Graft-versus-host disease (GVHD) is a complication of hematopoietic stem cell transplantation (HSCT). GVHD may also develop following solid transplants or blood transfusions if white blood cells are transferred. GVHD affects multiple organs, including the oral tissues. This pictorial review provides a background of GVHD to dental practitioners, describes the most common oral manifestations of GVHD, and highlights the main treatment modifications needed to deliver dental care to patients with GVHD. A narrative review enriched with clinical data was performed by searching the scientific literature for all articles regarding GVHD and oral manifestations/therapies. All articles without exclusion criteria, except animal tests, were included in the above review. Acute GVHD may manifest in the oral mucosa; however, it often develops immediately following HSCT when routine dental treatment is postponed. Chronic GVHD may manifest in the oral mucosa, the salivary glands, and the musculoskeletal compartment. It may indirectly affect the teeth and the oral flora, putting the patient at risk for infections. Importantly, GVHD poses an increased risk for oral cancer. GVHD has a wide range of oral manifestations, some of which may affect dental treatment. GvHD is known as the worst complication of allogeneic hematopoietic stem cell  transplants, making it the leading cause of morbidity and mortality associated with this transplant . The immGraft containing supply of immunocompetent cells Immunological dissimilarity between host and donorImmunosuppressed host.In 1960, Billingham established the criteria for the onset of GvHD:Resolution of the diseaseAllogeneic stem cell engraftment (production of the necessary space for the infusion)Bone marrow restoration by the infused cells after a period of aplasia (which takes about 100 days)Elimination of remaining diseased cells thanks to the graft-versus-tumor effect (GvT): allogeneically transplanted human hematopoietic cells can eliminate residual tumor cells in the recipient by an immune-mediated mechanism .The Billingham criteria can be found in allo-HSCT, a transplant that consists of the infusion of hematopoietic stem cells from a compatible donor into a recipient who has been appropriately conditioned with high-dose chemo- and radiotherapy . The goaThe main indication for this transplant is acute myeloid leukemia, but it is not the only one .The compatibility of HLA genes must be the same (autotransplant) or very similar since the reduction in compatibility is associated with an increasing risk of developing GvHD ,6. TechnBone marrow (BM).Peripheral blood stem cells (PBSC), which is the most innovative and most used technique to date.Umbilical cord blood, which, however, does not provide a quantity of stem cells sufficient to treat an adult.The sources of stem cells used can be:In patients who must undergo HSCT, the consensus is that all low-invasive dental care is necessary to eliminate any traumatic factors and infectious foci, postponing any elective treatments  after the post-transplant immune reconstitution . The treTraumatic factors  could be etiological factors in the development of oral ulcers or contribute to the development of oral mucositis in HSCT transplant patients who develop GvHD. Therefore, these should be eliminated . For theApproximately 35–50% of patients undergoing HSCT develop acute GvHD. In addition, it has been estimated that about 50% of patients with the acute form also subsequently develop the chronic form .Regarding prevalence, a 2018 study by the U.S. Research and Markets statistical center calculated that in the seven largest pharmaceutical markets, diagnosed cases of chronic and acute GvHD stood at around 18,408, set to rise above 22,000 in 2028.Persistent, if characterized by the persistence of signs and symptoms of classic aGvHD initiated before day 100 post-transplant;Recurrent, if it arises as a classic form that resolves but recurs after day 100 post-transplant;De novo, if it occurs after day 100 post-transplant without any signs or symptoms in the previous time frame.In the past, GvHD was divided into two main forms: acute and chronic. This designation was based exclusively on a temporal criterion, the so-called “10-day dividing line”. The 2005 NIH Consensus Conference abolished this classification criterion and redefined chronic and acute GvHD solely based on different clinical manifestations . Acute GAs far as the chronic form (cGvHD) is concerned, this can arise following the evolution of the acute form , after the resolution of a previous acute form (quiescent), or “de novo”. Also, cGvHD is divided into classic and superimposed forms, if it occurs with the typical acute form manifestations on a pre-existing chronic form .Afferent phase: this concerns the phase prior to HSC transplantation, i.e., conditioning. The use of high-dose chemotherapy and radiotherapy induces tissue damage in the patient, with the secretion of numerous pro-inflammatory cytokines such as IL-1 and TNF-alpha. These will lead to an overexpression of adhesion molecules and antigens on MHCs. This event will facilitate the recognition of these cells as non-self by donor immune cells once transplantation has taken place .Induction and expansion phase: after transplantation, the recognition of host antigens by donor T cells, which, once activated, will undergo proliferation and differentiation . The conEffector phase: after their activation in the previous phase, T cells secrete a disproportionate number of cytokines that lead to migration, activation, and proliferation of other immune cells. This phenomenon, due to the high production of cytokines, is called cytokine storm . CytokinThe pathogenesis of acute GvHD can be divided into three phases:TGF-beta is the cytokine involved in the stimulation of collagen synthesis in the sclerosis phenomena characteristic of skin and mucous membranes in this disease;IL-4 stimulates the production of IgG and IgE by B cells, but also the proliferation of mast cells that play a primary role in the skin alterations typical of cGvHD;IL-5 is correlated with an increase in circulating eosinophils;IL-10: the association of IL-10 and high concentrations of TGF-β, is associated with immunodeficiency.Despite the important progress in recent years in understanding the pathogenetic mechanisms underlying aGvHD, chronic GvHD is much less defined. Based on clinical features, chronic GvHD is now considered an autoimmune phenomenon in which tolerance for host tissues is lost and is characterized by the production of autoantibodies (mainly IgM and IgG), monoclonal gammopathies, and numerous connective tissue sclerotic phenomena. In the development of cGvHD, we have the failure of the response that involves mainly CD8+ and CD4+ lymphocytes with a lack of production of INF-gamma and IL-2, which are the cytokines characterizing acute GvHD and allow the selection of the Th1 phenotype . The proSkin involvement (81%) is characterized by the presence of a maculo-papular, itchy, violet-colored rash. The distribution of the rash is characteristic: at first, it involves the palms of the hands and feet soles, then it spreads to the cheeks, ears, neck, trunk, chest, and back. Histological findings show apoptotic phenomena of cells of the deep layers at the level of epithelial ridges, invaginations of epithelium that deepen in the dermis, with dermal–epidermal separation. Other typical findings are dyskeratosis, perivascular lymphocytic infiltration at the level of the dermis, and the presence of satellite lymphocytes in close proximity to dyskeratotic keratinocytes .Gastro-intestinal involvement (54%), where the most common symptom is diarrhea, but emesis, anorexia, abdominal pain, or a combination of painful cramps, occasional bleeding, and ileus  may also occur in severe cases. Histologically present are flattening of the intestinal villi, dilation of the intestinal lumen and thickening of the walls of the small intestine, inflammation of the lamina propria, destruction of the crypts, lesions ranging from unicellular necrosis of the mucosal epithelium to complete loss of the epithelium itself and possible ulcerations surrounded by erythematous halos .Hepatic involvement (50%), manifested by cholestatic hepatopathy, with or without jaundice, and hepatomegaly. In hematochemical examinations, direct bilirubin, gamma-GT, and alkaline phosphatase levels  are altered, while transaminases (GOT and GPT) show a nonspecific increase.Eye involvement, with dry keratoconjunctivitis and a peculiar pseudomembranous conjunctivitis ,26.The clinical manifestations of aGvHD, the expression of an immune deficiency, mainly concern:Skin (80%), in which skin lesions are characterized by initial dry skin and ichthyosis , then progressing to an itchy, purplish, plaque or papular rash, clinically indistinguishable from lichen planus. Another typical cutaneous manifestation is superficial or deep dermal fibrosis ,28. TherAt the musculoskeletal level, fibrosis can also affect the tendons and muscles, causing fasciitis, myositis with muscle weakness, myalgia, and muscle contractures that facilitate diagnosis; in fact, muscle biopsies show phenomena of degeneration, necrosis, and regeneration of muscle fibers. Musculoskeletal system impairment seriously compromises the patient’s life quality, impacting his mobility .Respiratory patients who see lung involvement are often asymptomatic or have nonspecific symptoms at an early stage and, as a result, diagnosis is often delayed. The patient often presents exertional dyspnea, sinusitis, reduced tolerance to physical exercise, and persistent cough at the time of diagnosis. The cause of these alterations is to be traced back to obliterating bronchiolitis, which if it continues without being subjected to therapy can lead to the death of the patient from serious superinfections .In the liver, the alterations are like the acute form, with cholestasis and increased serum levels of bilirubin and alkaline phosphatase (ALP).Ocular symptoms such as xerophthalmia and photophobia, due to keratoconjunctivitis sicca (KCS) also known as dry eye syndrome, or other types of keratopathies.In women, genital involvement may be the only sign of chronic GvHD. These signs develop on average 10 months after the transplant and include dryness, erosions, thickening of the mucosa with vaginal narrowing, frequent infections, and pain during sexual activity (dyspareunia). In men, more rarely, the presence of phimosis can be highlighted .The clinical manifestations of cGvHD, the expression of an autoimmune disease, mainly concern:The oral manifestations of GvHD can be divided into three groups: the manifestations derived from the conditioning regimen and those of the acute and chronic form of GvHD  25]..25].Oral mucositis represents a severe inflammatory picture of the oral mucosa, a complication often present in patients undergoing chemotherapy and radiotherapy, the frequency of which rises to 75–99% in cases of pre-HSCT conditioning, due to the high doses used .Grade 1: presence of erythema with slight discomfort, which is the initial state of the pathology.Grade 2: diffuse erythema and superficial ulcers that still allow solid nutrition.Grade 3: painful ulcers that force the patient to switch to an exclusively liquid diet due to the high chewing pain.Grade 4: extensive mucositis that requires parenteral nutrition is the most severe.The WHO divides oral mucositis into four degrees based on the severity of symptoms and lesions:The maintenance of excellent oral hygiene is essential for prevention, especially to minimize the risk of secondary fungal or bacterial infections. The guidelines of the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO) recommend the use of soft brushes, dental floss, and the use of saline or sodium bicarbonate rinses. All traumatic factors can contribute to the development of inflammation of the oral mucosa and must therefore be removed .Other methods to prevent the development of oral mucositis are the use of low-level laser therapy that improves tissue repair and reduces pain, zinc supplements (antioxidant), and recombinant human KGF. Analgesia in the treatment of mucositis is obtained with the use of mouthwashes containing 2% morphine, benzydamine , or 0.5% doxepin .The oral manifestations in acute GvHD are very infrequent and therefore there is no well-defined characterization in the literature. In fact, some authors such as Zeiser  in theirChronic GvHD is the main cause of functional impairment of the oral cavity in patients suffering from GvHD. The oral cavity appears to be the second most frequently involved site in the chronic form in PBSC transplants with a frequency of about 90% (second only to the skin) . The oraLesions of the oral mucosa○Localized or diffuse erythema associated with edema or atrophy of the mucosa that reveal the underlying vascular structures .○Lichenoid lesions, white or milky streaks like Wickham’s streaks observed in lichen planus, against which these lesions are compared in differential diagnosis. They usually appear as whitish plaques or spots with hyperplastic mucosa and may have preneoplastic potential ,37.○Ulcerations, interruptions in the continuity of the mucosa that emerge when the destroyed epithelium leaves the inflamed connective tissue exposed. Sometimes they can have a pseudomembrane. If they are chronic lesions, they do not heal spontaneously and the reason is that, despite the removal of the traumatic factor that predisposed the formation, there is a low percentage of local growth factors which is also associated with a reduced proliferative capacity of the cells resulting from the disease .○Mucoceles mainly localized on the palate, caused by extravasation of saliva secondary to the sclerotic process of the ductal walls, which obliterates the lumen of the minor salivary glands. The inflammation of the salivary glands, in addition to this stenosis process, is aggravated by the decrease in secretion and the increase in saliva viscosity. The most affected areas are the hard palate and the lower lip .Limitation of mouth openingOral cGvHD lesions can be divided into three groups:Chronic inflammation can also cause perioral sclerotic fibrosis, which limits the opening of the mouth due to the overproduction of collagen. CGvHD, as well as scleroderma, can involve any orofacial tissue. The limited opening and the resulting alteration of the oral cavity functions could contribute to the patient’s malnutrition and possible infections. The sclerotic process can also restrict tongue movement and extend to the throat and esophagus, resulting in dysphagia .3.Salivary gland dysfunctionCGvHD, as well as conditioning, can also affect the salivary glands leading to the destruction of the glandular acini with periductal fibrosis. The most frequent consequence is xerostomia with an increase in carious processes and fungal infections. These manifestations are very similar to those of Sjogren’s syndrome, and both are also associated with xerophthalmia. There are three characteristics that distinguish the histopathological alterations of cGvHD in the salivary glands: lymphocytic infiltration in the ducts of the salivary glands, apoptosis of the ductal epithelial cells, and destruction of the tissues of the glandular acini with periductal fibrosis .The treatment of mucocutaneous lesions from acute and chronic GvHD is often a difficult problem for the clinician . In addiThe systemic treatment of the disease consists of immunosuppressive drugs but only in a few cases leads to the healing of oral lesions . These pIn the current review, there are insufficient references in the literature regarding implant survival and success in patients with GvHD, in any of its forms . DespiteThe first case report is about a clinical case presented by Mahn D.H. of a 46-year-old non-smoker man with a medical history characterized by HSCT-treated non-Hodgkin’s lymphoma, which led to the development of cGvHD 1 year later. Clinical evaluation of the patient revealed remission of the disease, but poor oral hygiene and teeth that were severely compromised by carious disease. Severe gingivitis and gingival recessions were also present. The treatment plan, after evaluating the bone structure, provided for the simultaneous extraction of all the mandibular and maxillary dental elements and the contextual placement of five implants for the lower arch . The treIn the second case report, Curtis J.W. described the case of a patient with GvHD developed after HSCT. The patient presented with severe caries pathology and sharp enamel projections causing chronic trauma to the tongue and adjacent mucosa. In this case, the teeth were extracted and replaced with removable total prostheses delivered 6 months after the extractions. Only after 2 years, five mandibular implants were inserted to create a complete overdenture delivered 14 months after the insertion of the implants .In the third case report, A. Etebarian et al.  presenteMahn’s case report remains to date the only one that describes an implant success in a patient with GvHD in which dental extractions and simultaneous insertion of mandibular implants were performed ,50.In conclusion, what are the keys to successful case management? Attention to detail during the diagnostic, surgical, and restorative phases, management of patient expectations, and compliance with patient instructions.Extremely important, then, is patient compliance; only then can predictable results be achieved and complications averted.The mechanisms underlying the development of GvHD are becoming increasingly clear but enormous progress still needs to be made in this regard. Therapeutic approaches can be established only through a full understanding of the disease. Oral manifestations of the disease, especially in its chronic form, are highly frequent and their management is not easy for the dentist. The mucosa of the post-HSCT patient loses its ability to renew itself due to the impact of the treatments to which it is subjected. Treatment options, in the current review, are numerous but almost none of them are yet supported by randomized controlled trials (RCTs) demonstrating their benefits. Therefore, there is a need to develop new therapeutic techniques for topical use in addition to the traditional use of immunosuppressive drugs, such as platelet gels, and the use of new and interesting proposals that have the potential to become first-line treatments in dentistry for the resolution of oral lesions. Implant therapy in the GvHD patient also needs further study as it could become a very valid opportunity for rehabilitation of the oral cavity and significantly increase the quality of life of patients suffering from this pathology. In this context, the synergy between the dentist and other relevant medical figures is crucial to achieve predictable results. The relationship between the dentist and the specialist is bidirectional, as it is important that the dentist release a dental clearance before the patient can start HSCT. For this reason, as previously stated, it is essential to perform all the necessary treatments for the elimination of traumatic and inflammatory factors. When the dentist is faced with such a situation, it is good that he or she knows the characteristics and mechanisms of this pathology in order to be able to treat the oral lesions.


With extended life expectancy, the quality of life of elders is a priority. Loss of mobility, increased morbidity and risks of falls have dramatic individual and societal impacts. Here we consider the age-related modifications of gait, from a biomechanical and neurophysiological perspective. Among the many factors of frailty involved , loss of muscle strength and neurodegenerative changes inducing slower muscle contraction may play a key role. We highlight that the impact of the multifactorial age-related changes in the neuromuscular systems results in common features of gait in the immature gait of infants and older adults. Besides, we also consider the reversibility of age-related neuromuscular deterioration by, on the one hand, exercise training, and the other hand, novel techniques such as direct spinal stimulation (tsDCS). With extended life expectancy, the quality of life of elders is a priority. Loss of mobility, increased morbidity and risks of falls have dramatic individual and societal impacts. Among the many factors of frailty involved, loss of muscle mass and strength  and neurBiomechanical changes with age have garnered considerable scientific attention for nearly 50 years. The scientific community  most oftFor instance, with aging motor weakness is due in part to neuromuscular degeneration, but also to degenerative changes in the central nervous system. Thus, reduction in grey matter volume , number Using an electrophysiological approach, a way to get insight into spinal cord functioning is to look at the spatiotemporal organization of the total locomotor output by mapping multi-muscles EMG onto the spinal cord in approximate rostro-caudal locations of the motoneuron (MN) pools . By studThe major consideration of this review is the age-related remodeling of both the neural and muscular system and its relationship with locomotion changes with age, to shed light on the multifactorial age-related changes of gait. The alterations of the gait pattern in older adults are then compared to immature gait. Besides, we also consider the reversibility of age-related neuromuscular deterioration by, on the one hand, exercise training, and the other hand, novel techniques such as direct spinal stimulation (tsDCS) to mitigate the reduction of intrinsic spinal motoneuron excitability in older adults , and howAging is a natural and gradual process where the alterations in motor control and physical fitness are multifactorial . StrengtSeveral age-related modifications of muscle tissue have been described, such as loss of muscle fibers  or substEven the pathogenesis of sarcopenia is not yet fully understood, multiple etiological factors seem to be involved, including alteration of muscle proteostasis , mitochoWhile the causes of the age-associated loss of motor neurons are still unsettled, the neuromuscular junction integrity, and in particular the mitochondrial dysfunction at the neuromuscular junction, may have an important role . The chaThe multifactorial age-related changes in the neuromuscular system, summarized in the last section, are rather well documented. As people age, those changes result in alterations in gait patterns. In this section, we present different aspect of gait  pools, the activation of MNs tends to occur in bursts that can be associated with the major kinetic events of the gait cycle . In partvastus medialis muscle . Anothey Koller , and stey Koller , with loy Koller , and basy Koller , One mayAlso from a kinematic point of view, a simpler coordination pattern among the lower limb segments can be observed both during childhood and agedness . One wayBecause a link between center of mass (COM) trajectory and functional spinal cord topography has been previously highlighted , one mayBased on the well-documented change in muscle strength with aging described in the last section, a lot of efforts have been made to counteract it using exercise . PhysicaResistance training (RT) positively affects walking speed . For exaetc. For example, in a classical paper, Bornstein and Borstein  . PICs arAs described by Hassan et al. , the PICThe tsDCS has been increasingly used over recent years in the rehabilitation of patients following neurological injuries  or as anThis review outlines great similarities between the ‘first steps’ of infants and the ‘last steps’ of older adults. While part of the modifications observed in older adults may emerge from a lack of propulsive power, other neurodegenerative changes play a key role. In particular, slower muscle contraction is observed, resulting from the change in fiber type, the greater reinnervation of slow motor neurons or the lower motoneuron firing frequency with ageing, which is also an important peripheral contributor to the lack of adult-like locomotor patterns in early infancy . Gaining


Russo et al.). In IBD, the sealed intercellular junctions are damaged, either from a primary barrier function defect or from severe inflammation. Excessive inflammatory response leads to continued deterioration of the epithelium and exposure to the intestinal microbiome , thereby further worsening the inflammation (Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by intermittent chronic inflammation of the gastrointestinal tract, due to a dysregulated immune response against intestinal mucosa, leading to bowel damage . The carcinogenesis in IBD is a multistep progression, due to increasing degrees of histologic, molecular, and endoscopic alteration, from no dysplasia against chronic inflammation to low-grade dysplasia to high-grade dysplasia and eventually neoplasia  is the most critical IBD complication , plays a crucial role in IBD development and in the process leading to CAC . Each ofIn this landscape, this Research Topic provides an overview of immune cell roles in modulating intestinal epithelial cell functions in colon tissue immunopathology, such as inflammation, IBD and CAC, welcoming all those studies, performed in human IBD/CAC and animal models of colitis, which will help to elucidate cellular and molecular mechanisms driving tissue immuno-pathogenesis. In addition, the Research Topic examines the role of the immune microenvironment in the development of IBD and CAC by modulating inflammatory factors and the intestinal microbiome.Zhou et al. examines the mechanisms of inflammatory mediators in the IBD and colorectal cancer (CRC) microenvironment. It addresses the role of lactate, an intermediate by-product of glucose metabolism found in the gut microenvironment, in the inflammatory process. The authors examined its inflammatory/anti-inflammatory effect with a double approach: an in vitro study on macrophages stimulated by LPS and, for the first time, an “in vivo” study on a mouse model of DSS-induced colitis. They observed an inhibitory effect of lactate in the TLR/NF-κB signaling pathway and a promotion of the polarization of macrophages in the colonic tissue, inducing pro-inflammatory factors. In addition, the authors reported lactate involvement in the mucosal barrier-repairing process and in the protection of the intestinal tissue in the inflammatory condition. Therefore, they finally propose lactate as a promising and effective drug for treating inflammation through immunometabolism regulation.In this regard, the manuscript of Rubin et al.). In this context, the study of Zhang et al. improved the understanding of the role of neutrophils in UC and in its progression to CAC, providing new and more effective insights into CAC prevention and treatment. With the aim to identify differentially expressed genes and potential biological pathways, the authors first used a bioinformatic approach to analyse UC transcriptomic data. Using validation cohorts and mouse models, they observed an increased infiltration of neutrophils in UC tissue and augmented MPO and pSTAT3 expression. Thus, they classified the UC patients into two subtypes of neutrophil infiltration; interestingly, highly infiltrate of subtype B neutrophils of UC patients showed a higher risk of developing CAC. The authors suggested that neutrophils might promote the conversion of UC into CAC.As previously reported, CAC is considered the most serious complication of IBD; however, there is still a lack of clear understanding of its pathogenesis from UC , offering to Scanpy users the ability to annotate their cells of interest by means of manual selection, This tool is useful for the selection and sub-phenotyping of T-cell subsets implicated in IBD beyond standard clustering. The authors demonstrated that scSELpy might therefore become an important application for future single-cell transcriptomic analyses, supporting future immunological research.Moreover, technological advances and the introduction of novel therapeutic approaches –13, in cER wrote the manuscript, ER edited the manuscript, AA corrected the final version. All authors read and approved the manuscript.


One of the most important challenges for decision-makers and investors is location selection, which may be assessed using multicriteria decision-making (MCDM) methodologies. Problems with picking a location include deciding between alternative locations, analyzing alternatives, and identifying the best location for a hospital. Because they analyze options with multiple perspectives in terms of numerous competing criteria, MCDM approaches are useful instruments for solving decision-making challenges. The fuzzy set theory (FST), which represents uncertainty in human beliefs, may be effectively used with MCDM approaches to produce more sensitive, tangible, and accurate findings in this context. A hybrid fuzzy multi-criteria decision model (FMCDM) is proposed to find the optimal location based on a combination of factors. In the first stage, the Fuzzy Analytical Hierarchy Process (FAHP) is used to estimate the relative criteria classification through the evaluation process. In the second stage, the fuzzy technique of order preference using similarities to the perfect solution (FTOPSIS) is applied to rank the possible alternative sites. The findings from this study indicate that integrate FAHP and FTOPSIS is the most often used FMCDM approach in Aleppo for selecting the best location for a new hospital. A decade after the beginning of the Syrian crisis in 2011, the country’s healthy sector is facing many challenges and obstacles where Many hospitals have been destroyed were forced to considerably reduce their operations as a result of the destruction of the infrastructure of most of the healthy sector and lack of resources [By the end of May 2018, the mentioned results of the situation of hospitals are almost the same ; this shAll of that has created several issues for the health industry in general, and hospitals in particular, including a lack of supplies, equipment, human resources, and space, as well as placing strain on the whole healthcare system . Each coHowever, the decision-making process is a scientific way to assessing the possibilities for overcoming negative challenges that arise in the functioning of any institution and picking the best option among these options. When it comes to making decisions, the modern approach to operating a corporation necessitates the application of scientific methodologies that are upgraded and appropriate for today's situations. Making correct judgments necessitates a thorough understanding of the system in which issues occur, as well as the development of a trustworthy mathematical model  that accurately depicts the problem or problems. The range of scientific methodologies utilized in decision-making processes is now seen to be the secret of business success. Furthermore, quick changes and competitive conditions make it necessary to work together to solve difficulties and to employ current technical procedures .Site selection, which provides a systematic framework for establishing the norms and criteria for the geographical placement of production, commerce, and service activities, is relevant in this context and has been identified as a key research theme, attracting a growing number of researchers and decision-maker from numerous scientific disciplines. Furthermore, because of its considerable and long-term implications on commercial risks, expenses, and revenues, site selection is one of the most essential strategic business choices . SelectiMultiobjective decision-making and multiattribute decision-making (MADM) are two of the model's issues . BecauseThe multi-criteria decision-making (MCDM) approach, which encompasses several approaches, has been used to examine the bulk of site selection difficulties like analytical hierarchical process (AHP), Analytical Network Process (ANP), Decision Making Trial and Evaluation Laboratory (DEMATEL), Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS), VIsekriterijumska optimisacija I KOmpromisno Resenje (VIKOR), and others. Soft computing techniques including Multi-Objective-Decision-Making (MODM), fuzzy sets, the analytic method, mixed integer/linear integer/goal programming, cluster analysis, and others were also applied .Although there are many evaluation techniques, the MCDM model is a well-liked strategy that is successfully applied in many sectors for optimal site decision-making under several competing criteria. This approach is crucial in management science, which can improve service quality and aid in hospital ranking . Due to In fuzzy MCDM methods, the main reason of using FTOPSIS as basic technique is that fuzzy TOPSIS method has been used to address a variety of matters, including facility selection , choosinIn the tourist sector, Baki et al. recommended a fuzzy AHP-TOPSIS model to increase hotel website operating efficiency by boosting competition, brand value, and consumer volume . Given tHowever, the related literature on choosing the most potential site of hospital in Aleppo is unavailable, and this has not been fully researched and exploited to date. For this reason, the Fuzzy AHP and Fuzzy TOPSIS method are integrated to address our concerns regarding this problem. The study aims to efficiently assist investors or decision-makers in the evaluation and selection of suitable hospital locations in Aleppo. The literature procedure is organized as follows. Firstly, an evaluation of the criteria weightings is conducted using the fuzzy AHP method based on experts’ opinions combined with a literature review. Next, the alternatives to the healthy site are ranked by applying fuzzy TOPSIS. The model’s result assists investors in further development, based on the priority ranking of the hospital sites.Moreover, strengthening these results using sensitivity analysis and review 12 cases in which the weights (input data) were changed, the results were drawn, and the main results extracted from the use of the fuzzy TOPSIS technique were strengthened and contribute to providing a framework for decision support to address the problem of choosing the location of the temporary hospital in a cloudy environment of uncertainty. We presented a generalization of TOPSIS in an ambiguous environment and the use of the proposed technique in selecting the optimal site for hospital construction in Aleppo, a Syrian governorate according to a set of criteria.The remaining portions of the paper are divided into five categories. The literature review examines in the next section. In section "This section reviews prior research on selecting optimal location for building hospitals in Aleppo built on a set of criteria. The primary objective of this research is to develop a mathematical model capable of dealing with incomplete or inaccurate data and arriving at suggested solutions in which the decision-maker is an essential part of the decision-making process. There are three sections to this literature review. The first portion goes through the fundamentals of decision making and basic requirements for decision making. The second section discusses the process of location selection. Finally, the importance of multi-criteria decision-making (MCDM) is discussed in the last one.An overview of the main characteristics of MCDM methods and challenges is given in this subsection.Cj, with A typical MCDM challenge entails selecting the best option from a set of workable options that have been assessed using a variety of competing quantitative and qualitative criteria. Assume a decision-maker (DM) is asked to rank n alternatives , The problem definition, alternative selection, criterion selection, decision matrix creation, weight elicitation (determining the weight of the criteria), and alternative ranking are generally the primary steps of MCDM techniques. The decision criteria are frequently divided into two categories: benefit criteria, where the performance improves with increasing alternative score , and cost criteria, where performance improves with decreasing alternative score  , 107.Well-known and traditional MCDM techniques including WSM, AHP, ANP, WPM, TOPSIS, VIKOR, ELECTRE, PROMETHEE, GRA, and DEMATEL can be used to solve MCDM problem. Additionally, a lot of academics have tried to create new MCDM techniques to address problems in the real world with various features, such as COPRAS, WASPAS, BWM, SWARA, MULTIMOORA, SODOSM, ARAS, OPA, MARCOS, and GLDS.Around 100 MCDM approaches (with variations) have been documented in the literature, and Greco et al.  noted that DMs can be unsure of which one to use. The kinds of issues that MCDM approaches seek to solve, the theoretical foundations they are based on, and the kinds of conclusions they draw are all different , 87. As On the other hand, Gershon and Duckstein highlighted the main criticism of MCDM methods, pointing out that it is generally difficult to determine which MCDM method is more reliable for a given problem and that different methods may produce different results when applied to a specific decision problem . More imThe strengths and weaknesses of MCDM approaches for certain applications are well-documented in the literature. , for insWe are aware that there are various approaches to classify MCDM techniques. Multi-attribute utility theory (MAUT) techniques like TOPSIS and VIKOR and outranking techniques like ELECTRE and PROMETHEE can be used to categorize MCDM techniques as a whole . A pairwEveryone is aware that several units analyze how alternatives perform in relation to the choice criteria. To make several scales of measurement comparable, normalization procedures are used to the components of the provided decision matrix. There are various normalization approaches, and each one has its own advantages, disadvantages, and focal points . AdditioRegarding identifying places and locations, the TOPSIS mysterious method is considered one of the most prominent methods that have been used in this field. There are many previous studies, including , 38, KasThe previously mentioned multi-criteria decision-making (MCDM) methods are some of the frequently used decision-making tools that are well designed for complex problems involving multiple criteria with the need to prioritize alternatives. MCDM methods enable the decision-makers to evaluate the number of alternatives with the different data available such as crisp, fuzzy, interval, rough, etc. The criteria importance through inter-criteria correlation (CRITIC) approach is a well-known MCDM method, which is designed to determine the criteria's importance to an MCDM problem. Unlike other MCDM methods that focus on the weighing process, the CRITIC method does not require separate pairwise comparisons of criteria, because it uses an initial decision matrix that is generated to compare the alternatives, as one of the powerful MCDM methods presented recently.Decision making is a scientific way to assessing the possibilities for overcoming negative challenges that arise in the administration of any organization and choosing the greatest alternative among these possibilities.MCDM is a methodological frame that tries to suggest decision-makers with informed recommendations from a finite number of options  that have been examined from numerous perspectives, or criteria . The problem of selecting location is commonly referred to MCDM in the literature. As a result, traditional MCDM techniques have been used in problem-solving processes. MCDM techniques can be divided into four groups based on the principles that underpin them:(1) "multiattribute utility methods like AHP and ANP, (2) outranking methods like Elimination and Choice Expressing Reality (ELECTRE) and Preference Ranking Organization Method for Enrichment Evaluation (PROMETHEE); (3) compromise methods like Technique for Order Performance by Similarity to Ideal Solution (TOPSIS) and Multicriteria Optimization and Compromise Solution (VIKOR); and (4) other MCDM techniques like Simple Multiantibiotic Rating Technique (SMART) (DEMATEL)” , but in Hospitals all throughout the world are critical in the fight against the COVID-19 epidemic. During an epidemic, hospital executives are usually confronted with unexpected problems that need them to undertake jobs they are not used to [As the current coronavirus outbreak has demonstrated, many contemporary hospitals and healthcare systems lack the flexibility to handle unanticipated increases in patient numbers. Hospitals have reached capacity to treat COVID-19 patients suffering from extreme symptoms while also caring for individuals with mild symptoms or no symptoms, who pose an infectious danger to healthcare personnel and other patients.To address this issue, hospital architects have discovered new design options for healthcare systems, which have traditionally been built to support lean and efficient care operations, with an emphasis on delivering health services closer to patients' homes, inside community settings. In regard to their local surroundings, healthcare organizations and hospitals have three main options for transforming their environments in response to COVID-19.Spatial and organizational improvements have been implemented to better accommodate COVID-19 patients within a hospital, including the restructuring of internal 'foot traffic' routes and flows to separate persons infected with coronavirus from those who are not.For example, in Syria, the government team held a meeting in which it evaluated the decisions taken to strengthen the health work system in the country and to prepare hospitals to receive cases infected with the coronavirus, where the necessary measures were taken to ensure the increase of artificial respirators, intensive care beds, ambulances and medical equipment, and to secure their supplies of fuel and maintenance. In addition, December 16 in Damascus, Syrian health officials have activated an emergency hospital that was recently created to deal with an influx of patients that was established at a tennis court inside the Faiha sports stadium north of Syrian capital Damascus, the emergency hospital is equipped with 120 beds, 300 oxygen cylinders as well as 50 Continuous Positive Airway Pressure (CPAP) machines, in addition to a qualified and trained medical team to receive the COVID-19 cases.Criteria weights are important in multi-criteria decision-making methods. Although these weights carry many different meanings , these wThe MCDM technique, which is suggested to handle complex decision issues, includes the analytical hierarchy process (AHP) as a useful tool . With thThe complication of the system on which judgments will be made can sometimes rise, the significance of the ideas used to characterize that system can sometimes diminish, and there is a trend toward uncertainty. "Fuzziness" refers to the uncertainty of the terms used to describe an aim and a system. People's differing mental systems and perceptions might be seen as a cause of "fuzziness." There may be ambiguities due to under-maturation of human thinking, uncertainty, or "fuzziness" in some circumstances. In certain cases, numerical values cannot be utilized as decision-making input; instead, linguistic variables are employed, and fuzzy logic conditions are incorporated in the process.The characteristic function is generalized by fuzzy sets, which accept all values between zero and one. membership function  defines a fuzzy subset s 0 or 1 .The multi-criteria decision-making (MCDM) process benefited greatly from the fuzzy sets theory, and decision analysis has emerged as one of the most appropriate applications for this theory. Fuzzy MCDM was created, which marked a significant improvement in the field of MCDM by incorporating fuzzy sets into the MCDM procedure. Although the weights and priorities of the criteria are assumed to be precisely understood by the classical MCDM approaches, they fall short in modeling situations that are experienced in reality. In addition to permitting the use of linguistic factors in evaluating criteria and alternatives, fuzzy MCDM approaches also produce successful outcomes by quantifying unclear data.Many times, the data used in the decision-making process are incomplete or unreliable. When decision-makers must make a variety of decisions based on uncertain and ambiguous facts, fuzzy sets theory should be used. Furthermore, when solving real-world decision-making issues with fuzzy sets, the outcomes are more realistic. The main benefit of fuzzy decision making is that it provides a structure with more flexibility for coping with issues resulting from a lack of information . SimilarFuzzy set") Assume ("Fuzzy number") A fuzzy number  value using following Formula:Hwang proposed Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) approach is one of the most well-known multiple criterion decision-making (MCDM) methods. To identify the optimal option, the TOPSIS technique uses the shortest distance from the positive ideal solution (PIS) and the farthest distance from the negative ideal solution (NIS). While the PIS aims to maximize benefits while minimizing costs, the NIS aims to maximize costs while minimizing benefits.To use the TOPSIS approach, there must be at least two possibilities, which necessitates first identifying the criteria. TOPSIS uses two sorts of criteria in general: “benefit criteria” and “cost criteria”. In the Step 1: Assignment of ratings to the criteria and the alternatives.Let us assume there are Step 2: Assignment of ratings to the criteria and the alternatives.Compute aggregate fuzzy ratings for the criteria and the alternatives.If the fuzzy ratings of all decision-makers are described as triangular fuzzy numberIf the fuzzy rating and importance weight of the kth decision-maker are The aggregated fuzzy weights Step 3: Compute the fuzzy decision matrix.The fuzzy decision matrix for the alternatives Step 4: Normalize the fuzzy decision matrix.The raw data are normalized using linear scale transformation to bring the various criteria scales into a comparable scale. The normalized fuzzy decision matrix Step 5: Compute the weighted normalized matrix.The weighted normalized matrix Step 6: Compute the fuzzy positive ideal solution (FPIS) and fuzzy negative ideal solution (FNIS).The FPIS and FNIS of the alternatives are computed as follows:Step 7: Compute the distance of each alternative from FPIS and FNIS.The distance Step 8: Compute the closeness coefficient The closeness coefficient Step 9: Rank the alternatives.In step 9, the different alternatives are ranked according to the closeness coefficient Establishing a committee of decision-makersDetermining assessment criteriaDetermining linguistic variablesApplying F-AHP to defining the weight of criteriaForming the fuzzy decision matrix,Forming the normalized fuzzy decision matrix,Forming the weighted normalized fuzzy decision matrix,Determining the values of A* and Calculating the distance of each alternative from A* and Calculating the closeness coefficient of each alternative . The fuzzy TOPSIS method's flow diagram shows the steps as follows:These steps are briefly explained below:Step 1: judgments are collected from decision-makers , Halab Al Jadidah (A2), Salah Alden (A3), Al Sakhor (A4) regions, were accepted as alternative locations for the location selection problem. At this step, the evaluation criteria are determined. As the determination of the criteria that will be used for evaluation of alternative locations has a direct impact on the accuracy and quality of the results. Relying on previous studies as a study [ a study  and base Sakhor A regions,Step 3: This stage determines the proper linguistic variables for assessing both criteria and options, which may be expressed in positive triangular fuzzy numbers. Table Step 4: After choosing the appropriate linguistic variables, decision-makers determine the initial pair-wise comparison matrices as shown in Table Based on the examination of three decision-makers, the initial pair-wise comparison matrices are created. The linguistic scales are then transformed into a fuzzy number in Table The synthetic pair-wise comparison matrix of criteria is presented following Formula  shown inThe fuzzy geometric mean, fuzzy criteria weightage BNP values are demonstrated by applying Formulas –12), as, as12), Step 5: After Applying F-AHP To Defining the Weight of Criteria, the ratings of four alternatives under seven criteria are presented in Table Step 6: This step involves constructing the fuzzy decision matrix for ranking alternatives as in Table Step 7: At this step, the raw data are normalized to make comparisons across criteria. The normalized fuzzy decision matrix is constructed as in Table Step 8: After the normalized fuzzy decision matrix is constructed, since each criterion has a different importance, the weighted normalized fuzzy decision matrix should be constructed as in Table Step 9: At this step, the fuzzy positive ideal solution (A*) and the fuzzy negative ideal solution .


Liver cancer remains a global health challenge and its incidence is growing worldwide. The impact of hepatocellular carcinoma (HCC), the most common primary liver cancer, on global health is striking. In 2020, HCC was the sixth most diagnosed cancer, the fourth leading cause of cancer-related death, and the second leading cause of cancer-related mortality in men worldwide . With 90In this scenario, many efforts have been made and are currently directed toward the identification of novel biomarkers and/or pharmacological targets to be exploited for the rational design of new drugs, as well as for the evaluation of combination therapy strategies. This Special Issue aimed at providing an overview of the variety of novel molecular targets, therapeutic options, and biomarkers for early diagnosis and/or as prognostic indicators of treatment responses that could be useful in drug development.Many recent studies have been focused on finding biomarkers. The correlation between the tumor mutational burden (TMB), i.e., the total number of somatic non-synonymous mutations per coding area, and HCC prognosis has been investigated by many studies, as was reviewed by Gabbia and De Martin . In geneA large cohort study investigated the potential association of two minor variants of sorting and assembly machinery component 50 homolog (SAMM50) with HCC in patients with alcohol-associated liver disease . The preRecently, much attention has been paid to the diagnostic potential of liquid biopsies. The study by Manganelli and collaborators investigated, for the first time, the expression of telomeric repeat-containing RNA (TERRA) in HCC . Since TMany efforts have been devoted to unraveling the pathological mechanisms underlining the progression of chronic liver diseases to HCC, with the final aim being to find druggable targets to prevent or cure HCC. In this regard, the study of Andrade et al. suggests that the inhibition of the group VIA phospholipase A2 (iPLA2β), a protein involved in the regulation of epithelial cells and macrophage functions, could prevent HCC by inducing cell-cycle arrest . They deFor over a decade, the TKI inhibitor sorafenib has represented the main therapeutic option for advanced HCC. In the last few years, new therapeutic regimens have been approved as first- and/or second-line treatments, including immunotherapeutic agents and combinations, which have also shown promising results. A study performed on a rat model of DEN-induced HCC investigated the effect on tumor growth of the next-generation AKT inhibitor vevorisertib, which is characterized by improved pharmacokinetic and pharmacodynamic features compared to miransertib, another allosteric inhibitor currently under investigation for HCC treatment . This stThe study of Okumura and colleagues reported a positive role of the hepatocyte growth factor (HGF) in increasing the efficacy of chemotherapy with fluoropyrimidine drugs, e.g., 5-fluorouracil (5-FU), suggesting that the HGF/cMet axis plays a crucial role in the safety and success of this chemotherapy regimen . This stIn their review, Scagliola and collaborators summarized the relevant findings about the role of the eukaryotic initiation factors (eIFs) that control the hepatic translational machinery regulating the mRNA transcription of the oncogenic signaling cascade during HCC development . Since tIn conclusion, HCC is likely to gain more attention in the next few years within the oncology scenario due to its high mortality and growing incidence. The efforts of the scientific community must be driven toward the optimization of our current knowledge and the search for new approaches in finding feasible biomarkers for early diagnosis and clinical decisions, as well as specific druggable targets for novel therapies.


The limited regenerative capacity of the human body, in conjunction with a shortage of healthy autologous tissue, has created an urgent need for alternative grafting materials. A potential solution is a tissue-engineered graft, a construct which supports and integrates with host tissue. One of the key challenges in fabricating a tissue-engineered graft is achieving mechanical compatibility with the graft site; a disparity in these properties can shape the behaviour of the surrounding native tissue, contributing to the likelihood of graft failure. The purpose of this review is to examine the means by which researchers have altered the mechanical properties of tissue-engineered constructs via hybrid material usage, multi-layer scaffold designs, and surface modifications. A subset of these studies which has investigated the function of their constructs in vivo is also presented, followed by an examination of various tissue-engineered designs which have been clinically translated. The means of restoring mechanical functionality to damaged biological tissues has proven to be a longstanding challenge to medical practitioners. The complexity of the task is largely due to the intricacy of the native tissue, where biomechanical properties are largely dictated by the extracellular matrix (ECM) ,2. This The complexity of repairing extensively damaged tissues is such that contemporary regenerative medicinal practices are limited in treatment options . The traTissue engineering is a rapidly expanding field which aims to design constructs which supplement or replace damaged biological tissue. The fabrication of a tissue-engineered graft can be undertaken in a variety of ways, including phase separation, bioprinting, gas foaming and electrospinning techniques ,21,22,23A key challenge within this area is ensuring the greatest possible resemblance between the mechanical response of the tissue-engineered graft and the host’s native tissue. This is a crucial aspect of a successful design, as biological tissues are load-bearing by nature, regardless of function, from the strongest regions of cortical bone with mechanical strength in the gigapascal range  to the mOne can observe from To address this challenge, tissue engineering researchers are investigating a broad range of solutions to optimise the mechanical response of tissue-engineered grafts, while also maintaining the biocompatibility of the design. The current studies in this field include the use of multiple materials in conjunction with one another, such as polycaprolactone and collagen, bi- and multi-layered scaffolds which often delegate the functional requirements of the construct to each layer, and modifying existing scaffold parameters such that their performance may be tuned to better suit the conditions of the native tissue ,75,76. STo support the development of these designs, a broad range of literature is available which describes the mechanical properties of specific native tissue types and engineered tissue scaffolds. These include bone, cartilage, liver, kidney, osteochondral tissue, muscle, and tendon, and utilise a broad range of mechanical property assessment methods, including compressive, dynamic, nanoindentation, shear, and tensile testing, with additional methods including finite element analysis (linear and non-linear) and ultrasound ,80,81,82This work provides a review of the current techniques by which researchers have successfully modified the mechanical properties of tissue-engineered grafts. The scope of this review will encapsulate all applicable construction methods which are currently employed in this regard, and all tissue types will be considered in accordance with the focus of each study. A The mechanical properties of biological materials are a product of a complex array of proteins, cells, and interstitial fluid flow, whose interactions characterise the response of their respective tissue under load ,84. As aThe diversity in these results can not only be attributed to the structural composition of the tissues alone; factors such as hydration and age are also known to affect the mechanical response of biological tissues ,105. ThiIt is the cellular response to various conditions which allows the human body to maintain homeostasis, while also quickly adapting to environmental circumstances; vasoconstriction and vasodilation are common examples of this . HoweverThe non-linear biomechanical response of a tissue under load is difficult to reproduce in synthetic materials alone, as this response is characterised by complex biological structures and interactions, as described in The scope for hybrid biomaterial design is vast, which allows researchers to consider a broad range of materials. For example, several research groups have recently investigated the inclusion of multi-walled carbon nanotubes (MWCNTs), which are nanometre-diameter carbon-based tubular constructs, with the aim of utilising the nanotubes’ high tensile strength and electrical/thermal conductivity to enhance the overall biomechanical properties of their scaffold. Sang et al. dispersed MWCNTs with concentrations ranging between 1, 3, and 5% through a chitosan/polyethylene glycol scaffold, which was prepared by freeze-drying, for the purpose of neural tissue engineering . The ele2/acetate buffer solution. The degree of delignification induced a proportionate increase in the sugarcane stem porosity, albeit at the cost mechanical performance under compressive load, with the greatest extent—8 h of immersion—reducing the compressive modulus of 14.6 MPa for pure sugarcane stem to 4.82 MPa. An optimal soaking time of 4 h was established, which promoted an elongated elastic response from the scaffold under load whilst maintaining structural integrity [Hybrid plant-based designs are also promising in this area; a recent study by Jiawei et al. investigated the inclusion of hydroxyapatite into sugarcane stem, whose lignin had been removed  via soaking in a NaClOntegrity .The challenge of tuning the elastic response of a scaffold in tandem with balancing its biocompatibility characteristics has led several research groups to fabricate scaffolds consisting of multiple layers. This approach allows for the functionalisation of each stratum independently and more closely represents the layered nature of most biological tissue, such as arterial walls, osseous tissue, and oesophageal tissue ,131,132.While the properties of multi-layered scaffolds are largely determined by the material selection, several groups have investigated the potential of applying novel fabrication methods in order to construct a multi-layered construct which can function within the physiological load range. Killian et al. studied the combination of calcium phosphate cement (CPC), fabricated via 3D printing, and PCL, drawn using a melting electrowriting (MEW) process for the purpose of bone tissue engineering . These tIn addition, Thompson et al. employed a process known as embedded 3D printing to fabricate a multi-layer scaffold in an effort to replicate human vocal cord tissue . This meThe mechanical properties of engineered tissue are not necessarily set in stone. By design, a substance such as a polymeric compound may have its constituents altered such that it may better serve its intended function ,155. In Borassus flabellifer for the purpose of bone tissue regeneration [Surface modification also has the capacity to facilitate the functionalisation of more unlikely material candidates for this research into more suitable substances. An example of this is offered by Mahendiran et al., who examined the potential of cellulose scaffolds derived from neration . The scaNanotopographical roughness is a feature which may also be employed to modify the properties of a given scaffold. The influence of surface roughness on cell behaviour is well documented, with several groups reporting relative increases in cell proliferation, adhesion, and desired protein expression when seeded on irregular scaffold surface morphologies ,168,169.The mechanical and biological performance of a tissue-engineered scaffold can be analysed in a number of ways: mechanically, via the methods described in A construct designed to operate in such an environment, such as a vascular graft, would be expected to function under these load conditions; mechanical testing is therefore key, prior to the further development of such a design. However, classical mechanical assessment methods such as those outlined earlier in this section, while perhaps indicative of a particular design’s fundamental mechanical properties, are often incapable of evaluating the graft’s performance under true physiological conditions, as these are typically non-linear, heterogeneous loads which are nearly impossible to replicate via contemporary testing equipment .The complex nature of these forces has led scientists to explore several avenues of research in an effort to better comprehend, and design for, their impact on tissue-engineered designs. Recent advances in finite element analysis (FEA) and computational fluid dynamics (CFD) analyses have allowed researchers to model tissues such as pulmonary arteries , airwaysDespite the promising outlook of this research, a true estimation of the in vivo performance of a tissue-engineered scaffold is still beyond the grasp of contemporary computational or in vitro methods.The next logical step, therefore, is to assess the viability of tissue-engineered implants in vivo. This will allow researchers to understand how viable their scaffold’s design is once implanted into biological tissue, and will also validate the use of particular materials and construction methods within living organisms. The assessment of tissue-engineered designs in vivo can also offer insight into cell behaviour when uncommon scaffold morphologies are implanted within the animal. Feng et al. examined the effects of implanting a conch-like scaffold, featuring a helical inner structure, into the upper femoral region of New Zealand rabbits, with the aim of assessing such a design to promote guided bone regeneration . Formed Despite developments in this area, in vivo testing in animals, especially in the current exploratory phase of tissue engineering research, suffers from a widely variable animal-to-human translational success rate . This isOrgan-on-chip technology bears significant promise, as it may provide a more agile and less ethically challenging means of assessing tissue-engineered constructs. However, one can observe from The use of synthetic designs to supplant existing damaged native tissue is a long-established practice, with the earliest total hip arthroplasty, made with ivory, being recorded in Germany in 1891 . ScientiA further hurdle is that tissue-engineered designs are subject to various regulatory frameworks depending on the jurisdiction in which the design is to be marketed and sold within. While several jurisdictions in the European Union, United States of America, Canada, Australia, Japan, and South Korea have various classifications for tissue-based products, many others do not ; difficuRegardless, progress in this field is clear, with several novel tissue-engineered implants having recently been successfully trialled. A clear trend from Whilst the continuous utilisation of 3D printing technology as the basis for the clinical translation of tissue-engineered designs remains to be seen, alternative fabrication methods such as electrospun grafts, hydrogel systems, and bioprinting continue to be developed in parallel, bringing tissue-engineered constructs ever closer to clinical and commercial viability.The limitations of contemporary surgical and therapeutic techniques to restore the original functionality of damaged organic tissue have driven the development of various tissue-engineered platforms, which aim to support and encourage the regeneration of healthy autologous tissue. One of the key challenges in this area is establishing a high degree of similarity in the mechanical properties between the engineered scaffold and the surrounding biological tissue. This is due to the typical inability of manufactured materials to replicate the complex biomechanics of organic tissue. This capability, however, is crucial for a successful tissue-engineered design.In response to this issue, current tissue engineering research is examining a broad spectrum of potential designs aimed at enhancing the mechanical and biological compatibility of tissue-engineered constructs. From the studies described in this work, it is clear that relatively well-documented fabrication methods such as electrospinning and 3D printing can produce designs with, in some cases, a high degree of mechanical equivalence to native tissues. Techniques such as bioprinting and MEW, while promising, will likely require further validation before widespread use is achieved. In terms of materials, the usage of particular polymers such as PCL and PLA, ceramics such as HA and β-TCP, and hydrogels consisting of gelatine and alginate have seen widespread use, while the effects of more novel materials such as CNTs and quantum dots are yet to be fully examined in a tissue engineering context.A notable observation from these studies is that accounting for the complex range of mechanical properties present in biological tissues is generally beyond the remit of a single-material-based design. Rather, a multifaceted approach consisting of multiple material types, layers, or surface treatment methods working in tandem is likely to yield the most successful designs. In terms of translation to clinical use, the time-sensitive nature of surgical treatment suggests that 3D printing, as a fabrication method, is a strong contender for the successful realisation of these designs. Regardless of approach, it is clear that with further development, tissue engineering is set to act as a transformative treatment method.


The Neurotrauma Treatment Simulation Center (NTSC) is an innovative educational program, aimed at bridging the gaps among specialties and promoting a multidisciplinary treatment concept to neurotrauma care. In this event report, we highlight the achievements of the second edition of the Neurotrauma Treatment Simulation Center (NTSC). The program was built upon the success of its inaugural edition which brought together medical professionals from diverse specialties  and countries. This year’s course was held in Vienna, Austria, between the 16th and 21st of April and welcomed participants from Vietnam, Thailand, Ukraine, South Korea, Bosnia, and Azerbaijan who collaborated toward improving the neurotrauma patient’s pathway through the medical system and revolutionizing multidisciplinary neurotrauma management .One of the key features of the NTSC is its simulation center in Klinik Floridsdorf, which provides participants with a unique opportunity to refine their skills in a controlled environment. The simulation scenarios recreate emergency situations, enabling participants to enhance their knowledge of neurotrauma treatment complexities while practicing their collaborative skills under pressure. The inaugural NTSC-Vienna 2022 as well as NTSC-Vienna 2023 stressed the importance of multidisciplinary perspectives and experiences in developing effective treatment plans for patients with TBI.The Academy for Multidisciplinary Neurotraumatology (AMN), a forward-looking scientific organization dedicated to advancing research, treatment, and education in the field of neurotraumatology and it is endorsed by academic partners, including the European Federation of Neurorehabilitation Societies (EFNR) and other important stakeholders. By fostering strong ties with these esteemed organizations, the AMN is able to leverage shared expertise, resources, and networks, resulting in a collective effort to advance the field of neurotrauma.This program has been organized by The five-day training program was developed and coordinated by a team of distinguished faculty members :Christian Matula – Professor of Neurosurgery, Allgemeines Krankenhaus Wien (AKH), Vienna, Austria; AMN Chairman of the Educational CommitteeJohannes Leitgeb – Associate Professor of Trauma Surgery, Allgemeines Krankenhaus Wien (AKH), Vienna, Austria;Andreas Winkler – Medical Director of the Institute Neuromed, Center for Clinic Sciences in Neurology, Vienna, Austria;Vera Wohlgennant – Deputy Medical Director, AUVA Rehabilitationszentrum Meidling, Vienna, Austria;Peter Lackner – Head of the Department of Neurology at Klinik Floridsdorf, Vienna, Austria;Helmut Trimmel – Professor, Director of the Department Anaesthesiology, Emergency and Critical Care Medicine at Landesklinikum Wiener Neustadt, Vienna, Austria.As an integral component of the program and for the continued advancement of similar initiatives, the AMN representatives interviewed some of the NTSC program coordinators. During the interviews, the faculty members discussed their motivation for spearheading the NTSC training, obstacles encountered in neurotrauma management, discrepancies in neurotrauma practice, and the crucial role of guidelines, including the guidelines that the AMN is currently formulating.Drawing from their professional experience and expertise, the faculty members provided didactic sessions on neurotrauma management and investigation approaches, highlighting the value of multidisciplinary care and the necessity of long-term, ongoing patient monitoring. The training curriculum was conducted over five days at the following locations :Landesklinikum Wiener Neustadt on Day 1;Klinik Floridsdorf (Simulation Center) on Day 2;Allgemeines Krankenhaus Wien (AKH) on Day 3 and 5;AUVA Rehabilitationszentrum Meidling on Day 4.The first day of the NTSC started at Landesklinikum Wiener Neustadt, a teaching hospital affiliated with the Medical Universities of Vienna and Graz, and the University of Applied Sciences Wiener Neustadt. The airfield of the hospital serves as the operational base for the air rescue center.Air rescue system for primary and secondary missions’ by Dr. Daniel Csomor which showcased an overview of prehospital emergency medicine, specifically focusing on emergency call procedures in Austria, the dispatch center, and the overall emergency services and infrastructure. In further detail, Dr. Csomor delved into the composition of an air rescue team, consisting of three crucial members, namely the pilot, the emergency physician, and the paramedic, emphasizing the distinct responsibilities of the latter two within this team structure. In addition, Dr. Csomor highlighted the overarching vision of the Air Rescue Crew, which is to ensure comprehensive air rescue coverage for all individuals within their operational areas, regardless of circumstances, as well as their commitment to professionalism and unwavering passion for air rescue which forme the cornerstone of their mission.The first day of the training included engaging presentations, starting with the ‘Pre-hospital medical care in traumatic brain injury’, Dr. Guenther Herzer outlined the responsibilities undertaken by emergency physicians, from initial assessment to recommendations for management and diagnostics. Dr. Herzer emphasized the crucial nature of providing definitive treatment to patients with traumatic brain injuries, highlighting that the process commences and significantly influences the patient's outcome right at the accident scene. The key objectives encompass the following:In the next presentation entitled ‘Assessment of the patient's level of consciousness and evaluation of the pattern and severity of the injury.Ensuring the stability of vital functions, including breathing and circulation.Proper stabilization of the cervical spine to prevent further damage.Timely management of life-threatening associated injuries.Appropriately selecting the most suitable hospital for the patient's condition.Safe transportation of the patient to the designated hospital, along with meticulous documentation of the entire process.Dr. Herzer emphasized the critical role of emergency physicians in ensuring prompt and effective interventions, thereby maximizing the chances of positive patient outcomes.Following the informative presentations, the participants had the opportunity to visit the airshed, where they explored and engaged in discussions regarding the rescue mission equipment. Dr. Csomor guided the tour and shared insights about the structure of the rescue team, detailing the specific roles and responsibilities of team members during a rescue operation. Additionally, Dr. Csomor provided a comprehensive overview of the equipment used during both summer and winter rescue missions, ensuring a thorough understanding of the tools and resources available to the team in various scenarios.In the latter part of the day, the participants and speakers met for the official opening of the five-day training program. During this session, the faculty members presented the overarching objectives and plans for the week, setting the tone for the training program and outlining the key areas of focus.Prof. Helmut Trimmel initiated the discussions by emphasizing the crucial significance of transporting the patient to the appropriate hospital and highlighted the importance of administering neuroprotective medication as early as possible. The main message conveyed was that it is never too early to initiate the process of repairing and safeguarding the neurological well-being of the patient. Further on, Prof. Christian Matula discussed the objectives and goals of NTSC Vienna, highlighting the treatment paradigm shift from short-term focus to long-term follow-up, to ensure comprehensive care for patients throughout their recovery journey. Finally, all program tutors extended a warm welcome to the participants and provided a concise presentation about their respective days of training.The second day took place at Klinik Floridsdorf, where Prof. Peter Lackner offered the participants a captivating glimpse into one of the most sophisticated simulation centers globally. This cutting-edge facility boasts advanced technology, including complex mannequins capable of reacting to stimuli, as well as top of the line video and audio monitoring room. This advanced setup allows for realistic and immersive training experiences, enabling the enhancement of skills and knowledge in a dynamic and hands-on manner.Multidisciplinary treatment concepts for traumatic brain injury (TBI). He discussed the importance of an integrated approach to TBI treatment, with emphasis on maintaining optimal cardiovascular, respiratory, and metabolic conditions while avoiding or aggressively addressing hypotension, hypoxia, and hyperthermia. The key messages conveyed during the presentation were as follows:Prof. Peter Lackner shared an insightful presentation focused on Multidisciplinary treatment is essential for patients with traumatic brain injury.Care pathways play a vital role in connecting individuals to appropriate services and improving the overall management of TBI patients.Registries provide a structured framework for optimal patient management, enabling knowledge transfer and facilitating benchmarking among trauma centers.Simulation-based teaching courses are ideal for imparting multidisciplinary knowledge and promoting a comprehensive understanding of the entire chain of TBI care.Prof. Lackner's presentation underscored the significance of a coordinated and comprehensive approach to treating traumatic brain injuries, emphasizing the importance of collaboration, structured pathways, registries, and simulation-based training to enhance patient outcomes.The highlight of the day was an engaging simulation exercise involving neurotrauma cases. Participants actively collaborated to stabilize and treat a patient portrayed by a highly realistic mannequin. The activity aimed to provide practical experience in emergency scenarios and equip participants with the skills to handle challenging situations, both as leaders and team members. The training underlined the importance of effective communication within the team and maintaining smooth coordination among members, to enhance participants' abilities to work cohesively and ensure seamless functioning during critical moments. By actively engaging in this simulation exercise, participants gained valuable insights into the practical application of their knowledge and skills in a realistic and dynamic environment. To ensure the seamless execution of the day's activities, the participants were divided into two groups. One group actively participated in simulation training, while the other group observed the unfolding scenarios closely via a video feed. This arrangement enabled them to engage in discussions with specialists and experts, facilitating a comprehensive learning experience. The groups later swapped roles, allowing for a well-rounded interactive approach. By adopting this method, the training aimed to optimize the participants' exposure to diverse perspectives and promote valuable discussions, ultimately enhancing their knowledge and proficiency in managing neurotrauma cases.The day culminated with a captivating guided tour, expertly led by Prof. Lackner, granting participants an insightful glimpse into the hospital's Stroke Unit and Neurological Ward. During the tour, attendees had the unique opportunity to witness firsthand the specialized care and treatment delivered to patients suffering from strokes and neurological conditions.The third day of the NTSC was held at Allgemeines Krankenhaus Wien (AKH) - Vienna General Hospital commencing with a concise overview of the hospital's care unit, presented by Prof. Christian Matula. The subsequent presentation shifted toward Neurotrauma Management at the University Hospital of Vienna, offering three distinct perspectives:the anesthesiologist's viewpoint (Prof. Klaus Klein)the traumatologist’s viewpoint (Prof. Johannes Leitgeb)the neurosurgeon’s viewpoint (Prof. Christian Matula).These three approaches collectively provided a comprehensive understanding of the multidisciplinary approach employed at the University Hospital of Vienna for effective neurotrauma management.Subsequently, the participants were divided into three groups, affording them the opportunity to visit critical areas of neurotrauma management: the operating room (OR), the endovascular interoperative magnetic resonance imaging (MRI), and the intensive care unit (ICU). These visits provided firsthand insights into the specific procedures and cutting-edge technologies utilized in neurotrauma management. The OR visit provided a glimpse into the surgical interventions and techniques used in treating neurotrauma cases. The endovascular interoperative MRI showcased advanced imaging technologies utilized during neurosurgical procedures. Lastly, the ICU visit offered participants the opportunity to observe the specialized care provided to patients recovering from neurotrauma, emphasizing the importance of intensive monitoring and support. By organizing participants into smaller groups and facilitating rotation through these different areas, the activity effectively fostered a comprehensive and immersive learning experience. This approach enabled participants to witness various facets of neurotrauma management firsthand and attain a deeper understanding of each stage of patient care.Later in the day, participants had the opportunity to engage in interactive discussions about real-life neurotrauma cases with specialists. By collaborating with the hospital doctors, the participants could delve into the complexities of each case, share their insights, learn from the expertise of the medical professionals, and gain a deeper understanding of the decision-making process and the various factors to be considered in neurotrauma management.The fourth day of NTSC took place at AUVA Rehabilitationszentrum Meidling, a renowned rehabilitation center in Meidling, Vienna. Specializing in neurotrauma rehabilitation, the center offers comprehensive, personalized, and patient-centered care to support recovery and improve quality of life.TBI rehabilitation in Austria, emphasizing the significance of early rehabilitation intervention and the essential components of TBI rehabilitation, such as a robust rehabilitation infrastructure, the involvement of specialized multidisciplinary teams, and the focus on restoring the best possible individual functional outcome. Dr. Wohlgennant also underscored the significance of comprehensive rehabilitation in helping patients regain their independence during the rehabilitation process and optimizing outcomes for individuals with TBI.Dr. Vera Wohlgennant delivered a presentation on Neurorehabilitative aspects in the early stages of traumatic brain injury (TBI) focusing on the significance of clinical findings, imaging techniques, and various diagnostic tools such as somatosensory evoked potentials (SSEP), transcranial Doppler (TCD), and electroencephalogram (EEG) in assessing and monitoring patients with TBI. The presentation also highlighted the importance of complication detection and prevention, as well as treatment strategies in influencing the prognosis and planning rehabilitation interventions. The key message conveyed by Dr. Murg-Ageny was the crucial role of initiating rehabilitation therapy as early as possible in the management of TBI. This emphasis on early intervention reflects the understanding that timely rehabilitation can contribute to optimizing outcomes and achieving the best possible functional recovery.Dr. Murg-Ageny discussed Throughout the day, the participants attended presentations covering essential topics concerning traumatic brain injury rehabilitation. These sessions delved into critical aspects like swallowing and language function. Notably, a demonstration of the implementation of a nasogastric tube for dysphagia rehabilitation was also featured, providing valuable insights into the practice.Additionally, the faculty discussed neuropsychological TBI rehabilitation, emphasizing the psychological and cognitive aspects of recovery, the role of physiotherapeutic strategies in early rehabilitation to promote functional improvement, and occupational therapy and orthopic treatments, with a focus on enhancing daily living skills and addressing musculoskeletal challenges in TBI rehabilitation. These presentations collectively provided a comprehensive understanding of the multidisciplinary nature of TBI rehabilitation and the diverse strategies employed to support patients throughout their recovery.The last day of NTSC took place at Allgemeines Krankenhaus Wien (AKH) - Vienna General Hospital. The participants' implementation plans, developed over the course of the week, stood as manifest to their creative thinking and innovative approaches in addressing the gaps in neurotrauma management within their respective home countries. By leveraging their newfound expertise and assimilating the insights gained during the training, these plans were strategically designed as comprehensive roadmaps. With these well-structured plans in place, participants are poised to enhance their healthcare systems and effectively implement strategies that will ultimately lead to improved patient outcomesThe NTSC program not only fostered knowledge exchange but also empowered the participants to take tangible steps toward advancing neurotrauma care in their regions.Additionally, Dr. Agata Andrzejewska (Poland), a participant in the 2022 program, returned to Vienna for this year's program and delivered updates on their country's implementation plan, showcasing the progress made since the previous year's training. Dr. Andrzejewska's presentation emphasized the significance of engaging even the most resistant individuals, as this would pave the way for gathering support from the entire team and highlighted the importance of unity and her team’s initial focus on engaging the neurosurgeon, recognizing their pivotal role in driving transformative change. Another crucial point of the presentation was the adoption of the 5Ps framework: plan, patient-centered care, protocols, preparation, and practice. Acknowledging the existing challenges, the talk embraced a proactive stance, emphasizing the collective understanding that improvement could be attainable. In her message to the 2023 NTSC participants, Dr. Andrzejewska highlighted the practical application of the knowledge and skills gained in the previous year offering inspiration for this year’s attendees to pursue ambitious goals.The day's proceedings culminated in extensive discussions centered around the pivotal takeaways from the five-day program. Participants engaged in reflective conversations, openly sharing their valuable insights, drawing significant conclusions, and offering constructive feedback. These discussions served as a platform for evaluating the program's overall effectiveness, identifying areas for enhancement, and capturing diverse perspectives on the experience. The feedback gained during these discussions will play a pivotal role in refining future NTSC-Vienna programs, ensuring their continued success in fostering collaboration, facilitating robust knowledge exchange, and driving advancements in the field of neurotrauma treatment.The Neurotrauma Treatment Simulation Center (NTSC) program plays a pivotal role in advancing the knowledge and skills of healthcare specialists involved in the comprehensive treatment chain of neurotrauma. Recognizing the complex nature of neurotrauma cases, NTSC is dedicated to promoting multidisciplinary collaboration and providing a platform for experiential learning that transcends traditional boundaries.The NTSC program is brought to life through the dedicated involvement of its faculty members and participants . These sIn summary, NTSC is a dynamic and transformative initiative that brings together specialists from various disciplines to advance the understanding and treatment of neurotrauma. By promoting multidisciplinary collaboration, emphasizing long-term follow-up, and fostering transformative learning experiences, the program is poised to make a significant impact in advancing neurotrauma treatment and improving patient outcomes.


Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. To date, systemic treatment for patients with unresectable or advanced disease was composed of sorafenib and other multikinase inhibitors, with limited efficacy and high toxicity. Nevertheless, immune checkpoint inhibitors (ICIs) have greatly broadened the treatment landscape of unresectable HCC . SpecifiTo date, there are no definite biomarkers in HCC that can accurately predict response or resistance to ICIs, while as the HCC treatment regimens have shifted towards immunotherapy, the identification of potent predictive and prognostic biomarkers has attracted attention. Although HCC formation has been attributed to certain viral or non-viral causes, nonalcoholic steatohepatitis (NASH), is a major driver of HCC as well . Recent The tumor immune microenvironment (TIME), being heterogeneous and comprised of a multitude of immune and stromal cells, is an essential factor that leads to tumor metastasis and relapse, as well as resistance to therapy, whereas the way in which different TIME cell subtypes are connected with the clinical relevance in liver cancer remains unclear . Indeed,Neutrophils have considerable phenotypic plasticity and can exist in both tumor-promoting (TAN2) and tumor-suppressing (TAN1) states. Neutrophils may also have the ability to influence ICIs therapy. Recent data report that CXCR2+ neutrophils were found in human NASH and within the tumor of both human and mouse models of NASH-related HCC. The resistance of NASH-related HCC to anti-PD1 therapy is being overcome by co-treatment with a CXCR2 small molecule inhibitor, with evidence of reduced tumor burden and extended survival . Anti-PDFurthermore, another important study , by inteThrough in vitro induction of TANs and ex vivo analyses of human TANs, a recent study also showed that CCL4+ TANs can recruit macrophages and that PD-L1 + TANs can suppress T cell cytotoxicity . MonocytHowever, an important unmet clinical need is demonstrated by the lack of accurate biomarkers that can influence therapeutic choices. This unfulfilled need is being met by very few novel studies that incorporate multiregional single cell-dissection landscape of tumor and immune cells in HCC with the sole purpose of shedding light on the biological tumor characteristics and identifying potential tumor and blood biomarkers, in order to categorize specific groups of TIME and identify patients who might have a benefit from a specific treatment option. In brief, the combination of two single-cell RNA sequencing technologies , produceAdditionally, Sun et al. , by perfIn a molecular study of HCC in patients with NASH, NASH-related HCCs were characterized by bile and fatty acid signaling, oxidative stress, and inflammation, and demonstrated an increased fraction of Wnt/TGF-β subclass of tumors and a decreased fraction of the CTNNB1 subclass. In comparison to other etiologies, NASH-related HCC had a considerably higher prevalence of an immunosuppressive cancer field . MoreoveInterestingly, treatment modalities aiming towards specific genomic alterations form the basis of personalized medicine and constitute the epitome of systemic treatment for many malignancies, but are still not available in HCC. Tools such as liquid biopsy and circulating tumor DNA (ctDNA), even though most studies have not analyzed HCC tissue concomitantly, may be of aid in identifying biomarkers of early diagnosis, response, or resistance to treatment, and their role in HCC represents an ongoing research field . In addiTaking into account the aforementioned complex molecular omics alongside the heterogeneous cellular landscape of the TIME of HCC, future studies are expected to highlight in a simple way that is practical for clinical use, the hepatic and peripheral blood inflammatory and immunosuppressive tumorigenic function and composition of TANs and TAMs in NASH-related HCC in comparison with other aetiologies and, more importantly, to shed further light on potential prognostic or predictive molecular markers for future immunotherapies targeting TANs and TAMs, acting in synergy with ICIs, in order to overcome resistance and eventually improve the percentage of patients with HCC that respond to treatment. In addition, we underline the significance of predictive biomarkers of response to ICIs in order to (i) enhance the overall survival of patients that are likely to respond to therapy, (ii) reduce the risk of treatment-related adverse effects conveyed through the combination of drugs such as bevacizumab, (iii) maximize efficacious application, and therefore the cost-effectiveness of different treatment modalities, and (iv) characterize the molecular landscape of patients with advanced HCC responding to anti-PD1 therapy and define a novel tool for patient selection in future clinical trials.All of these data render HCC an oncological diagnosis in which spontaneous immunogenicity is critical for the efficacy of immunotherapy. Although the predictive value of histopathologic assessment is unparalleled, TIME immunogenicity is influenced by density, functional polarization, and distribution of the infiltrate. The diversity of the HCC TIME and the demand for readily applicable biomarkers rather than complex transcriptomics is still challenging, while the ultimate goal of expanding the reach of effective cancer immunotherapy to a wider proportion of patients via clinical stratification of trial participants or targeted testing of novel combinations prognostically modulating adverse traits, such as TANs and TAMs infiltration, is of the utmost importance.