of this microenvironment also seems depend on granulocyte recruitment  and a plvia the release of ADP and MMP-2  and elevation of markers of platelet activation have both been correlated with physiological aging . MoreoveTaken together, changes in virtually all aspects of hemostasis have been associated with physiological aging. As older adults often show signs of chronic inflammation, it is likely that changes in hemostasis—particularly those involving platelet function—may be part of a more general inflammatory process. So far, however, the age-dependent mechanisms involved in the modulation of hemostasis and platelet function are not completely understood. In the next sections, we advance the idea that cellular senescence might explain, at least in part, some of the hemostatic changes that lead to thrombosis and cancer.Typical hallmarks of physiological aging include impaired tissue regeneration and repair, a functional impairment of progenitor cells, and alterations of the immune system . While tin vitro , a function that only becomes evident in the context of complex tissues. As mentioned in the following sections, these non-cell autonomous capabilities of senescent cells are also emerging as key contributors to the pathogenesis of age-related conditions, including chronic inflammation, fibrosis, and, paradoxically, cancer.via SASP adds a further layer of complexity to the implications of cellular senescence to tissue homeostasis and disease  to produce and secrete pro-inflammatory factors that can result in the activation of platelets. Active platelets—acting synergistically with other components of the tumor stroma—can then promote or enhance tumor progression and metastasis. Paradoxically, many of the factors secreted by tumor cells or tumor-associated inflammatory cells with a known effect on platelet activity are also produced and secreted by cells undergoing senescence, a process originally regarded as tumor suppressive. Indeed, the evidence indicates that cellular senescence may also play an active role in driving, rather than suppressing, tumor formation, a non-cell autonomous role that seems to be largely dependent on the SASP. Accordingly, factors released by senescent cells may help create a pro-tumorigenic microenvironment that enhances proliferation and migration of neighbor cells . AlthougAlterations in hemostasis involving platelet dysfunction or alterations in the process fibrinolysis are at the core of thrombogenesis . As withCV contributed to writing the manuscript, figures, and the final submission. RQ contributed to writing specific sections of the manuscript. RM-C and NB contributed to writing, editing, and discussing the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


National Centers of Competence in Research (NCCR) are funded by the Swiss National Science Foundation to strengthen research in areas of strategic importance for the future of Swiss science, business, and society. NCCRs promote research of the highest quality with a strong emphasis on innovative and interdisciplinary approaches. NCCRs also aim to establish collaborations between academic and non-academic public and private partners, contribute to knowledge and technology transfer, support talented doctoral students and postdocs, and improve the career prospects of women in sciences.The NCCR MUST (Molecular Ultrafast Science and Technology) was launched in 2010 and currently brings together 19 Swiss research groups working in Ultrafast Science across the fields of physics and chemistry. Besides its scientific activities, MUST has a rich program in advancement of women, technology transfer, and education outreach. The Women Professors Forum (eth-wpf.ch) is starting to become an establishment at Swiss universities, and the book “A Journey into Time in Powers of Ten” (Editors Anna Garry and Thomas Feurer) has helped to promote ultrafast science at schools and public events. MUST has also been instrumental in establishing several start-up companies.The collection of articles in this special issue is intended to summarize and review the research carried out within the NCCR MUST and also to give perspectives for future research directions. For centuries, scientists have used theoretical modeling and imaging techniques to understand things invisible to the naked eye and thus advance our knowledge. New theoretical and experimental tools foster new science and new science requires new tools. No matter which perspective one takes, there has been, and always will be, a strong interplay between theoretical, technological, and scientific advancements. Today's requirements on theory and imaging tools have increased well beyond the known, and new frontiers in physics, chemistry, and biochemistry demand the ability to theoretically model and visualize events evolving on ultrafast time and nanoscopic length scales. As a result, MUST scientists are constantly pushing the limits of ultrafast theoretical and experimental visualization tools in pursuit of understanding electronic, atomic, and molecular dynamics and their correlations in space and time.A solid theoretical foundation relies on an adequate modelling of atoms, molecules, and solids interacting with electromagnetic fields and the dynamics induced by the latter. Within MUST, this is pursued on different levels of complexity and quantum, semi-classical, and classical models are used to describe ultrafast dynamics. Ultrafast phenomena are often accompanied by the occurrence of non-adiabatic effects which, from a theoretical perspective, requires us to go beyond the time-independent Schrödinger equation and the Born-Oppenheimer approximation and to identify ways to solve the full time-dependent electronic and nuclear quantum problem in a highly non-equilibrium regime. Within MUST, non-adiabatic processes appear, for example, in tunnel ionization of atoms in strong laser fields, radiation-less relaxation through conical intersections, or coupling of vibrational modes.A continued effort of several groups is to understand the implications of short time scale dynamics on long time processes. This includes vibrationally induced dissociation of small molecules in the gas phase or vibrational and internal energy redistribution through conformational dynamics but also the dynamics of proteins over many time scales. The systems investigated highlight that a comprehensive understanding of how structure, flexibility, energetics, and dynamics contribute to functional dynamics requires a concerted effort of experimental and computational studies.A promising new experimental tool to study and control structural dynamics originates in the dramatic developments of intense pulsed THz sources. Since many dipole-active modes in solids, as well as molecules, lie in this frequency range, there is a tremendous potential to use them to study linear and nonlinear dynamics in such systems.A large fraction of MUST activities is devoted to the understanding of charge transfer processes, which are ubiquitous in nature and play a fundamental role in many areas of chemistry, physics, biology, and materials science. More than 60 years after the seminal work of R. A. Marcus, charge transfer is still an active research field often revitalized by the ability to resolve ever faster temporal processes, even down to the attosecond time scales. Charge transfer occurs when an electron is forced to leave an atom; it occurs within molecules, between molecular centers and ligands, or along hydrogen-bonded molecular chains; and it is at the heart of most natural and artificial light harvesting processes.For example, in light driven ionization, we have seen tremendous advances in our ability to measure the dynamics of photo-induced ionization in various systems in the gas, liquid or solid phase. MUST addresses fundamental questions such as: how long does it take to remove an electron from an atom, molecule or solid, or how many electrons are emitted in a given unit of time? But even before ionization occurs, laser fields are often strong enough to become part of the electronic potential and sometimes even dominate the Coulomb contribution. This manipulation of atomic potentials and of the associated states and bands finds fascinating applications in gases and solids, both in the bulk and at the surface and has important implications on electron dynamics.A highly relevant topic in the context of charge transfer is electron transfer and subsequent charge separation across donor-acceptor heterojunctions, for example, in dye-sensitized solar cells, conjugated polymer- and small molecule-based organic photovoltaics or high-efficiency lead halide perovskites. It is particularly important to unravel the dynamics of photo-induced electron transfer, carrier trapping and association, energy transfer, and relaxation.Surfaces and interfaces often exhibit a chemical activity that is different from the bulk properties. Decisive properties like charge transfer, molecular dipole, and sticking coefficient for molecular adsorption are solely determined by the local coordination of the adsorption sites and, therefore, by the structural arrangement of molecules and surface atoms. Due to the high surface sensitivity of electron-based methods, (photo-) electron diffraction, in general, is one of the most important tools to study adsorption geometries and surface reconstructions.The latest addition to the imaging toolbox of ultrafast science is X-ray free electron lasers. They allow for unambiguous studies of crystalline condensed matter systems where the effects of intense ultrashort light pulses are probed using X-ray diffraction or absorption. Conventional concepts, which are valid at thermodynamic equilibrium, must often be modified in order to adequately describe time-dependent changes in the material properties. For example, a material may be described as a collection of quasi-thermal subsystems in thermal contact with each other or depicted as a function of the fully coherent dynamics of a complex network of excitations. X-ray lasers also allow us to study different subsystems in a crystalline condensed matter system via associated X-ray diffraction peaks. This gives access to the systems themselves but also correlations between them. In novel low-dimensional materials, topological protection and/or electronic correlations result in exotic charge, spin, or orbitally ordered ground states having new functionalities such as multiferroelectricity, high-temperature superconductivity, skyrmion magnetism, and Weyl semimetallicity.The majority of papers in this special issue are concerned with the study of ultrafast phenomena in molecular and solid state systems. These studies have produced new scientific results and advances in theoretical and technological imaging methodologies, and promise to deliver exciting insights and developments in the future.


For achieving the power maximum transmission, the electrical impedance matching (EIM) for piezoelectric ultrasonic transducers is highly required. In this paper, the effect of EIM networks on the electromechanical characteristics of sandwiched piezoelectric ultrasonic transducers is investigated in time and frequency domains, based on the PSpice model of single sandwiched piezoelectric ultrasonic transducer. The above-mentioned EIM networks include, series capacitance and parallel inductance (I type) and series inductance and parallel capacitance (II type). It is shown that when I and II type EIM networks are used, the resonance and anti-resonance frequencies and the received signal tailing are decreased; II type makes the electro-acoustic power ratio and the signal tailing smaller whereas it makes the electro-acoustic gain ratio larger at resonance frequency. In addition, I type makes the effective electromechanical coupling coefficient increase and II type makes it decrease; II type make the power spectral density at resonance frequency more dramatically increased. Specially, the electro-acoustic power ratio has maximum value near anti-resonance frequency, while the electro-acoustic gain ratio has maximum value near resonance frequency. It can be found that the theoretically analyzed results have good consistency with the measured ones. Sandwiched piezoelectric ultrasonic transducers are widely applied in areas such as non-destructive testing (NDT) , structuD) model , it can Regarding the investigation of EIM for piezoelectric transducers, the published articles mainly focused on researching the electrical effect, such as bandwidth, the received amplitude, and the power of the acquired signal ,10,11,12For investigating the effect of EIM networks on the electromechanical characteristics, a simulated model of the piezoelectric ultrasonic transducer with EIM is highly needed. It is well known that the BVD model is determined from an impedance analysis of piezoelectric transducers, but it cannot be used to directly investigate the electromechanical characteristics of piezoelectric transducers. Based on the Mason’s equivalent circuit model  of piezoGiven the above-mentioned considerations, based on the established piezoelectric transducer PSpice model , the effIn this section, the EIM theory for piezoelectric ultrasonic transducers, the used model of single sandwiched piezoelectric ultrasonic transducer, and the parameters calculation of EIM networks, the definition of performance parameters for the single sandwiched piezoelectric ultrasonic transducer, and the pitch-catch setup are illustrated in detail as follows.An ultrasonic wave transmitter usually can be simplified, as shown in Here, However, as for an optimal electrical impedance matching network, the input and output electrical impedance of the EIM network can be indicated asHere, The sandwiched piezoelectric ultrasonic transducer with EIM networks is shown in The EIM networks can effectively implement the compensation of the reactance and the tuning of the resistance for single sandwiched piezoelectric ultrasonic transducer. The piezoelectric ceramic stack is composed of four identical piezoelectric rings, which are thickness polarized in opposite directions. The arrow represents the polarized direction of piezoelectric ceramic rings as shown in =0.0263Ω . Also, tOn the basis of the PSpice model as shown in The resistance n detail . Then, tHere, In this section, the parameters, such as input electrical impedance, reactance and resistance, electro-acoustic power and gain ratio, and vibration velocity ratio, effective electromechanical coupling coefficient are defined.The input electrical impedance can be expressed asHere, From Equation (3), the reactance and resistance can be obtained asHere, From Then, the vibration velocity ratio between the front mass and the back mass is expressed asHere, Similarly, from Here,In addition, the effective electromechanical coupling coefficient cated as :(9)keffcHere, In this section, the parameters calculation of EIM networks for the single sandwiched piezoelectric ultrasonic transducer is illustrated. The specific calculation process mainly has two steps: (1) By using impedance analyzer , the input electrical impedance at resonance frequency is derived; (2) The parameters of EIM networks are conveniently obtained using the Smith chart tool . The EIM networks that are used in this paper, which mainly include I type  and II type , as shown in In the case of matching single sandwiched piezoelectric ultrasonic transducer, the load impedance is the input electrical impedance, which is likely to be seen at the far right end of the Smith chart as shown in In this section, the effect of EIM networks on the electromechanical characteristics of sandwiched piezoelectric ultrasonic transducers is investigated in depth in time and frequency domains on the basis of the PSpice models of single sandwiched piezoelectric ultrasonic transducer and the pitch-catch setup, respectively. The detailed analysis process is described as follows.Nowadays, electromechanical impedance technique has been widely used to analyze the electromechanical characteristics of piezoelectric devices and systems ,27. HereThen, the input electrical impedance and phase, the electro-acoustic power and gain ratio are derived by using AC analysis. For verifying the accuracy of the analysis results, the experimental platform is built which is composed of an impedance analyzer , single sandwiched piezoelectric ultrasonic transducer with EIM circuits, as shown in According to From In addition, In order to research the time domain effect of EIM networks on sandwiched piezoelectric ultrasonic transducers, transient analysis is performed by the PSpice model of single sandwiched piezoelectric ultrasonic transducer, as shown in It needs to be pointed that the above-mentioned transient analysis results are derived under no load. The greater the vibration velocity of the front mass is, the greater the ultrasonic wave inserted in the detected objects is.For further investigation the effect of EIM networks on sandwiched piezoelectric ultrasonic transducers, the AC analysis is performed based on the PSpice model of the pitch-catch setup as shown in The detailed analysis results are illustrated in below. When comparing I type with II type EIM networks, the former makes the resonance and anti-resonance frequencies more substantially decrease. Then From For further investigation regarding the time domain effect of EIM networks on the pitch-catch setup, transient analysis is carried out by the PSpice model, as shown in The experimental platform is primarily composed of two sandwiched piezoelectric ultrasonic transducers, digital oscilloscope, arbitrary waveform generator, personal computer, and some inductors and capacitors, as shown in The detailed transient analysis results for the pitch-catch setup are illustrated in In light of For further investigating the effect of EIM networks on the sandwiched piezoelectric ultrasonic transducers, the frequency and power spectrum analysis of the received voltage signals are performed and the analyzed results are shown in The specific frequency and power spectrum analysis results for the pitch-catch setup are listed in But, for the difference of the simulated and measured results in (1)When I and II type EIM networks are connected with single sandwiched piezoelectric ultrasonic transducer, the resonance and anti-resonance frequencies, the electro-acoustic power ratio, and the received signal tailing are decreased, while the electro-acoustic gain ratio and the power spectral density are greatly increased.(2)When compared with I and II type EIM networks, the former makes resonance and anti-resonance frequencies more substantially decrease; the former makes the effective electromechanical coupling coefficient increase, while the latter makes it decrease. Then, the latter makes the electro-acoustic power ratio and the received signal tailing more substantially decrease, while it makes the electro-acoustic gain ratio and the power spectral density larger at resonance frequency.(3)The electro-acoustic power ratio has maximum value near anti-resonance frequency, while the electro-acoustic gain ratio has a maximum value near resonance frequency.By means of the PSpice models of the single sandwiched piezoelectric ultrasonic transducer, the effect of EIM networks on the electromechanical characteristics of the sandwiched piezoelectric ultrasonic transducers is systematically analyzed. To sum up, based on the analysis mentioned above, these conclusions can be drawn as follows:The effect of EIM networks on the electromechanical characteristics for sandwiched piezoelectric ultrasonic transducers is investigated in time and frequency domains by using the PSpice model of the single sandwiched piezoelectric ultrasonic transducer in this paper. For single sandwiched piezoelectric ultrasonic transducer, the effect of EIM networks on the performance parameters is analyzed in detail. The parameters focused attention mainly include the resonance and anti-resonance frequencies, the vibration velocity ratio, the electrical impedance phase, and electro-acoustic power and gain ratio.When compared with the theory analysis method that is based on the Mason’s equivalent circuit, the proposed analysis method has the following advantages. First, it is extremely easy to obtain the parameters of EIM networks and the performance parameters mentioned above only by AC and transient analysis. Second, the proposed analysis method has great flexibility, which can be very beneficial to optimize the topology of EIM networks. Last but not least, it is certain that the proposed analysis method can provide guidance and basis for choosing the EIM networks. Meanwhile, it should be noted that the equivalent series resistance of the inductances that are used in EIM networks and the prestressed bolt of the sandwiched piezoelectric ultrasonic transducer are neglected. However, in fact, the pre-stress can affect the electromechanical characteristics of the sandwiched piezoelectric ultrasonic transducers. The effect of the pre-stress can be considered in the PSpice model by modifying the related material parameters of the front and back metal masses, the piezoelectric ceramic ring. This will be expected to further investigate in our subsequent work.


Juvenile idiopathic arthritis (JIA) is the most common chronic disease of childhood. Improved understanding of its pathogenesis has led to international cooperation in clinical studies. Multicenter, international collaborations and research facilitate rapid enrollment of enough patients to enable a variety of studies, including those of epidemiology, diagnostic and classification criteria, genetic disease predisposition, pathogenesis, outcomes, and treatment protocols. In the last 20 years, the vision of the Pediatric Rheumatology International Trial Organization (PRINTO) has become a reality of worldwide collaboration in pediatric rheumatology research, including North American and European research groups. Major advances have been made in treating systemic JIA and its main complication, macrophage-activating syndrome (MAS). Single Hub and Access Point to Pediatric Rheumatology in Europe (SHARE) is a project of the European Society of Pediatric Rheumatology with the goal of improving clinical care. Based on evidence in the scientific literature, position papers regarding optimal clinical approaches and care have been published. Formal, validated assessment tools to evaluate response to treatment have been developed. Recommendations have been established to encourage international research collaborations, especially in light of major advances achieved in the genetics of pediatric rheumatologic diseases and the need to share biological samples among different countries and continents. Every participating country has disease information available for patients and families. Additionally, educational programs and updated syllabi for pediatric rheumatology have been written to promote similar, high-level academic training in different countries. These efforts have resulted in significant improvements in treatment and in patient prognosis. However, improved cooperation is needed to enhance research with biological and genetic samples. The Israeli Research Group for Pediatric Rheumatology is very active and has made significant contributions to the field. One in 1,000 children is affected by the various subtypes of chronic juvenile idiopathic arthritis (JIA).Cooperative studies have been conducted in many areas of pediatric rheumatology, including systemic lupus erythematosus, juvenile dermatomyositis, vasculitis, and autoinflammatory diseases, to name a few. In this review we will focus on three recent, major targets for cooperation: JIA therapy, systemic onset JIA (SoJIA), and macrophage-activating syndrome (MAS).Due to cooperative efforts over the last few decades, the mechanisms underlying these diseases have been progressively elucidated, and as a result treatment has improved tremendously. The once frequent image of a sick child sitting in a wheelchair is nowadays very rarely seen. The goal of medical care today, the “treat-to-target” T2T) approach, is disease remission, or at least to achieve low disease activity with minimal side effects. Most children today can achieve this goal.T approacPediatric rheumatologic diseases are relatively rare. Some might even be considered orphan diseases. Thus, cooperative efforts have been undertaken in several areas. One objective was to obtain sufficient patient populations for clinical therapeutic trials. Another goal was to standardize assessment of disease activity, to enable every center to use the same internationally accepted and validated assessment tools. Improved cooperation is also needed among patient and parent organizations, with the vision of improving the care of pediatric rheumatology patients, globally.Joint collaborative research in pediatric rheumatology has been conducted successfully for several years. The main study groups are The Childhood Arthritis & Rheumatology Research Alliance (CARRA), Pediatric Rheumatology Collaborative Study Group (PRCSG), and the Pediatric Rheumatology International Trial Organization (PRINTO). The American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and the Pediatric Rheumatology European Society (PRES) are considered the primary rheumatology societies supporting cooperative efforts. A few examples resulting from this international cooperation, mainly between PRINTO and CARRA-PRCSG, can be found in the literature.12Advances have occurred primarily under the auspices of PRINTO.Another more recent major cooperative effort is the SHARE project, which stands for Single Hub and Access Point to Pediatric Rheumatology in Europe. The SHARE project was established in 2012, funded by the European Union. It was developed with the express goal of optimizing cooperation among rheumatology scientists and physicians.One of the aims of the SHARE initiative was to map the current state of the disease in every country in Europe regarding pediatric rheumatology centers, medical and paramedical staff, patient access, treatment with advanced biological medications, accessibility of joint injections, etc. Internet questionnaire surveys were conducted in each country. National representatives of PRINTO, pediatric rheumatology centers, representatives of parent societies for childhood arthritis, and parents of children with JIA participated.As expected, accessibility and level of treatment are better in Western than in Eastern European countries. Remarkably, Israel is one of the leading countries in the field in terms of the level of medical treatment, use of novel biological drugs, and very good accessibility to pediatric rheumatologists.The main goals of treatment are preventing joint damage, ameliorating systemic signs, improving quality of life of patients and parents, preventing bone loss, preventing growth retardation, and enabling the child and family to participate in a healthy social life and in educational and peer activities.Advances in treatment have been achieved due to increased understanding of the molecular mechanisms involved in JIA. This includes the role of the cytokines underlying the inflammation, which enables blocking their activity. The first generation of biological medications targeting the cytokines signaling disease activity included anti-tumor necrosis factor (TNF) agents. These medications profoundly changed the course of the disease, while improving the health and quality of life of the sick children. Subsequently, after basic research and discovery of the roles of other cytokines in inflammation, other rationalized biological drugs were developed. These include those that block other cytokines, such as interleukin (IL)-1 or IL6 (the pathogenic cytokines in SoJIA), abatacept, which targets the connections between antigen-presenting cells and T cells, and rituximab, which blocks B cells.One of the most vicious diseases in the field of pediatric rheumatology is systemic onset JIA (SoJIA). Systemic onset JIA is characterized by high, spiking fever once or twice a day, rash, hepatosplenomegaly, lymphadenopathy, pericarditis, and very high, inflammation-related laboratory parameters due to high pro-inflammatory cytokine levels. Most patients develop severe chronic disease with a strong dependence on steroids, failure to grow, and destructive arthritis. Their quality of life is poor.New England Journal of Medicine editorial accompanying the publication of these two phase III studies stated that they represent “a new era in the field of Pediatric Rheumatology.”2The mechanism underlying disease progression involves increased IL1 and IL6 cytokine activity. Drugs that target these cytokines induce disease remission and are currently the treatment of choice. Multicenter studies involved 177 patients in the canakinumab trialAmong children with SoJIA, 10% might develop macrophage-activating syndrome (MAS), a severe, life-threatening complication evolving from high levels of pro-inflammatory cytokines. An international effort to clarify this syndrome led to the cooperation of many centers for data collection. It included SoJIA patients with MAS, patients with active SoJIA but without MAS, and a control group with bacterial infections. Analyzing this large data set helped define several criteria of this syndrome, as well as recommendations for treatment that were determined by a consensus committee meeting of senior pediatric rheumatologists and hematologists.16In the past, randomized, placebo-controlled trials were conducted to assess the effects and side effects of new therapies. Today, a more ethical practice is followed for clinical studies in pediatric rheumatology. In the first stage, all patients are treated with the active drug. In the second stage, patients that responded according to the accepted criteria are divided into treatment and control groups, and the time until relapse in all patients is followed. In the third stage, all patients in both groups are again treated with the active medication, including those that relapsed during the second stage of the study while on placebo. Patients who did not respond to the drug in the first stage may be treated with it again in the third stage.Conducting such studies in JIA demonstrated the efficiency and safety of anti-TNF compounds such as etanercept,Historically, response to therapy was evaluated subjectively by the treating physician. Formal validated assessment tools are used today. The American College of Rheumatology (ACR) established six criteria to evaluate response to treatment. These include a general assessment and physical examination by a physician, and patient or parental evaluation including subjective assessment of the general disease , physical examination counting the number of active inflamed joints, and one laboratory parameter of inflammation). The ACR response criteria are evaluated as follows: clinical response is considered good when at least 30% improvement in at least three of the six parameters is achieved. One criterion might deteriorate and become worse. The functional questionnaire was validated in every participating country, including Israel.18In recent years, the Juvenile Arthritis Disease Activity Score (JADAS) has become widely used, among other reasons due to its user-friendly structure.This evaluation score was also validated in the language of every participating country, including in Hebrew. According to the results of this assessment, disease activity is defined as in remission, mild, moderate-to-severe, or relapsed. When the patient is categorized with moderate-to-severe disease activity, enhanced treatment should be considered.One important goal of SHARE was for the European Union for Pediatric Rheumatology to establish and implement guidelines for diagnosing and treating rheumatologic diseases of childhood, in parallel to the guidelines written for adult rheumatology patients.A thorough search of the literature from 1970 to the present was performed using PubMed, Embase, and Cochrane databases. The most relevant papers were chosen by the primary researchers. The strength and validity of each study was evaluated by at least two independent specialists. Based on the information obtained from the chosen papers, recommendations for diagnosis and treatment were framed. These were validated by a wider group of specialists.A consensus meeting was held, and the final recommendations were established using the Delphi technique. An 80% majority was required to approve an item. In this way, updated, evidence-based recommendations for diagnosing and treating JIA were established.22www.printo.it/pediatric-rheumatology) was written by an international group of senior pediatric rheumatologists. It provides professional, reliable, up-to-date information regarding all the pediatric rheumatology diseases and treatments, for parents of patients with these diseases. The information is available in almost 50 languages. In Israel there are over 1,000 new entries to the website each month, highlighting the relevance and importance of this site.23The content of the PRINTO website  will benefit in these areas, which will promote improvements in diagnosis, treatment, research, and education. Importantly, Israel is one of the leading countries in patient accessibility to pediatric rheumatologists and in having high standards of care. This is definitely due to the devotion of the pediatric rheumatologists in the country.


Nitraria shrubs and Haloxylon. The main results were as follows. (1) The correct selection of endmembers is important for improving the accuracy of vegetation cover estimates, and in particular, shadow endmembers cannot be neglected. (2) For both the Nitraria shrubs and Haloxylon, the Kernel-based Nonlinear Spectral Mixture Model (KNSMM) with nonlinear parameters was the best unmixing model. In consideration of the computational complexity and accuracy requirements, the Linear Spectral Mixture Model (LSMM) could be adopted for Nitraria shrubs plots, but this will result in significant errors for the Haloxylon plots since the nonlinear spectral mixture effects were more obvious for this vegetation type. (3) The vegetation canopy structure (planophile or erectophile) determines the strength of the nonlinear spectral mixture effects. Therefore, no matter for Nitraria shrubs or Haloxylon, the non-linear spectral mixing effects between the photosynthetic / non-photosynthetic vegetation and the bare soil do exist, and its strength is dependent on the three-dimensional structure of the vegetation canopy. The choice of linear or nonlinear spectral mixture models is up to the consideration of computational complexity and the accuracy requirement.Desert vegetation plays significant roles in securing the ecological integrity of oasis ecosystems in western China. Timely monitoring of photosynthetic/non-photosynthetic desert vegetation cover is necessary to guide management practices on land desertification and research into the mechanisms driving vegetation recession. In this study, nonlinear spectral mixture effects for photosynthetic/non-photosynthetic vegetation cover estimates are investigated through comparing the performance of linear and nonlinear spectral mixture models with different endmembers applied to field spectral measurements of two types of typical desert vegetation, namely,  Arid and semiarid regions occupy 41% of the world's whole land area, where the ecosystem are prone to desertification due to the irrational use of natural resources and climate change. Desert fpv) and NPV (fnpv) information simultaneously will be of great value for desert vegetation studies. Remote sensing has considerable potential for providing accurate estimates of fpv and fnpv of desert vegetation. Spectral Mixture Analysis (SMA) is a widely used technique to retrieve fpv and fnpv an anK . The smaller the p-value, the larger the significance. RRMSE is a measure of the deviation rate with percent as the unit, and values closer to zero are indicative of a better fit. The relevant equations are as follows:R2 is the square of the correlation coefficient, RRMSE is Relative RMSE of the estimated model spectral value or estimated cover fraction of endmembers, n is the number of fields or available wavebands, xi is the estimated cover fraction or the estimated mixing spectral value of the ith field, yi is the measured cover fraction or measured mixing spectral value of the ith field, In cases where accurate ground reference data are available, the quality of the sub-pixel abundance estimates can be assessed more reliably by checking the discrepancy between the estimated and reference endmember fractions. The spectral mixture model fit was checked by using the unmixing error of the spectral mixture model, the PV/NPV/BS/shadow ground validation RMSE (Eq )40], th, th40], R2 (Eq ) 7], th, thR2 (EMSE) (Eq )61]. Th. ThR2  were  were fpvers Eqs  and 15)  fpv and ers  and Haloxylon plots . In summary, the KNSMM considering the nonlinear parameters was better than the LSMM and BSMM.With the KNSMM, the model unmixing RMSE and the fractional cover estimation RMSE of the endmembers were lower than those of the LSMM and BSMM for both vegetation types. Especially for the Haloxylon plots, the model unmixing RMSE decreased from 0.0133 to 0.0079, while the relative RMSE% decreased from 6.25% to 3.88% when the KNSMM was used. Regardless of the RBF or PKF kernel function, there was a stronger correlation between the estimated and measured fractional cover of each endmember in the 4-EM models with the KNSMM than those in the LSMM and BSMM. The RBF kernel function can deal with the complexity of space well, and the PKF kernel function is useful for illustrating the physical meaning of the space and the high-order statistical properties of the inter bands. For the effects of different kernel, the RBF kernel function with the NSMM was more reliable than the PKF kernel function with the NSMM for vegetation cover estimations both in the Nitraria shrub plots and Haloxylon plots  and model simplicity (number of model terms) should ultimately be used to select the most appropriate model. According to Nitraria shrub plots, but slight differences were observed in the Haloxylon plots whereby the simulated pixel spectral lines of the KNSMM corresponded better to the measured pixel canopy spectral line than the simulated lines of the LSMM and BSMM.According to the pixel spectral unmixing results from the on plots , the KNS2 and RRMSE of the fpv and fnpv in the Nitraria shrub and the Haloxylon plots shown in Nitraria shrub, but NSMM made a great progress to estimate the fractional cover of PV and NPV in the Haloxylon plots. All experimental verified results indicated that there is multiple interactive photon scattering in the canopy spectra in the Nitraria shrub plots and the Haloxylon plots, but the scattering influence on the fractional cover estimation of PV and NPV was more outstanding in the Haloxylon plots than in the Nitraria shrub plots. However, in view of the multiple photon scattering terms between three-dimensional (3D) structures  and two-dimensional (2D) structures  on the ground surface, the precision of models indicates that multiple photon scattering on the spectral mixture was determined by the canopy structure of tree. Above all, LSMM is the most appropriate model to estimate fpv and fnpv in Nitraria shrubs plots, but KNSMM is the best fitting model to estimate the vegetation cover in Haloxylon plots.From the estimation RHaloxylon vegetation[There are advantages and disadvantages to the different spectral unmixing models, LSMMs, BSMMs, and KNSMMs. KNSMM was proved performing best, and BSMM, considering the mutual endmembers scattering explicitly, worked better than the LSMM. Consistent with the previous studies, 65, 66,egetation–45, 54. egetation, 60. In In the previous studies, the contribution of shadows to the mixed spectra was considered to be only 0–1% or negligible, 29, 68.Haloxylon plots than in the Nitraria shrub plots. According to the BSMM results, the spectral multiple photon scattering processes mainly occurred between PV and NPV, which means that the canopy structure is one of the primarily factors for the photon non-linear scattering. For the two selected desert vegetation type, Nitraria shrubs presents planophile canopy, characterized by short height, sparse leaf, which tends to decrease the chance of multiple photon scattering in the canopy. Instead, Haloxylon shows erectophile plants canopy characterized by higher height, dense and needle leaf, which is more prone to multiple photon scattering. These conclusions are consistent with the previous studies[Haloxylon and Nitraria shrub determines the strength of the nonlinear spectral mixing effects.Multiple photon scattering process was comparatively more likely to happen in the s studies, 74. Thes studies that theNitraria shrubs and Haloxylon, were investigated through comparing the PV/NPV estimation performance with different LSMMs, NSMMs, based on field measured spectra at the plot scale. Overall, the major conclusions can be summarized as follows.In this study, the nonlinear spectral mixture effects between PV/NPV and bare soil in Nitraria shrubs and Haloxylon. The 4-EM models, including the shadow endmember, could effectively improve the model unmixing accuracy. The unmixing RMSE (%) were improved by 25.64% and 16.97% in the Nitraria shrubs plots and the Haloxylon plots respectively. Therefore, the correctness of the selection of the endmembers plays a significant role in improving the unmixing accuracy.Shadows should not be neglected for modeling the mixed spectra of fpv and fnpv estimations, which means that the non-linear mixing effects do exist in desert vegetation. However, the improvements in Nitraria shrubs are not obvious as in Haloxylon. For the performance of NSMMs in Haloxylon plots, KNSMMs are obviously better than BSMMs. Considering computational complexity and accuracy requirements, the LSMM may be adopted to Nitraria shrubs plots for estimating fpv and fnpv, but, for Haloxylon plots, NSMMs should be used to deal with the obvious non-linear mixing effects.Generally, NSMMs work better than LSMM for The non-linear mixing effects are closely related to the plant canopy structure, whose strength is greater in vegetation with erectophile canopy  than with planophile canopy (Nitraria shrubs).


Cannabis use disorder increases both overall mortality and several cause-specific mortalities. However, an unexpected finding has been that, in patients with schizophrenia, cannabis use disorders were associated with a decreased risk of death from causes related to the digestive organs. Further indications of potentially beneficial effects of cannabis were supported by a 2016 systematic review showing protective effects of cannabis in patients with established gastrointestinal disorders. Further, schizophrenia, either in itself or through the use of antipsychotics, may interact with cannabis in various organs, potentially leading to different associations. For these reasons, we aimed to investigate the associations between cannabis and later development of disorders of the digestive organs, both in patients with schizophrenia and in healthy controls.We used the nationwide Danish registers in a prospective cohort study. All individuals born since 1955 in Denmark and diagnosed with schizophrenia were included, and matched to approximately ten controls on age and sex to healthy controls. Cannabis use disorders and alcohol and other substance use disorders (SUD) were identified through combinations of several health registers, as were the outcomes. We investigated the following outcomes: Any disorder of the digestive organs, cancers of the digestive organs, non-cancer disorders of the digestive organs, inflammatory bowel disease, disorders of the gut-brain axis, non-cancer disorders of the pancreas, non-cancer disorders of the liver, and a category of disorders of the digestive organs considered to be severe. For each analysis, people with a corresponding digestive-organ diagnosis before either the date of schizophrenia or the controls’ corresponding match-date were excluded.The number of patients with schizophrenia varied between 17,718 and 22,636 in different analyses. After adjusting for other SUDs, cannabis use disorders showed protective effects in patients with schizophrenia against disorders of the gut-brain axis , and serious disorders of the digestive organs . Non-significant protective effects were also apparent for non-cancer disorders of the digestive organs , inflammatory bowel disease , and non-cancer disorders of the liver . These protective effects were never shown in healthy controls, where cannabis use disorders generally were not associated in any direction with digestive-organ disorders in the fully adjusted analyses.Cannabis use disorders may show protective effects against certain disorders of the digestive organs in patients with schizophrenia. The explanations may be causal, which would however require further explanations as to why the same effects are not seen in healthy controls. This may be due to use of antipsychotic medication interacting with cannabis, or due to higher levels of cannabis consumption in cases with schizophrenia than in controls. The effect may also be in part explained by comorbid use of tobacco, as nicotine is also known to interact with the gastrointestinal system.


We hope to provide an understanding of the human-protozoal pathogen-microbiome interaction and to speculate on how that might be leveraged for treatment.Parasitic protozoan infections represent a major health burden in the developing world and contribute significantly to morbidity and mortality. These infections are often associated with considerable variability in clinical presentation. An emerging body of work suggests that the intestinal microbiota may help to explain some of these differences in disease expression. The objective of this minireview is to synthesize recent progress in this rapidly advancing field. Studies of humans and animals and  Entamoeba histolytica, Giardia, Cryptosporidium, Blastocystis hominis) or vagina  or cause systemic infections   . Changesciparum) .Entamoeba, Cryptosporidium, and Giardia, resulted in 33,900 deaths and the loss of 2.94 million disability-adjusted life years  and quantitative PCR demonstrated that TTGE profiles clustered into four significantly different groups, i.e., groups that are positive for munities .Faecalibacterium prausnitzii and E. coli have been used as a marker of the inflammatory bowel disease (IBD)-induced dysbiosis associated with increased E. coli levels  was independently confirmed by in vivo experiments with La1-treated gerbils, which were protected against Giardia infection and mucosal damage . Un. Un73). The development of murine models of parasitic protozoan infections has allowed for more-detailed immunophenotyping of the mammalian host response to changes in the microbiota and its influence on infectious disease , 75. MurClostridium SFB   was alsoGiardia duodenalis infection, for example, antibiotic alteration of the microbiome was shown to prevent CD8 T cell activation by Giardia  maintained by different vendors, Jackson Laboratory, Taconic Farms, the National Cancer Institute/Charles River (NCI), and Harlan  alteration of parasite virulence, (ii) induction of dysbiosis or perhaps even beneficial shifts in the microbiota that increase competition for the niche of the lumen of the gut, and finally, (iii) modulation of host immunity to the parasite. The courses of both mucosal and systemic parasite infection may also be shaped by specific members of the microbiota, and in turn parasite infection may alter the microbiota in such a way that the unique signature can be diagnostic of the presence of the parasite.The exact mechanisms underlying microbiota modulation of host immunity are not yet fully understood; however, it is becoming increasingly apparent that components of the microbiota can alter both innate and adaptive immune cell populations so that a more robust response is mounted following subsequent challenge with infectious agents, including parasitic protozoa. Mechanisms underlying this shift might include the recently described concept of trained innate immunity, in which epigenetic changes enable innate immune cells to more effectively clear unrelated pathogens, and by enhancement of adaptive immunity. Ultimately, further exploration of interactions between the gut microbiome and parasitic protozoans will provide additional tools and approaches that will help in the diagnosis and treatment of infectious and inflammatory diseases. Study of protozoan interactions with the host immune system and the microbiota also help us to better understand fundamental mechanisms of mammalian immunology.


Delirium is a relevant condition in critically ill patients withlong-term impacts on mortality, cognitive and functional status and quality oflife. Despite the progress in its diagnosis, prevention and management duringthe last years, its impact persists being relevant, so new preventive andtherapeutic strategies need to be explored. Among non-pharmacologic preventivestrategies, recent reports suggest a role for occupational therapy through aseries of interventions that may impact the development ofdelirium. The aim of this review is to evaluate the studiesevaluating the role of occupational therapy in the prevention ofdelirium in critically ill patient populations, andsuggests perspectives to future research in this area. This complication is relevant due to itshigh incidence and its potential to affect patient outcomes in the short and longterm.,2 Different pharmacological and non-pharmacologicalstrategies have been evaluated for the prevention and treatment of ICUdelirium, with heterogeneous results to date.,4 New strategies to limit the impact of this condition arenecessary despite advances in the field.Intensive care unit (ICU) ,7 Some of these studies have explored deliriumas a principal or secondary outcome. In view of these recent studies, our objectivewas to review the literature exploring the role of OT in the ICU, particularly inthe area of delirium prevention.Recently, some studies have explored the role of occupational therapy (OT) in the ICUalone or more frequently as part of the rehabilitation team.www.wfot.org), OT is the art and science of enabling engagement ineveryday living through occupation. The primary goal of OT is to enable peopleto participate in the Activities of Daily Living (ADL). Occupational therapyinterventions directly affect the person via sensorial, motor or cognitiveinterventions and/or the environment with physical and social interventions.These interventions targeting different components of health are intended toimprove functional performance and social inclusion.According to the World Federation of Occupational Therapy .Occupational therapy-based cognitive rehabilitation for these pathologiestypically includes sensory stimulation, cognitive training , and caregiver/family education. Repetitiveexercises and tasks specific to practice BADLs  are used to improve physical functions, and environmental modificationis applied to facilitate cognitive and functional performance.,19 In terms of cognitivefunction, a significant proportion of ICU patients experience some degree ofmemory, attention, or executive function deterioration, with symptoms thatsometimes linger for years after discharge.,21 Therefore,the development of interventions from the ICU that impact the long-termcognitive status, quality of life and functionality is a priority.Therapeutic advances have increased survival for patients admitted to the ICU.However, ICU patients with severe pathologies and/or prolonged ICU stays have ahigher risk for long-term neuromuscular, cognitive, functional, and overallhealth complications.-25In this context, over last ten years, researchers have explored multidisciplinaryrehabilitation strategies for early interventions in the ICU. Most of thesestudies have focused on physical therapy (PT) protocols that use earlymobilization during the ICU stay to prevent neuromuscular dysfunction andprogressively advance patients from mechanical ventilation to sitting, standing,and eventually walking. This trial included anintervention group that received progressive rehabilitation involving bothphysical and occupational therapists, beginning with passive mobility andadvancing toward walking. Detailed descriptions of the physical and occupationaltherapy interventions are available. The focus of the OT intervention was training in ADLsand function training. For most of the sessions, the patients were able toparticipate in active mobility, sit on the edge of the bed, or simulate eatingand grooming. Intubated patients were able to sit in an armchair duringapproximately one in three sessions, and the patients were able to participatein walking exercises during approximately 15% of the sessions. The primaryendpoint for the study was functional independence in BADLs at discharge; theauthors reported that the independence scores were significantly higher for theintervention compared with the control group . After this study, other authors explored the feasibility, safety, andvalidity of the participation of OT in the ICU with similar results.,26-28 OTinterventions in the studies referred to above are shown in The first study that formally included OT as part of an early rehabilitationprotocol in the ICU was performed by Schweickert et al.Despite the progressive evidence supporting the role of OT as part of therehabilitation team in the ICU, there are limitations on available data. All ofthe studies identified involve OTs as part of a multidisciplinary team wherephysical and occupational therapists work closely together, which makes itdifficult to quantify the effect of the OT intervention alone, and theeffectiveness of a specific pool of interventions.,5,29,30 Different strategies havebeen studied for the prevention and treatment of ICU delirium.They are grouped into non-pharmacological and pharmacologicalinterventions.,4 Several medications have beenstudied for the prevention and therapy of delirium, includingdifferent neuroleptics , dexmedetomidine, rivastigmine, dexamethasone andstatins. Althoughrecent guidelines on the use of sedatives, agitation anddelirium in critically ill patients do not recommend theuse of pharmacological prevention, a recent systematic review suggests apotential role for antipsychotics in surgical patients and dexmedetomidine inventilated patients.,31 New studies will help clarifythe role of pharmacological prevention of ICU delirium.Over the past 15 years, delirium in ICU patients has become a major topic inhealth care due to its high incidence and impact on long-term outcomes.delirium. Interest in these interventions comes fromevidence from multicomponent programs for the prevention of delirium in elderlyhospitalized patients.-34 Indeed, recent guidelines ofthe American Geriatric Society suggest implementing multicomponent programs fordelirium prevention in older patients.,36Much attention has also given to different non-pharmacological interventionseither individually or clustered into groups of measures for the prevention ofdelirium in the ICU have been evaluated to date,as shown in ,37 Several of these interventions are part of the actionsfor which occupational therapists acquire skills during their professionaleducation, including patient and health provider education, orientation,cognitive therapies and physical activities.More than 10 different types of interventions for the non-pharmacologicalprevention of delirium as a secondary endpoint for this trial andreported that the delirium duration was significantly reducedfrom 4 days in the control group to 2 days in the group that received thephysical and occupational therapy interventions (p = 0.03). Similarly, the study of Needhamet al., which included a before-after design to evaluate a quality improvementprocess, showed a significant increase in days without deliriumin the patient group by including a team promoting early rehabilitation,including physical and occupational therapists.Protocols with physical and occupational therapy are strategies with evidence ofefficacy. Schweickert et al.'s study included an a priori evaluation of,39 Theprimary objective of this study was to evaluate the efficacy of an experimentalnon-pharmacological intervention (standard intervention plus early and intensiveOT) in reducing the delirium incidence. A standard interventionwas applied in both groups, which consisted of reorientation, mobilityexercises, sensory deficit correction, environmental management, sleepprotocols, and minimization of the use of drugs with the potential to triggerdelirium. The experimental early/intensive OT intervention included multisensorystimulation, positioning, cognitive stimulation, and BADL training. A detaileddescription of the interventions is available online: http://www.medicina.uchile.cl/noticias/133590/terapia-ocupacional-disminuye-el-delirium-de-los-adultos-mayores.These findings and evidence supporting the efficacy of OT for other cognitiveconditions prompted us to develop a clinical trial at our center fornon-ventilated older adults admitted to the ICU. The preliminary and finalresults of this study have been recently published.versus 20%, p = 0.001), a higher level of functionalindependence  at discharge of 53versus 31, p = 0.001), and better cognitive performance in the experimental compared to the control groupafter adjusting for age and education level.The results showed a significantly lower incidence of delirium (3%delirium. However,there are important limitations that are relevant and should be reviewed. Themain limitation is that there are few studies in this área. In most ofthe studies reviewed, delirium was a secondary outcome in studies exploringother primary outcomes. Further studies involving OT interventions in the ICUare necessary to assess the impact on delirium as a primaryoutcome. Additionally, most of the studies reviewed jointly evaluated theimplementation of strategies that included physical and occupational therapy.Therefore, differentiating the specific impact of OT is very difficult. The onlystudy that independently evaluated OT activity was the study of Alvarez et al.,but this study was implemented in less severely ill patients who wereunventilated and in intermediate care units. Moreover, the specific set ofinterventions applied for the prevention of delirium in ICUpatients by occupational therapists are not defined because some differencesexist in the described protocols. An economic evaluation of this intervention isnot available because the available information to date only includesmulti-professional rehabilitation programs in the ICU. Finally, evidence to documentthe long-term benefits of early OT interventions, including the impact ondelayed cognitive and functional outcomes, is not available.According to these articles, the information available suggests the feasibility,safety and efficacy of OT in preventing delirium in the intensive care unit, but additionalstudies are needed to confirm and expand upon these findings. Under the potentialbenefits of the involvement of occupational therapists in the critical care team,particularly for the prevention of delirium, we suggest formallyevaluating the incorporation of occupational therapist to the intensive care unitmultiprofessional team. Specific interventions for implementation depend on thecharacteristics of each unit, especially its unique integration. Ideally, theinterventions should be part of the early rehabilitation teams with physical andrespiratory therapists. Older adults and ventilated patients will potentiallybenefit the most from early intervention.To date, promising studies have suggested a role for occupational therapy inpreventing


It provides a depolarizing signal for a variety of neuronal population in the immature central nervous system, thereby directly influencing neuronal activity. While in the neocortex, taurine probably enhance neuronal activity, in the immature hippocampus, a tonic taurinergic tone might be necessary to attenuate activity. In summary, taurine must be considered as an essential modulator of neurodevelopmental events, and possible adverse consequences on fetal and/or early postnatal development should be evaluated for pharmacological therapies affecting taurinergic functions.A variety of experimental studies demonstrated that neurotransmitters are an important factor for the development of the central nervous system, affecting neurodevelopmental events like neurogenesis, neuronal migration, programmed cell death, and differentiation. While the role of the classical neurotransmitters glutamate and gamma-aminobutyric acid (GABA) on neuronal development is well established, the aminosulfonic acid taurine has also been considered as possible neuromodulator during early neuronal development. The purpose of the present review article is to summarize the properties of taurine as neuromodulator in detail, focusing on the direct involvement of taurine on various neurodevelopmental events and the regulation of neuronal activity during early developmental epochs. The current knowledge is that taurine lacks a synaptic release mechanism but is released by volume-sensitive organic anion channels and/or a reversal of the taurine transporter. Extracellular taurine affects neurons and neuronal progenitor cells mainly via glycine, GABA(A), and GABA(B) receptors with considerable receptor and subtype-specific affinities. Taurine has been shown to directly influence neurogenesis  GABAA receptors are heteropentameric complexes composed from total 19 subunits  receptor, albeit again with a rather low affinity  seem to be more sensitive to taurine and mediate considerable tonic currents at submillimolar taurine concentrations  the taurine concentration of 25 μM measured in the mature CNS under zero-flow conditions by means of microdialysis probes s probes , it can s probes .During development, neurons undergo specific steps of maturation, including neurogenesis, neuronal migration, differentiation, and pruning. The cerebral cortex of vertebrates originates from the two telencephalic vesicles. The earliest neurons generated in the neuroepithelium of this vesicles form the PPL . The proin vitro activity was replaced by a distinct set of large-scale network events, beginning with spontaneous and glutamate receptor dependent early network oscillations  neuronal migration is influenced by GABAA receptors even in the absence of synaptic neurotransmitter release e levels , allowine levels . Taurineeceptors . In the A receptors significantly reduced neurogenesis . Similar effects were also found for human neuronal precursor cells, where proliferation is also enhanced by millimolar amounts of taurine, albeit it is not clear whether this process requires GABAA or glycine receptors  release , suggesting that GABA is not required as endogenous ligand for the GABAA receptors regulating migration. This suggestion was substantiated by the findings that (i) the tonic currents in migrating neurons were unaffected by GABA depletion but (ii) enhanced in the presence of the TauT blocker GES, and (iii) attenuated after blockade of taurine synthesis with D-cystein . And in line with these in vitro experiments, indicating that taurine is probably the most relevant endogenous agonist of extrasynaptic GABAA receptors, depletion of taurine by maternal D-cystein administration accelerated migration in both wild-type and homozygous GAD-67 mice in vivo . In line with the high intracellular Cl- concentration in these cells . While no evidences for a synaptic activation of glycine receptor were found, inhibition of taurine transport with GES, hypoosmotic stimuli, and strong electrical stimulation evoke a putative nonsynaptic release of taurine, which activated glycine and probably also GABAA receptors . Pharmacological experiments revealed that about 80% of the tonic taurine-induced currents in these neurons are mediated via glycine, and about 20% via GABAA receptors  and are abolished in the presence of the glycinergic antagonist strychnine. As similar GABAergic PSCs could also be evoked by tonic application of glycine , which was associated with a massive increase in action potential discharges in the majority of GABAergic interneurons . Also in SP neurons, the activation of glycine receptors mediates a depolarizing action . Taurine-mediated currents were identified on most major neuronal populations in the immature neocortex (2+ transients, which are causal for many neurodevelopmental events like migration or differentiation (in vitro (in vivo conditions, since in this situation activation of GABAA receptors mediates depolarizing but inhibitory effects in the developing neocortex (in vitro taurine mediates mainly excitatory network effects in the neocortex, but an inhibitory net action in the hippocampus, it would be interesting to uncover the effect of taurine on the excitability in other regions of the CNS, like thalamus, basal ganglia, hypothalamic nuclei, amygdala, and the spinal cord. The essential role of taurine for neuronal development entails that any interference with the taurinergic system during pregnancy or early childhood increases the risk for developmental disorders. Accordingly, the adverse effect of the antiepileptic drug vigabatrin, which severely impaired neuronal development (Taurine can be considered as an important neurodevelopmental modulator (eocortex . Due to ntiation . In addiin vitro . Taurinein vitro . In the in vitro , due to in vitro , indicateocortex . Given telopment , has alrelopment .WK and AF drafted, wrote, and revised the text. WK and AF approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Data about psychosocial sequelae of childhood Hematopoietic Stem Cell Transplantation (HSCT) are limited and the association with a specific donor type or other medical factors is largely unknown  with a mean age of 14.4 years  were recruited. Twenty-six patients underwent an allogenic HSCT  and 11 patients received an autologous HSCT. The children psychological aspects were assessed using the Youth Self Report (YSR)  when compared to healthy peers (mean = 1.5). The parent CBCL scores on “child total competence” exceeded the normative clinical cutoff in 48.6% cases. Inter-rater agreement between parent and patient reports was present only in three scales: total competence score , somatic complaints  and attention problems . According to Ancova models, internalizing problems were more frequent in HSCT from family donors  or in the presence of acute complications .Conclusion: In contrast to the perception of parents, pediatric HSCT survivors reported good psychological health. However, they complained about more somatic problems as compared with healthy peers. Medical aspects such as donor source and the presence of acute complications should be taken into consideration for the psychological approach in order to improve pediatric HSCT survivor care. Hematopoietic Stem Cell Transplantation (HSCT) is a medical procedure involving the collection and re-infusion of multipotent hematopoietic stems cells, aimed at the reconstitution of a normal hematopoietic function  assess the presence of psychopathology in HSCT survivors at distance from transplantation; (b) compare the psychological aspects of pediatric HSCT survivors with the ones of healthy peers; (c) detect whether parents and children differed in their perception of mental health status; (d) identify medical and socio-demographic factors associated with psychopathology.According to literature, it has been supposed that HSCT survivors present higher levels of psychological distress compared with healthy peers even many years after the experience of transplantation. It is hypothesized that parents perceive less stress and a better quality of life than patients themselves.-being <18 years old;-being an ex-patient that had undergone HSCT at least 5 years previously;-absence of intellectual disability;-a stable health condition.The research involved subjects of pediatric age that had undergone HSCT at least 5 years before the recruitment phase (a range of time pointed out by the literature as adequate to consider the subjects as “survivors”) and their families (HSCT Group), and a comparison group of healthy peers (HEALTH Group). The inclusion criteria for the HSCT Group were:From 2012 to 2014, 77 families were drawn from the HSCT database of the Laboratory of Pediatric Onco-Hematology at the University Hospital of Padua. The families were subsequently recruited through a preliminary phone contact aimed at illustrating the objectives of the study. Families that agreed to participate in the research were sent a folder containing a brief description of the study, informed consent and self-report questionnaires. Subsequently, psychological consultations were carried out during medical post-transplant follow-up visits.The present study is part of a broader study with the main aim of exploring every aspect of HSCT survivors' lives, including mental health and Quality of Life, using specific psychopathological inventories or questionnaires. Data about the Quality of Life perceived by patients and their parents will be the subject of future reports.M = 15.07, SD = 2.36) recruited in schools, youth groups and universities, through a project aimed at assessing their psycho-social well-being. In order to be included in the HEALTH Group the subjects should not have had experiences of intense hospitalizations or chronic disease. After receiving informed consent, questionnaires were completed online. Written informed consent was obtained from all the parents, whereas all the minors gave their verbal informed consent.The HSCT Group was matched to the HEALTH Group according to age, gender and geographic origin. The HEALTH Group (M:F = 22:12) was composed of unselected adolescents aged 15–25 years  that has been subsequently put in relation with the results of self-report measures.The Achenbach System of Empirically Based Assessment was developed within a theoretical and empirical paradigm aimed at collecting information regarding adjustment, competence, and emotional/behavioral problems in children and adolescents, emerging in different situations, and collected through multiple informants (a). This latter quality allows the system, based on a multi-axial approach, to reach a measurable global frame of the individual. The assessment groups the identified problems into syndrome scales which can be compared to standardized normative values matched for age and gender. For the purpose of the present study the participants were given the Child Behavior Checklist/6–18  whereas the second part investigates the presence of behavioral/emotional problems through 113 items, which can be classified as “normative,” “borderline” or “clinical” according to specific syndrome scales or DSM-Oriented scales. Each item is scored on a 3-point Likert scale  in accordance to the behavior reported. The syndrome scales are: Anxious/depressed, Withdrawn/Depressed, Somatic Complaints, Social Problems, Thought Problems, Attention Problems, Rule-Breaking Behavior, and Aggressive Behavior. The syndrome scales can be grouped into more general summary scales: Internalizing Problems, Externalizing problems, and Total Problems. Moreover, the CBCL/6–18 can be scored in terms of DSM-Oriented scales that, although not directly equivalent to a DSM diagnosis, can help to relate standardized, quantified, normed assessment of behavioral/emotional problems to DSM categories. The scales are: Affective Disorders, Anxiety Disorders, Somatic Problems, Attention Deficit and Hyperactivity Problems, Oppositional Defiant Problems, and Conduct Problems. Finally, the system allows the calculation of scales for Obsessive-Compulsive Problems, Stress Problems, and Sluggish Cognitive Tempo. For the purpose of the present study Italian normative values where adopted  which can be grouped into summary scales . Moreover, the raw scores can be converted into DSM-oriented scales . The YSR/11–18 has been successfully applied to different cultures and languages, and reported from good to excellent reliability  23.0] . Descriptive analyses  were performed on the CBCL and the YSR scores in order to assess the presence of psychopathology. Subsequently, Cohen's kappa coefficient was applied in order to measure inter-rater agreement between the parents and the survivors' reports on psychopathology; for this purpose, contingency tables with the CBCL and the YSR were made. Finally, ANCOVAs were carried out in order to assess the effect of the single independent variables in predicting the presence of psychopathology.Descriptive analyses  were run on data concerning the demographic and medical information of the HSCT Group.Thirty seven families (M: F = 23:14) agreed to participate to the study. Table SD = 6,0; range 36–61), while for mothers it was 45.0 . Thirty one couples (84%) were conjugated or cohabiting while in 14% of cases they were separated. In the majority of couples (62%), both parents were employed; in 35% of cases one parent was unemployed, while in only one situation both parents were unemployed.As can be seen from Figure Descriptive statistics were performed on the results of the CBCL and of the YSR in order to assess the presence of psychopathology in the survivors as referred by the survivors themselves or their parents. The results are shown in Tables Total Competencies (49%) and Activities (22%). Regarding behavioral/emotional problems, on the other hand, the parents seemed to identify more internalizing difficulties, especially regarding Somatic problems , Post-traumatic stress disorder , Sluggish cognitive tempo , Obsessive-compulsive disorder . According to the parents' perception inherent socialization and externalization difficulties maintained mostly sub-clinical values.As it can be seen Table , as far Total competencies , Social competencies (13%) and Somatic complaints (8%). The other scales mostly maintained scores within the normative range.As regards the YSR, as can be seen in Table T-test was applied to investigate the presence of differences in the mean scores of the Competence Scales and of the Syndrome Scales between the HSCT Group and the HEALTH Group. Statistically significant differences emerged regarding Somatic symptoms , which were higher in the HSCT Group compared with the HEALTH Group. No significant differences (p > 0.05) were found regarding other variables .The paired sample Total competencies , Somatic problems  and Attention problems . The other scales  did not show significant agreement (p > 0.05). However, basing on Cohen's kappa interpretation by which there is a scarce concordance if kappa assumes values between 0 and 0.4, there was really no overlap between parents' and children's ratings.In order to measure inter-rater agreement between the parents and the survivors' perception of psychopathology Cohen's kappa coefficient was applied; for this purpose, the results of the CBCL and of the YSR were organized into contingency tables. Statistically significant agreement was found for Preliminarily, correlation analysis, and ANOVAs were run on variables referring to psychopathology and on medical and socio-demographic variables. The distribution of the factors was estimated as normal. In the preliminary Pearson's correlations, the medical variables  did not result significantly associated with the psychopathological scales.Internalizing problems, Externalizing problems, and the Total problems scale. The independent variables concerned: type of transplantation , presence of GvHD (no/yes), hospitalization during intensive therapy (no/yes), double intensification of therapy (no/yes), and gender (M/F). As covariates the model included: sum of acute and long-term complications, sum of psychophysical problems, age at transplantation, time elapsed between transplantation and assessment, days of hospitalizations in the Transplantation Unit, time elapsed between the communication of the need to transplant and effective transplantation. ANCOVAs were run also on the CBCL syndrome scales. Table Subsequently, in order to investigate whether specific demographic or medical aspects could influence behavioral/emotional problems in HSCT survivors, ANCOVA models were carried out on the CBCL scores . The dependent variables included: As can be seen from the table, the Total problems were higher in the case of: a female offspring, related allogeneic HSCT, more frequent acute and long-term sequelae, more psychophysical problems, a higher amount of time elapsed between the communication of the need to transplant and the actual transplantation. Externalizing problems, in a similar way to what happens with aggressiveness, were predicted by the presence of more acute consequences. Regarding Internalizing problems, the predictive risk factors were: allogeneic familiar transplantation, a higher number of acute consequences, less time elapsed between the communication of the need to transplant and the actual transplantation, a higher number of psychophysical problems reported, the presence of double intensification therapy.Table Anxiety symptoms were more frequent if the ex-patients: were female, they spent longer time in the Transplantation Unit, showed more acute consequences, were not exposed to double intensification therapy, had a shorter time occurred between the communication of the HSCT need and the actual HSCT, reported higher psychophysical problems.Depressive symptoms were more evident in the case of a higher presence of acute consequences and of a higher latency between the communication of the need to transplant and the actual transplantation.The Somatic complaint scale was influenced by: absence of GvHD, allogeneic familiar transplantation and younger age at assessment.Social symptoms were predicted by a longer hospitalization after transplantation, the presence of double intensification therapy during treatment, and where a higher amount of time had elapsed between the communication of the need to transplant and the actual transplantation.Attention symptoms were shown to be negatively influenced by acute consequences and by a longer time elapsed between the communication of the need to transplant and the actual transplantation.R2 = 0.23) with amount of time passed from transplantation to the assessment , the only factor that impacted significantly on depressive symptoms.Subsequently, in order to investigate whether specific demographic or medical aspects could influence behavioral/emotional problems as reported by the HSCT survivors in the YSR, hierarchical linear regression analyses (HLM) were run inserting as dependent variables in the model the YSR scales and the following variables as independent ones: age at transplantation, amount of time elapsed from HSCT, amount of time elapsed from the communication of the need to transplant and the actual transplantation, days of hospitalization in the Transplantation Unit, sum of acute complications, sum of chronic complications, sum of psychophysical problems. The first block included socio-demographic variables and objective medical variables  whereas the second block included variables referring to the psychological and physical consequences of transplantation . The results of HLM with depressive symptoms as a dependent variable highlighted that the second model explained the majority of variance  where these problems were significantly influenced by a higher presence of psychophysical problems  and days of hospitalization post HSCT .HLM with social problems as a dependent variable showed the third model as the best one  assess the presence of psychopathology in HSCT survivors at distance from transplantation, (b) compare the psychological aspects of pediatric HSCT survivors with those of healthy peers, (c) detect whether parents and children differed in the perception of mental health status, and (d) identify medical and socio-demographic factors associated with psychopathology. For these purposes, the CBCL and the YSR were given to a group of HSCT survivors and their families and to a comparison group matched according to age, gender and geographic origin.Total competence scale, highlighting the presence of difficulties in the domains concerning activities and social competencies. These results seem to be in line with the hypothesis made by some authors that the experiences associated with transplantation could somehow interfere with adjustment and social competence , both the parents and the survivors reported scores above normative cut offs for the Post-traumatic stress problems scale. It is possible to speculate as to whether HSCT survivors could experience anticipatory fear linked to their previous traumatic experience and express it through worries about physical well-being, a hypothesis that could in part explain the parallel presence of high scores on somatic symptoms and low scores on post-traumatic stress symptoms , the comparison between the HSCT Group and the HEALTH Group highlighted differences only regarding somatic symptoms. No differences were found with respect to the other variables. This is not surprising, given the high probability that the majority of survivors has to experience physical late effects after transplantation , suggesting a different perception of psychopathology between the survivors and their parents. More specifically, the results showed higher scores on the CBCL, suggesting the perception of higher behavioral/emotional difficulties on the parents' side. The low agreement between child and parent reports has already been described by other studies , the comparison between the CBCL and the YRS reported low inter-rater agreement only in a few scales , the results evidenced an association between specific medical and socio-demographic variables and the risk of experiencing higher psychological distress. More specifically, with respect to the It is interesting to observe that the presence of acute consequences predicted higher externalizing symptoms, which could thus be interpreted as a possible reaction to the “internal,” physical and psychological sufferings linked to disease and transplantation.On the other hand, regarding the syndrome scales, again female survivors were identified at higher risk of experiencing anxiety. Anxiety symptoms were also predicted by a higher amount of time passed in the Transplantation Unit, by the presence of acute consequences and psychophysical problems, and by a shorter time elapsed between the communication of the need to transplant and the actual transplantation. On the contrary, a longer amount of time passed before the intervention predicted depressive symptoms, suggesting the need to schedule the “right” timing between the different phases that follow diagnosis, in order to favor a more functional regulation of the emotional aspects involved in this delicate process.Moreover, somatic complaints were predicted by a younger age at the moment of diagnosis. This result, that seems somehow to contrast with other studies that suggest older age to be a significant variable associated with poorer psychological functioning (Parsons et al., One limitation of the present study concerns the small number of participants, which prevents the generalization of the data obtained; in any case, these results seem to be in line with the existing literature in confirming the presence of an increased risk of experiencing psychological distress and psychopathology in ex-patients exposed to HSCT during childhood. This risk seems to be enhanced by the presence of specific demographic and medical variables, which should thus be taken into account during the different phases that precede, accompany, and follow HSCT. Taken together, these results could help to inform intervention and prevention programs, since attention to the aforementioned demographic, medical and psychological variables could help identify which subjects could still require services and support once the process of reintegration to normal routines following HSCT has begun.SZ: wrote the central part of the manuscript, partecipated in collecting data. AT: wrote the discussions section of the manuscript; partecipated in critical interpretation of data. MTr: prepared data set, performed statistical analyses. FS: prepared data set, performed statistical analyses. AP: wrote the introduction section of the manuscript and participated to the organization of collected data. GP: performed analyses and supervised statistical analyses. ND: prepared tables and figures; recruited the sample and wrote the references. FC: recruited the sample and followed patients in every steps of the project. AM: recruited the sample and collected medical data; carried out follow up visits. MTu: recruited the sample and collected medical data. CC: prepared the study design and supervised the mental health research team. GB: prepared the study design and supervised the research team. CM: prepared the study design and supervised the research team. All authors reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


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