The body of mammals harbors two distinct types of adipose tissue: while cells within the white adipose tissue (WAT) store surplus energy as lipids, brown adipose tissue (BAT) is nowadays recognized as the main tissue for transforming chemical energy into heat. This process, referred to as ‘non-shivering thermogenesis’, is facilitated by the uncoupling of the electron transport across mitochondrial membranes from ATP production. BAT-dependent thermogenesis acts as a safeguarding mechanism under reduced ambient temperature but also plays a critical role in metabolic and energy homeostasis in health and disease. In this review, we summarize the evolutionary structure, function and regulation of the BAT organ under neuronal and hormonal control and discuss its mutual interaction with the central nervous system. We conclude by conceptualizing how better understanding the multifaceted communicative links between the brain and BAT opens avenues for novel therapeutic approaches to treat obesity and related metabolic disorders. While this alarming trend is global (with the exception of sub-Saharan Africa and Asia), obesity itself and the entirety of associated comorbidities is, of course, preventable. Understanding how the human body orchestrates the input of dietary fuels and output of energy and thus facilitates homeostasis (and why this obviously does not work efficiently in obese patients) will be key to face the upcoming obesity pandemic and to design smart prevention and treatment strategies. Luckily, groundbreaking basic and translational research in the area of metabolism and metabolic diseases has sparked the scientific interest in one peculiar (and often overlooked) tissue which eventually could turn into the most attractive target to fight the imminent health crisis. This review article focusses on the function and complex regulation of this promising and exciting metabolic organ.The year 2016 represents a dramatic and alarming turning point in the history of humankind: According to the World Health Organisation (WHO), for the first time there are more people killed by overweight than by underweight. With an incredible 2 billion adults being overweight and 650 million obese  with numerous small lipid droplets and an unusually high number of mitochondria was discovered in the interscapular region at the back of marmots. Due to the high iron content of the mitochondria and the distribution of lipid droplets throughout the cytoplasm, this tissue appears histologically dark red to brown why it was referred to as ‘Brown Adipose Tissue’ (BAT). This designation contrasts with the White Adipose Tissue , which usually contains only limited mitochondrial mass and one big liposome conveying its typical yellowish appearance. While WAT is well recognized as the main tissue for storing excess calories in the form of lipids , BAT was long thought to be exclusively devoted to the regulation of body temperature during hibernation. It took until the beginning of the 20th century to discover that the BAT is not only a heat-producing organ in hibernating mammals but is also regulating thermogenic function in non-hibernating organisms in response to external stress conditions, i.e., acute cold stress and long-term cold acclimation (for review see ). How faTechnical advances in the field of imaging technology, particularly hybrid positron emission tomography/computed tomography (PET-CT), and functional analyses using traceable glucose analogs (such as 18F-fluoro-2-deoxy-d-glucose/FDG), have greatly contributed to unraveling more important details on BAT morphology and function. The relative mass and distribution of BAT dramatically change during early development and across the entire life span. Neonatal mammals and infants are largely protected against cold stress due to dense BAT depots within their interscapular regions. In contrast, adult mammals (in addition to hibernating species) were long time believed to harbor only minor remnants of BAT without physiological relevance. In this regard, the years 2007–2009 represent a major turning point since several groups independently demonstrated the presence, functional activity and metabolic plasticity  of BAT conserved in adult humans ,4 with s‘batokines’ [BAT is now recognized as the main tissue in the organism for transforming chemical energy (stored in the form of lipids) into thermic energy . This process, referred to as ‘non-shivering thermogenesis’ (as opposed to the shivering of muscles that generates heat as a byproduct of muscle activity), fulfills at least two important functions: First, it represents a safeguarding mechanism both under short-term cold stress and long-term cold acclimation conditions to protect key organs from hypothermic damage by warming the blood flow. Second, BAT thermogenesis is a major regulatory process ensuring systemic metabolic homeostasis by increasing glucose uptake and combusting energy in response to surplus nutrient conditions . In atokines’ ,9) comprtokines’ ,11,12.Given this central role of BAT for both energy dissipation and endocrine/paracrine control of metabolic balance, significant attention has been directed within the last years toward exploiting BAT thermogenic function for the treatment of obesity and associated comorbidities. In fact, there are several interesting arguments for targeting BAT activity in the development of novel therapies for weight management and metabolic diseases. First, concerning the overall metabolic function of BAT, it was demonstrated that cold-induced BAT activity as determined by 18)FDG-PET correlates with human leanness  and thatFDG-PET c+) across the inner membrane of the respiratory chain usually drives the phosphorylation of ADP to ATP via the activity of the F0/F1-ATP synthase. Therefore, under physiological conditions, respiration is directly coupled to ATP production. In BAT adipocytes, this fundamental mechanism is hijacked and exploited to translate chemical energy into thermic energy by bypassing (‘uncoupling’) the electron transport from ATP production  represents a member of the large mitochondrial anion carrier family whose members facilitate the shuttling of ions across mitochondrial membranes. It is a multi-pass transmembrane protein spanning the inner membrane within mitochondria. In the presence of free fatty acids (derived from TG breakdown by lipolysis), UCP1-channels mediate the leakage of Hynthesis ,22  on brown adipocytes . Engagem2+ ATPase 2b, an ATPase that represents the pivotal pump for sequestering calcium from the cytosol into the endoplasmatic reticulum (ER) and thus is involved in ER stress responses [Importantly, while UCP1-dependent mitochondrial uncoupling appears to be the most prominent pathway for thermogenesis in BAT (mainly induced by cold and nutrient surplus), recent reports have identified interesting alternative pathways that act either in concert or entirely independent of UCP1. Adipocytes within the WAT that acquire brown-like features upon appropriate stimulation (sometimes referred to as beige or brown-in-white/‘brite’ adipocytes) have been shown to exploit a calcium cycling mechanism selectively for heat production. This mechanism relies on Caesponses . Moreoveesponses ). Finallesponses .In general, the concept is emerging that molecular mechanisms that result in a decrease in the cellular ATP/ADP ratio convene on exerting thermogenic activity, either via UCP1 or in a UCP1-independent fashion.In the following paragraph, we would like to review current knowledge about how the Central Nervous System (CNS), together with other signaling pathways, is equipped to regulate BAT activity in a bidirectional manner systemically, and how these regulatory pathways adapt during the process of metabolic disease, as such might offer interesting options for complementary management of obesity and related diseases.Given the pivotal importance of energy homeostasis for the organism, it is not surprising that BAT activity is regulated by various pathways that jointly integrate environmental as well as internal signals in order to fine-tune thermogenesis and nutritional energetics in an orchestrated manner ,28 Figu. Owing tIt is important to note that, in addition to β3AR signaling, alternative ligand/receptor systems for activation of BAT have been identified: Using animal models and both genetic and pharmacological intervention, Thorsten Gnad and colleagues from Alexander Pfeifer’s group demonstrated convincingly that engagement of adenosine receptors A2A and A2B can also efficiently activate BAT activity and differentiation (‘browning’) of WAT ,31. TheyHypothalamic activation of this SNS-to-BAT signal is controlled by several upstream input circuits whose exact identity, mode of regulation and interdependencies are only beginning to be explored . So farthermoregulatory pathway, thermoreceptive neurons monitor the temperature of the skin. These neurons (which represent selective receptors for either warmth or cold) transmit thermal signals to one prominent nucleus within the hypothalamus termed the ‘preoptic area’ (POA) that serves as the central integrator of temperature signals. As demonstrated in preclinical models, cold exposure or direct hypothermic sensations within this nucleus result in POA-mediated SNS-to-BAT signaling and subsequent activation of BAT thermogenic activity [Raphe pallidus (Rp) located in the ventral tegmentum, the intermediolateral nucleus (IML) within the spinal cord), finally resulting in sympathetic activation of BAT activity. An additional level of inhibitory regulation is facilitated by neuropeptide Y (NPY) expressing neurons within the DMH, which have been discussed to inhibit BAT activity by their negative regulatory role on glutamatergic DMH neurons [As part of the activity ,34,35. Tactivity . Signals neurons . Importa neurons .inflammatory fever is unresolved. Several studies used advanced model systems  to analyze the role of BAT in heat production during febrile responses. These studies identified glutamatergic neurons within the median preoptic area (MnPO) that project to the DMH to be crucial for fever-related BAT thermogenesis [A recent report by Makwana et al. complements this picture by demonstrating in a genetic mouse model that calcitonin gene-related peptide α (CGRPα)—expressing heat-sensing neurons in the skin also significantly contribute to adaptive thermogenesis and diet-induced obesity . In the ogenesis ,38,39. Oogenesis . Importaenergy homeostasis pathway comprises several distinct yet probably interconnected signaling systems which receive input from other extrahypothalamic brain regions (such as the nucleus of the solitary tract) to regulate food intake and energy expenditure:The hypothalamic endocannabinoid system has recently emerged as a major contributor to the beneficial effects of bariatric surgery on metabolic improvements through its effects on thermogenesis. Endocannabinoids (EC) are endogenous fatty acid-based neurotransmitters that act via their cognate receptor proteins (endocannabinoid receptor—1/CB-1 and CB-2) in the CNS and the periphery. Responding to a plethora of stimuli , they mediate several vital biological functions, including regulation of energy balance, development, immune functions, mood and appetite regulation [The gulation ,43,44,45gulation ,47. Thesgulation ,49,50. Igulation . These oMelanocortins  represent a family of peptide hormones also involved in the regulation of food intake and energy homeostasis. Responding to the respective nutritional status and eating behavior, MC release from the pituitary gland is controlled by two important hormones which are functionally intertwined, the adipose tissue-derived leptin (sometimes dubbed the ‘starvation hormone’) and the ‘hunger hormone’ ghrelin, secreted predominantly by endocrine cells within the gastric mucosa. Secreted MCs act via binding to G-protein coupled receptor (GPCR)—type MC receptors (with MC3-R and MC4-R being mainly expressed within the brain). These receptors are both activated by the binding of α-MSH and inhibited by the intrinsic antagonist Agouti-related peptide (AgRP). Using transneural retrograde tracing by Pseudorabies virus, the group of Timothy J. Bartness has shown that SNS innervation of interscapular BAT (iBAT) originates in brain regions that significantly express MC4-R [-/- mice with reduced brain MC signaling experience gain in WAT fat mass due to increased lipogenesis and proliferation of WAT cells. These effects were conveyed by efferent innervation of the vagus nerve, as shown by subdiaphragmatic vagotomy [ss MC4-R . In liness MC4-R ,46. Focuvagotomy . The vagIt is important to note that most of the above-mentioned experiments concerning MC signaling were performed in hibernating animals whose major BAT depot is located in the interscapular region. As evidence for the functionality of iBAT depots in human adults is still limited, the scope to which these mechanistic insights of BAT activation via MCs from rodent models could be used for the treatment of metabolic disease in humans is still unclear . On theRaphe pallidus) or even regions in the brain stem . Mechanistically, VMH-to-BAT signaling via SF1 neurons is dependent on AMPK and mTOR signaling pathways and is effectively activated by both leptin and insulin  were originally considered to be the major hypothalamic nuclei in the thermoregulatory network , recent  review: ). This aAs sketched above, BAT thermogenesis is not exclusively controlled by hypothalamic signaling via the SNS alone, but a variety of other neuronal populations in other regions of the CNS appear to contribute to the hormonal regulation of BAT-mediated thermogenesis. These include hindbrain neurons , GABAergdirect neuronal link between the two major adipose tissue types: Using a Siberian hamster model Garretson and colleagues analyzed BAT innervation by neurons residing within WAT depots. They tested the hypothesis that lipolysis in WAT activated neuronal activity of WAT afferent neurons and demonstrated that lipolysis-dependent fFA production triggers neuronal activity in WAT, which is capable of activating BAT thermogenesis [While the neuronal control of BAT activity by the CNS is well established in preclinical models, recent data may point to an unexpected ogenesis . This meIn addition to the CNS, a number of non-neuronal endocrine signaling systems have emerged as important players in the control of BAT thermogenic activity. Interestingly, they derive primarily from the gastrointestinal (GI) system. The involvement of the GI tract and its signaling to the brain in multiple aspects of energy homeostasis and metabolic control has clearly been demonstrated by the impressive clinical success of bariatric surgical procedures. In fact, nothing currently available is nearly as effective in yielding sustained weight management and improvement of cardiometabolic complications. Adaptive mechanisms of the intestine involving increased numbers of endocrine cells have raised enormous interest in the possibly therapeutic role of postoperatively altered gut signals that act in the brain and other organs to modulate energy balance and metabolic control. Only within the last two decades have the molecular mechanisms of appetite control advanced to a point where drug discovery can be rationally pursued with suitable tolerability and safety .In fact, recent clinical trials with advanced therapeutic candidates, including the gut-derived glucagon-like peptide 1 (GLP1)-, the glucose-dependent insulinotropic polypeptide (GIP)- and the pancreatic glucagon (GCG)-receptor signaling agonists arouse huge clinical expectations as to successful weight management based on carefully designed drug combinations. The current weight loss drugs in clinical development signal via specific cognate receptors, which all belong to the G-protein coupled receptor (GPCR) family and thus represent attractive pharmacological targets. Importantly, while the downstream signaling mechanisms of the three hormones are very similar, the expression profile of the cognate receptors is highly specific and thereby conveys their tissue-specific effects.The peptide hormone Glucagon/GCG is produced by alpha cells of the pancreas and represents the main catabolic hormone of the human body. Together, insulin and GCG control glucose levels in a counter-regulatory manner. The Glucagon receptor (GCGR) is expressed dominantly in the liver (and to a minor extent in the kidneys) but not in the CNS. After engagement by its ligand, GCGR mediates hepatic glucose production via hydrolysis of glycogen and gluconeogenesis. GCG has also been shown to increase energy expenditure and influence BAT function under cold exposure conditions, i.e., during adaptive thermogenesis ,66. As aincretins [Based on their shared function in orchestrating post-prandial glucose- and lipid metabolism, GLP-1 and its sister hormone, GIP, are collectively referred to as ncretins ,68,69. Gncretins ,70,71. Gncretins . ImportaThese three molecules, GLP-1, GIP and GCG, are currently taking center stage in promising drug development strategies focusing on obesity and diabetes. The current status of this fascinating quest for novel therapies is further described in chapter 3.secretin results in the activation of secretin receptors on BAT adipocytes [Another major breakthrough in understanding nutrient handling was made by recent findings of Martin Klingenspor’s group, which demonstrated that food-dependent release of the gut hormone ipocytes . StimulaGiven the tight interaction between nutrient uptake, energy homeostasis and hormonal control of metabolic traits, it is not surprising that hormonal signals from the gastrointestinal tract and the thyroid gland  are pivotally involved in BAT activation. The TH receptor expression is high in BAT, and activation of these receptors results in the upregulation of UCP1 and amplification of NE–mediated BAT thermogenesis (review: ). The imAnother currently fervently discussed concept in line with the gut-adipose tissue crosstalk is the capability of the intestinal microbiome  to modulate adipose tissue activity effectively. It is well accepted that the iMB  represents an important modulator of host metabolism and thus contributes to the modulation of the health status of its host. By taking up and converting nutrient components by anaerobic fermentation, the iMB produces and provides a plethora of metabolites to the portal vein system and systemic circulation. These metabolites include short-chain fatty acids (such as butyrate and acetate), branched-chain amino acids and secondary bile acids (such as glycine- or taurine- conjugates). By activating GPCR-mediated signaling cascades on host cells, microbial metabolites can affect their host’s nutrient and energy balance. In particular, rodent models have provided evidence that alterations in the gut microbiota composition  affect the thermogenic program in BAT and modulate browning effects in WAT, presumably via altered metabolite signaling and/or by the involvement of the endocannabinoid system (reviewed in ). MoreovBmal1 in mice, they uncovered the underlying mechanism, demonstrating that the observed oscillations in BAT activity over 24 h day–night cycles are mediated by clock genes such as RevErb-alpha which  acts as a transcriptional inhibitor of Ucp1 [Ucp1 abundance and activity.Finally, novel findings suggest that BAT exhibits circadian rhythms in its thermogenic activity and is entrained into the environment via external cues  such as light exposure and timed food intake. While several routes of control may exist ,73,74, i of Ucp1 , thus leTaken together, multiple pathways converge to control the activity of BAT cells, thus integrating various extrinsic and intrinsic signaling cues. However, does this communication network also work in the opposite direction?raphe pallidus and the hypothalamic paraventricular nucleus [While the scientific focus layed a long time on the outgoing signals from CNS to functional BAT control, it is clearly less well understood how fat tissue returns activation signals to the CNS in order to orchestrate energy homeostasis. Sophisticated transneuronal tracing tools involving specific strains of herpes simplex virus-1 (HSV-1) that travel anterogradely along the outflow of sensory nerve signals have been utilized to study potential feedback circuits between fat tissues and the brain ,82,83,84Over the last 50 years, we have faced a world-wide and further proceeding epidemic of obesity, which is essentially driven by a chronic energetic imbalance where energy intake chronically exceeds energy expenditure. All efforts to prevent a further rise in prevalence, together with currently available pharmacological anti-obesity strategies, have proven ineffective in solving the pandemic development. All the more has the control of excess ectopic fat depots become one of the greatest healthcare challenges of our time, and the demand for novel weight-centric strategies as a primary treatment goal for obesity-associated cardiometabolic diseases is high. The rediscovery of functionally active BAT in adults almost 15 years ago triggered a resurgence in BAT research combined with the hope to exploit physiological thermogenesis to achieve the necessary net energy balance required for sustained weight management . Overaliew, see , whereasiew, see . Interesiew, see . As to iiew, see  and fat iew, see . Moreoveiew, see  as well iew, see . Interesiew, see . Thus, wiew, see ,7,88 comThe early and conceptual appeal to pharmacologically activate BAT metabolic activity via sympathomimetics and enforced induction of β3AR signaling was mainly hampered by adverse effects on the cardiovascular system . HoweveOne current strategy focusses on targeting Melanocortin receptors as potential drug targets in the context of obesity and eating disorders . This isThe emerging role of incretin hormones  and the insulin-counteracting Glucagon/GCG on metabolic function has sparked huge interest in targeting the associated GPCR-mediated pathways for therapeutic purposes. In the context of obesity, GLP-1 and its receptor GLP-1R have prominently entered center stage in the pharmacological treatment of T2D and obesity. Sequence-optimized GLP-1 agonists (such as Semaglutide and Liraglutide) have been shown to induce weight loss and improvement of glucose homeostasis via complementary signaling effects, like modulation of hunger and satiety sensation, delaying gastric emptying, facilitating insulin secretion and decrease of hepatic gluconeogenesis. However, BAT activation and thermogenesis also take part in the orchestration of GLP-1-induced weight loss. For example, it was demonstrated in mice that the central application of Liraglutide induced BAT thermogenesis and WAT browning . MoreoveIntriguingly, recent developments in drug development focus on the use of molecules that engage not only one but multiple relevant pathways at the same time to harness the complementary metabolic effects of specific signaling pathways via this complementary approach. These efforts aimed to design, optimize and finally apply single molecules that activate GLP-1R in parallel to receptors for GIP and/or GCG to optimize effects on nutrient uptake, lipolysis and energy expenditure. Chimeric peptides resembling a molecular mosaic of two or three of these ligands  and ‘triple’ (GGG) agonists), which are chemically modified for improved stability and uptake, have successfully passed clinical trials and/or are awaiting approval for clinical use and market entry . By addiIt is important to note that the three receptor types display a very distinct expression profile which may result in organ-specific effects of the chimeric drugs, depending on the exact combinatorial structure. This phenomenon is part of the drug design strategy but may also lead to unexpected cross-reactions . NevertIn this context, it is also noteworthy that the combined effect of these designer drugs on several additional pathologically relevant pathways  may, in the future, also be relevant not only for targeting BAT as a therapeutic option against obesity but also for fighting other diseases types, e.g., neurodegenerative disorders like Alzheimer Disease ,104.The engagement of BAT as a therapeutic target in metabolic diseases implies several advantages but also some disadvantages : On theIt follows from these observations that it may be useful to conceptualize the pharmacological treatment of obesity diseases as one would approach other chronic conditions, such as essential hypertension or T2D. Just as hypertension is often treated with combinations of sympatholytics, ion channel blockers, and enzyme inhibitors, the pharmacological approach to obesity will likely require a combination of drugs that suppress appetite, impair absorption and increase energy expenditure in parallel (or at least in an orchestrated manner). While a BAT-centric approach may be one facet in this composite endeavor, the above-mentioned pitfalls render this strategy challenging, at last, unless pharmacological intervention succeeds in designing non-adrenergic signaling control of BAT thermogenesis. Interestingly, there is a number of alternative BAT-centered approaches that could harness the knowledge of underlying BAT-regulating mechanisms for the design of successful therapy. These include BAT transplantation, usage of progenitor or stem cells that give rise to brown adipocytes (or precursor cells that can be further differentiated), modulation of the gut-brain signaling axis either by targeted shifts in the gut microbiome or by tweaking of metabolite or bile acid profiles, or precise modulation of brain-to-BAT signaling  by tailored agonists of respective signaling pathways. Along this line, a major aim of current and future therapeutic approaches would thus be to harness known neural signal routes in order to fine-tune BAT activity in obese patients. Consequently, drugs that fine-tune CNS to BAT neuronal signaling or feedback signaling will open avenues for therapy or even prevention of obesity and its comorbidities. Intriguingly, there is another fascinating perspective: The recent realization that cold-induced thermogenesis is not exclusively restricted to BAT but is also happening in beige adipose tissue and in muscle (reviewed in ) may proIn conclusion, as non-surgical therapies for obesity are urgently needed, harnessing the growing knowledge about brain-to-BAT-to-brain signaling in combination with other controlling instances may provide promising future therapies for metabolic diseases. One major task will be the identification of feedback mechanisms, e.g., how body weight and the energy storage state are monitored within the body and integrated into the CNS to orchestrate energy expenditure and homeostasis. Further research in this area, leading to a detailed understanding of this ‘Baristat’ and its regulatory mechanisms, will help us to identify promising targets and open novel avenues for therapies against the imminent obesity pandemic.


Drug-influenced gingival enlargement (DIGE) or overgrowth manifests as abnormal enlargement of the gingiva due to an adverse effect of certain drug reactions in patients treated with anticonvulsants, immunosuppressants, or calcium channel blockers (CCBs). As the gingival enlargement became significant, it may interfere with the normal oral hygiene measures, aesthetics, as well as masticatory functions of the patients. The exact mechanism of how this undesirable condition develops is yet unknown, and complicated, with non-inflammatory and inflammatory pathways involved. This review illuminates these putative pathways of DIGE and highlights various treatment approaches based on existing research and current observations. Gingival enlargement, initially known as gingival overgrowth, is an enlargement of the gingival tissues that can be localized or generalized. This term has taken the place of gingival hyperplasia (increase in cell number) and gingival hypertrophy (increase in cell size) as these are histological diagnoses and do not fully characterize the pathological processes found within the tissues . It is nDrug-influenced gingival enlargement (DIGE) is an unwanted effect commonly associated with medications ,4. RecenClinically, DIGE usually affects the interdental gingiva of the anterior teeth and confined to the attached gingiva. It may extend coronally, as the tissue enlarges, become thickened and lobulated appearance Figure . DIGE alHistologically, there was an increased in epithelial thickness of the gingiva which commonly observed in nifedipine and cyclosporin A-induced gingival enlargement and is associated with increased mitotic activity, particularly in the spinous layer of oral epithelium . There iAlthough DIGE were reported elsewhere, the mechanism underlying this condition remains unclear and thought to be multifactorial . This reThe mechanism of DIGEThe underlying mechanisms behind DIGE were divided into non-inflammatory  and inflammatory pathways ,17. The Non-inflammatory  pathwayInhibitory Effect of Sodium/Calcium Ion Influx Upon Cation Channels MechanismsIt has been proposed that all the drugs that induce gingival enlargement, namely anticonvulsants, CCBs, and immunosuppressants have a similar mode of action at the cellular level, by which they inhibit the intracellular calcium (Ca2+) and sodium (Na+) ion influx through cation channels, resulting in decreased folate cellular absorption and consequent folate insufficiency ,22. ThesDefective Collagenase Activity Due to Decreased Uptake of Folic AcidFolic acid cellular uptake is dependent upon both an active transport regulated channel and passive diffusion . Folate Additionally, the activation and inhibition of collagenase enzymes is a complex mechanism dependent upon multiple biochemical pathways at the cellular level. The interplay among these biochemical pathways includes transforming growth factor (TGF), tissue inhibitors (TIMP), MMP-1, Smad proteins, E-cadherin, and activator protein (AP)-1 . Smad prInflammatory pathwayAlteration in the Production of Inflammatory Cytokines and Interaction of Chemotactic FactorsThe gingival tissue is subjected to multiple invasions that induce a state of permanent tissue repair involving the inflammatory cells, fibroblasts, and chemotactic factors . For insGrowth factors (GFs) have been studied as well, and their activation may play an important role in the mechanism of DIGE. Basic fibroblast growth factors are a fibroblast and keratinocyte mitogen molecule with morphogenesis and differentiation functions related to fibroblastic proliferation in gingival enlargement . VasculaTGF-β1 is an important regulatory cytokine secreted by a variety of cells including macrophages. Apart from being involved in collagen metabolism, it also stimulates the fibroblastic population and the ECM deposit of the fibronectin and GAGs . HoweverIn addition, CTGF regulates the proliferation and differentiation of connective tissue cells stimulating ECM production. The binding of CTGF to integrin α6β1 forming an insoluble collagen accumulation was observed to appear in gingival human fibroblast cultures and eventually stimulates ECM production . TrackmaBesides, fibroblast collagen phagocytosis is the regular catabolism for ECM degradation which is related to some biochemical modifications at the integrin receptors when collagen adheres to the cell membrane. A decrease in the expression of integrin α2 by influencing drugs, or a decrease in collagen adhesion due to the presence of pro-inflammatory cytokines, could inhibit phagocytosis and give rise to the development of gingival enlargement -39.Immunological Changes and Inflammatory Process in DIGEThe immune system consists of two types of defense mechanisms, which are innate immunity and adaptive immunity. Innate immunity is the first line of defense against an invading pathogen; it represents as a barrier function provided by the lining epithelium of different mucosal tissues which contains a number of cells including neutrophils and macrophages, dendritic cells, natural killer cells, and mast cells ,41. MeanThe immunological changes and inflammatory features associated with DIGE include increased macrophage reparative/proliferative phenotype, up-regulation of essential GF, IL-1β, IL-6, antibodies, and variable lymphocyte proportions ,42-44. TImmunoglobulin A (IgA) is the predominant immunoglobulin isotype in human saliva. Salivary IgA has been shown to absorb and affect the adhesion of oral microorganisms in dental plaque biofilm . The resPrevention and treatmentPatients who are at risk or who have already developed DIGE require close dental care. DIGE management strategies employ a number of treatment approaches which include non-surgical and surgical approaches.In non-surgical treatment approaches, the modifying factors need to be controlled . EliminaWith regards to DIGE by CCBs, a multidisciplinary input or onward referral to the physician may be required in severe DIGE cases . When this treatment approach is taken, it may take one to eight weeks for the remission of DIGE . HoweverHowever, when the growth compromises oral hygiene procedures or chewing function, as well as aesthetics, surgical removal of DIGE is usually recommended. For this approach, the gingivectomy and/or gingivoplasty by internal/external bevel incision could be done. Few techniques for surgical interventions can be applied such as scalpel gingivectomy, electrosurgery, and laser approaches. Occasionally, it may be technically sensitive or impractical for example in pediatrics and special needs children, or in patients suffering from impaired hemostasis . In thesTo date, the mechanism of DIGE development is complex in that it is applicable to all common drugs affecting gingival enlargement. Further molecular approaches are needed to clearly establish the mechanism of DIGE and to provide better therapeutic modalities.


Multifactorial diseases are caused by a combination of genetic and environmental factors and various risk factors that accumulate with age. Cardiovascular diseases, chronic kidney disease, chronic obstructive pulmonary disease, metabolic (dysfunction) associated fatty liver disease, and cancers are the most common multifactorial diseases and impose a considerable healthcare burden. The simultaneous manifestation of two or more of these diseases represents various clinical challenges as each disease interferes with the treatment of the other. This review summarizes several lines of evidence concerning the bi-directional relationship between multifactorial diseases and cancer. Moreover, this article aims to increase clinicians’ awareness regarding the risk of cancer development among patients with other multifactorial diseases. Within the aging population, the frequency of cancer is increasing dramatically. In addition, multiple genetic and environmental factors lead to common multifactorial diseases, including cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and metabolic-associated fatty liver disease. In recent years, there has been a growing awareness of the connection between cancer and multifactorial diseases, as well as how one can affect the other, resulting in a vicious cycle. Although the exact mechanistic explanations behind this remain to be fully explored, some progress has been made in uncovering the common pathologic mechanisms. In this review, we focus on the nature of the link between cancer and common multifactorial conditions, as well as specific shared mechanisms, some of which may represent either preventive or therapeutic targets. Rather than organ-specific interactions, we herein focus on the shared mechanisms among the multifactorial diseases, which may explain the increased cancer risk. More research on this subject will highlight the significance of developing new drugs that target multiple systems rather than just one disease. During the late 20th and early 21st centuries, a pronounced shift in global demographics towards older ages became more and more evident, reflecting the development of public health systems, improvements in the practice of medicine, and amelioration of socio-economic standards. According to the United Nations Department of Economic and Social Affairs Population Division 2019, the worldwide population over 65 is expected to exceed 1.5 billion in 2050 [Multifactorial diseases are caused by a combination of genetic and environmental factors, as well as various risk factors that accumulate with age. Cardiovascular diseases (CVD), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), metabolic (dysfunction) associated fatty liver disease (MAFLD), and malignancies are the most common multifactorial diseases, and impose a considerable healthcare burden , particuRecently, the bidirectional links between multifactorial diseases and cancer attracted scientific interest. Cancer treatment and management are associated with potential sequelae, including but not limited to cardiotoxicity, pulmonary toxicity, renal injury, and liver damage ,13,14,15Cardiotoxicity induced by cancer therapy is gradually accumulating and becoming increasingly evident despite an increased survival rate for cancer patients. For instance, anthracycline-based treatment can result in 5–48% irreversible cardiac damage and HF in a dose-dependent manner . EmerginWe have extensively discussed the bidirectional link between these two syndromes and provided a 5-tier classification system to categorize cardio-oncology syndromes (COS) that characterize the features of the link between cancer and cardiovascular diseases. In summary, COS Type I represents the mechanisms by which cancer can lead to cardiovascular dysfunction. COS Type II comprises the mechanisms by which cancer therapies can result in acute or chronic CVD. COS Type III refers to the pro-oncogenic milieu created by the release of cardiac factors. COS Type IV includes CVD management, including therapies and diagnostic practices that have been associated with promoting or unmasking malignancies. COS Type V refers to common factors causing systemic and genetic predisposition to both diseases . Moreovemin mouse model. The authors found that HF resulted in an increased intestinal tumor load and the severity of HF was strongly associated with tumor growth, independent of hemodynamic changes. This was explained by factors secreted by failing hearts, which stimulated the proliferation of colon cancer cells [hi monocytes to an immunosuppressive phenotype in the circulation and tumor [hi monocytes in tumor tissue, enhanced the chromatin accessibility of Ly6Chi monocytes in pathways regulating stress responses, and reduced the chromatin accessibility in pathways related to immune and inflammatory responses. For instance, the binding sites of PU.1, CCAAT-enhancer-binding protein (CEBP), and interferon regulatory factor (IRF)-8 of Ly6Chi monocytes were less accessible after MI, which impaired myeloid cell differentiation and transcriptionally inhibited numerous genes regulated by PU.1, CEBP and IRF-8 such as CD40 and CD86 genes involved in T cell activation, resulting in an immunosuppressive phenotype that persists in tumor monocytic myeloid-derived suppressor cells (mMDSCs) [The first preclinical study to assess the effect of HF on cancer development discerned the role of myocardial infarction (MI)-induced HF on intestinal polyp formation in the APCer cells . This stnd tumor . Compare(mMDSCs) . The autCancer progression was also assessed in another mouse model of a different HF etiology, namely, pressure overload-induced cardiac hypertrophy. The transverse aortic constriction (TAC) model was performed, followed by cancer cell implantation of breast cancer or lung cancer cells. TAC-operated mice displayed larger tumors and more severe metastatic lesions in the lung compared to control groups . SimilarShared pathways underlying the pathogenesis of both HF and cancer , such asNowadays, cardiologists and oncologists recognize the cardiotoxic effects of antineoplastic treatments, which has resulted in the establishment of cardio-oncologic clinics. Nevertheless, less awareness is given to ‘’reverse cardio-oncology’’, where HF itself constitutes a risk factor for cancer. Exploring pathways theoretically linking HF to cancer is a growing field of research, with the goals of understanding the bidirectional link between HF and cancer, finding common therapeutic targets, and improving the treatment of patients.Throughout the last two decades, the link between CKD and other diseases including cancer has progressively become acknowledged. CKD and malignancy are correlated in several ways in both directions.  It is we2 and kept rising linearly as eGFR was decreasing. Independent of smoking and age, the authors found that each 10 mL/min/1.73 m2 reduction in eGFR was associated with a 29% increased risk of new-onset cancer. This association appeared to be cancer site specific, and was more significant in lung and urinary tract malignancies [It remains unclear at which stage of CKD cancer incidence starts to rise. A cohort study reported a higher cancer risk in patients with moderate CKD, although this trend was only observed in men . Cancer gnancies . A retrognancies . Comparagnancies . Howevergnancies . TherefoCancer incidence for up to five years has been evaluated among patients with end-stage renal disease (ESRD) and before they underwent renal replacement therapy. These patients demonstrated a higher risk of several cancer types such as renal cell carcinoma, bladder cancer, multiple myeloma, sarcoma, and lymphoma . CorrespOne of the main features of CKD is a persistent inflammatory state associated with high production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). It is well established that inflammation is one of the main risk factors and a key mechanism in cancer formation and development. An inflammatory milieu allows malignant cells to escape host immune surveillance, stimulating angiogenesis, tumor growth, and invasiveness. An incessant low and chronic inflammation in CKD patients will activate the generation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and myeloperoxidase (MPO) by polymorphonuclear neutrophils and monocytes macrophages, which promotes the production of reactive oxygen species (ROS) and initiates a state of oxidative stress . Under pPatients with ESRD have higher levels of carcinogenic compounds and nitrogen-containing substances accumulating in the blood . CarcinoCOPD and lung cancer are two leading public health issues and causes of morbidity and mortality. Both diseases share common risk factors such as exposure to smoking and genetic predisposition. Approximately 15–20% of lifelong smokers will develop COPD or lung cancer . FurtherSome well-known gene families of proteinases, detoxifying enzymes, and inflammatory cytokines play roles in COPD development . SeveralEpigenetic modification is another important link between COPD and lung cancer . Common COPD is characterized by chronic lung inflammation as well as immune cell recruitment and activation . InflammAnother major driving mechanism in the pathogenesis of COPD is oxidative stress, which is well established as being causative for cellular proliferation in lung cancer . The dysThe NF-kappa-B transcription complex (NF-κB) molecule is an important transcription factor that promotes the production of inflammatory mediators . The NF-Although the exact mechanism underlying COPD and lung cancer is not fully explored, growing evidence suggests that the two diseases may be linked at the molecular level. However, the available literature is limited to animal models and small clinical trials. Large clinical trials and combined models of COPD and lung cancer are required to investigate the processes that link COPD and lung cancer.MAFLD, previously known as non-alcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease in Western countries. The change in nomenclature to MAFLD was recently proposed by a group of experts to better emphasize the essential role of metabolic disorders in the pathogenesis of fatty liver disease . MAFLD iMetabolic disorders are the major causes of MAFLD. Excessive fat intake, as consumed with the western diet, leads to lipid uptake in the liver far extending the ability to oxidize the lipids or to export via very low-density lipoprotein (VLDL), resulting in hepatic lipid accumulation . In addiMAFLD may be considered a multisystem disease ,111 Fig. MAFLD hThe association between MAFLD and hepatocellular carcinoma (HCC) has been studied most extensively. MALFD significantly increases the risk for HCC ,118,119.MAFLD has not only been associated with an increased risk for HCC but also with several extrahepatic cancers, including CRC, kidney cancer, thyroid cancer, and breast cancer ,112,119.Over the last few years, MAFLD has become the fastest-rising cause of HCC in the US . ObesityHowever, fatty liver disease itself can also affect HCC. Cirrhosis is a major risk factor for HCC. Epidemiological studies indicate that in 11–38% of the HCC patients cirrhosis was identified as the underlying etiology ,126. In Accumulating evidence suggests that steatohepatitis can also stimulate tumorigenesis, irrespective of cirrhosis, in several ways. Recent studies showed that in individuals with steatohepatitis, 12–14% of cancers occur prior to cirrhosis ,135,136.Interestingly, MAFLD-associated HCC may also be induced by changes in the gut microbiome. Several studies have observed microbial dysbiosis in MAFLD patients . Fatty lThese data build on the evidence that MAFLD may be considered a multisystem disease, and with the increasing incidence of MAFLD, it is important to study the connection between MAFLD and other diseases such as cancer .In this review, we discuss several lines of evidence suggesting a common pathophysiologic background and a bi-directional relationship between different common multifactorial diseases and cancer. Although the corresponding evidence base has gained increasing scientific interest in recent years, there are still no specific therapeutic interventions with potential clinical applications in this context. Coincidentally, one such example was seen in the landmark CANTOS trial, in which patients with a previous myocardial infarction were treated with canakinumab, a monoclonal antibody targeting IL-1β. It has been shown that canakinumab not only improved cardiovascular outcomes but also reduced the incidence of lung cancer and mortality ,151. AltInflammation is often a connection point between cancer and the discussed diseases, so it represents one of the central therapeutic target candidates. COPD patients, for example, can be screened for changes in the epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) and, if necessary, treated with immunosuppressive drugs. Known ones are EGFR inhibitors such as erlotinib  or VEGF-Physicians managing patients with chronic conditions, such as COPD, HF, CKD, or MAFLD, should maintain an increased level of suspicion for the potential pro-oncogenic role of these diseases. This review focuses on common multifactorial diseases that have been shown, in clinical and pre-clinical studies, to have a link with cancer. Nevertheless, it is worth mentioning that there are other common diseases such as prostatic hyperplasia. The latter may share similar signaling pathways with prostate cancer since treatments for benign prostatic hyperplasia may also benefit prostate cancer .Multifactorial diseases and cancer are all driven by shared pathophysiological pathways , includiThere is a bidirectional relationship between cancer and common multifactorial diseases , and they share common risk factors and a pathophysiologic basis. Although the exact nature of these commonalities and bidirectional interactions remains incompletely understood, a high index of suspicion for incident cancer combined with intensification of patient education and modification of shared risk factors are important supplementary measures that should be followed. Lastly, although there are currently no dual-role therapeutic interventions effective for either end of this bidirectional relationship, potential future targets may include immunomodulatory treatments, modulation of microbiota, and reduction of oxidative stress.


Electrospun fibrous membranes loaded with chemotherapy drugs have been broadly studied, many of which have had promising data demonstrating therapeutic effects on cancer cell inhibition, tumor size reduction, the life extension of tumor-bearing animals, and more. Nevertheless, their drug release profiles are difficult to predict since their degradation pattern varies with crystalline polymers. In addition, there is room for improving their release performances, optimizing the release patterns, and achieving better therapeutic outcomes. In this review, the key factors affecting electrospun membrane drug release profiles have been systematically reviewed. Case studies of the release profiles of typical chemotherapy drugs are carried out to determine the preferred polymer choices and techniques to achieve the expected prolonged or enhanced release profiles. The therapeutic effects of these electrospun, chemo-drug-loaded membranes are also discussed. This review aims to assist in the design of future drug-loaded electrospun materials to achieve preferred release profiles with enhanced therapeutic efficacies. The International Agency for Research on Cancer (IARC) has estimated over 19 million new cancer cases and almost 10 million deaths from cancer based on the 2020 global cancer statistics (GLOBOCAN) database, which covers most of the countries in the world [These situations brought out the demands for better local therapeutic measures to ultimately limit the reoccurrence rate of cancers and inhibit tumor growth in sensitive areas where operations were seldom applicable. A series of local cancer therapies, like tumor sclerosis, tumor embolization, and intra-tumoral injection, were developed . In addiElectrospun membranes could be fabricated using various techniques with numerous combinations of parameters. These parameters include polymer choices, solution preparation methods, fabrication techniques, drug types/loading methods, etc. All of them could affect the drug release profiles of electrospun membranes. Nevertheless, these parameters have not yet been systematically determined, confusing many researchers.This review provides insight into the key factors affecting the release profiles of the implantable electrospun membranes tailored for local carcinoma. Their release patterns and therapeutic effects are categorized and concluded to assist in the future design of drug-loaded electrospun delivery systems.Synthetic biodegradable polymers were applied broadly in clinical implantable products like bone/ligament fixing screws ,9,10,11,PLA is the most thoroughly studied and broadly applied biodegradable polyester . It reprg) of about 36 °C, just close to human body temperature, which allows it to be applied in suture material or other tissue engineering equipment that needs faster degradation. Degradation of medical PGA implants like scaffolds and stents is relatively fast, taking just a few months [Polyglycolic acid (PGA) is another FDA-approved biodegradable polymer utilized widely in the medical field. It is the most hydrophilic among the standard medical polyesters . Glycoliw months . Observaw months . Comparew months ,44.Polylactide-co-glycolide (PLGA) is a polymer that combines the many advantages of both PLA and PGA. As a copolymer, PLGA allowed flexible tuning of the ratio and arrangement of lactide and glycolide units, resulting in a more tunable degradation time, mechanical properties, and hydrophilicity. Medical implants made of PLGA, like bone scaffolds , cartilaPolycaprolactone (PCL) is another extensively utilized biodegradable polyester. It is semi-crystalline ,55 with Chitosan is a polymer generated by the deacetylation of an abundantly seen natural chitin. It has a number of advantages, including affinity for organ tissue surfaces , well-reBlend electrospinning is the most straightforward fabrication technique for drug-loaded fibrous membranes a. All thCoaxial electrospinning b is a teAnother path to achieving core-shell structure is to prepare a polymer blend as an emulsion, called “emulsion electrospinning” c. This mSurface modification is an extension of electrospinning techniques with multiple advantages d. It oveAlthough the key factors affecting the drug release from electrospun membranes are clear, situations become complicated when multiple variables are combined. In order to make a practical analysis from the sea of related research, we selected the release data targeting four types of representative cancer drugs , and refined those results to match two major aims: prolonged control-release for hydrophilic chemotherapy drugs and enhanced release for hydrophobic chemotherapy drugs. The release profiles of electrospun membranes loaded with typical hydrophilic/hydrophobic chemotherapy drugs that successfully achieved these aims are collected and sorted in Researchers have fabricated delicate electrospun materials with anti-tumor or even multiple functions. Unfortunately, some did not achieve satisfying release profiles that might decrease their therapeutic efficacies and shorten their anti-cancer time range. The issue mainly focused on incompatible drug-polymer systems. Implantable hydrophobic polymers like PLA, PLGA, and PCL possess excellent mechanical properties and stability that are attractive to many researchers. However, when blended with hydrophilic drugs, the polar incompatibility will cause an uneven distribution of drugs in the polymers. A part of the drug would accumulate on the surface of the electrospun materials . Burst cHydrophilic chemotherapy drugs share properties like fast effects through rapid concentration elevation and short retention times in the human body. In order to maintain a specific local drug concentration, these chemotherapy drugs had to be applied repeatedly in a short period, which increased the suffering of patients; furthermore, a rapid elevation of drug concentration is closely related to acute toxicity events. As a result, electrospun membranes for local chemotherapies should be tuned to possess prolonged logistic and even linear release profiles for hydrophilic chemotherapy drugs, reducing their burst release to achieve reliable drug effectiveness.It is critical to match the polarity between drugs and polymers to achieve proper controlled release of hydrophilic chemotherapy drugs from the electrospun membrane. Nevertheless, most long-term degradative polymers are relatively hydrophobic and thus natively incompatible with hydrophilic chemotherapy drugs. This contradiction has presented challenges for researchers. To address this problem, polymer systems for electrospinning membranes should be tuned to be relatively less hydrophobic and easier to degrade in water. The strategies include incorporating amphiphilic chemicals like low- to mid-Mw PEG that is mostly safe for human tissue  and addiThe trickiest thing about applying hydrophobic chemotherapy drugs is increasing their solubility and bioavailability. Raw hydrophobic drugs are usually crystalline particles that precipitate in an aqueous environment without entering the cancer cells. Electrospun membranes should be designed to largely enhance their release quantity over the polymer degradation period and act as carriers to increase their compatibility with an aqueous environment. PLA, PLGA 50:50, and PCL electrospun membranes could achieve logistic release of more than 50% encapsulated PTX or cisplatin for 30 days or longer ,71,87,89Properly tuned electrospun chemotherapy drug membranes with prolonged and controlled release profiles were proven effective against the activities of cancer cells in vitro and inhibited the growth of local tumors while extending the lives of tumor-bearing animals. For in vitro cell toxicity studies, DOX-loaded PCL/PLA-based controlled release membranes were mostly reported to exhibit antiproliferative effects against the MCF-7 human breast cancer cell line ,82,103 aFor in vivo anti-tumor studies, a local application of DOX-loaded controlled release membranes was reported to reduce glioblastoma by nearly 80% at day 20, borne by naked mice . A PCL/PUnfortunately, there are not yet any FDA-approved products of electrospun chemo-drug-loaded membranes on the U.S. market. There are currently two electrospun material products listed on the clinical trial database of the U.S. National Institute of Health (NIH). One is an antibacterial electrospun material loaded with ciprofloxacin (CIP), metronidazole (MET), and minocycline (MINO) for immature necrotic teeth . The other is a tissue repair scaffold for treating dermatologic wounds created by the surgical removal of non-melanoma skin cancers . Hopefully, there will be chemotherapy drug-loaded electrospun material products available for clinical trials against local carcinoma.In this review, the key factors affecting the release profiles of chemotherapy drug-loaded electrospun membranes were systematically discussed with mechanistic elaborations and case studies. Research on electrospun membranes loaded with several representative chemotherapy drugs  with varied polymers and techniques are selected and categorized to demonstrate the reality of drug release and to provide meaningful experiences towards desirable release profiles according to varied needs. Their therapeutic evidence, with both in vitro antiproliferative cell studies and in vivo local anti-tumor effects, was also refined and demonstrated. Hopefully, this review could serve as a strategic guide for the design of drug-loaded electrospun membranes, especially to be applied as implants against local carcinoma, to unravel the relationship between elements of drug membranes and their overall release profiles.


Gliomas are common primary brain tumors that account for a high number of cancer-related deaths worldwide. Patients with aggressive gliomas have poor prognoses due to resistance to current treatment regimens. Anatomical barriers between the brain and the peripheral circulation make glioma drug delivery particularly challenging. Recently, the potential for dendrimers—nanomaterials characterized by a unique branching structure with many binding sites—to deliver therapeutic and diagnostic cargo directly to the site of gliomas has been explored. An increasing number of studies in glioma cell lines and animal models suggest that this dendrimer-based delivery approach may serve to decrease drug toxicity and allow for the use of nontraditional therapeutic and imaging agents in glioma. Here, we review the physical characteristics of dendrimers, strategies for modifying dendrimers to target glioma cells, and novel applications of this nanotechnology in glioma models.Novel therapeutic and diagnostic methods are sorely needed for gliomas, which contribute yearly to hundreds of thousands of cancer deaths worldwide. Despite the outpouring of research efforts and funding aimed at improving clinical outcomes for patients with glioma, the prognosis for high-grade glioma, and especially glioblastoma, remains dire. One of the greatest obstacles to improving treatment efficacy and destroying cancer cells is the safe delivery of chemotherapeutic drugs and biologics to the tumor site at a high enough dose to be effective. Over the past few decades, a burst of research has leveraged nanotechnology to overcome this obstacle. There has been a renewed interest in adapting previously understudied dendrimer nanocarriers for this task. Dendrimers are small, highly modifiable, branched structures featuring binding sites for a variety of drugs and ligands. Recent studies have demonstrated the potential for dendrimers and dendrimer conjugates to effectively shuttle therapeutic cargo to the correct tumor location, permeate the tumor, and promote apoptosis of tumor cells while minimizing systemic toxicity and damage to surrounding healthy brain tissue. This review provides a primer on the properties of dendrimers; outlines the mechanisms by which they can target delivery of substances to the site of brain pathology; and delves into current trends in the application of dendrimers to drug and gene delivery, and diagnostic imaging, in glioma. Finally, future directions for translating these in vitro and in vivo findings to the clinic are discussed. Gliomas are a common type of primary brain tumor, accounting for about a third of all primary brain tumors and 80% of malignant ones . They arRapid advances in molecular genetics have necessitated the creation of new CNS tumor guidelines by the World Health Organization. These guidelines, developed in 2016 and then revised in 2021, use largescale genetic analyses of patient tumor samples to group gliomas into molecular types and subtypes based on their natural histories and treatment responses, thereby reflecting the importance of genetic drivers in tumor progression . As geneEven with these advances, the challenges in treating aggressive glioma remain formidable. Current treatment regimens are based on the triad of surgical resection, chemotherapy, and radiotherapy . While tA few logical strategies exist to overcome these delivery challenges. One strategy is to bypass the BBB and BBTB by delivering the therapy centrally via intranasal or intrathecal administration, convection-enhanced delivery (CED), or intratumor implants ,14. A seThis third strategy has been the focus of an explosion of research within the field of nanotechnology. Central to this approach is the use of nanocarriers to efficiently deliver drugs and genomic materials to the brain. Due to their extremely small size, nanomaterials can condense cargo, cross anatomic barriers, and efficiently permeate tumor environments. This latter characteristic can be attributed to the enhanced permeability and retention (EPR) effect, by which disorganized and highly vascular tumors with low levels of lymphatic drainage can be passively targeted . NanomatDendrimers are globular, homogenous, highly symmetric molecules with a regular, highly branched architecture consisting of an interior core surrounded by repeating layers ,17. DendDivergent and convergent syntheses are used to produce dendrimers; each reaction produces an extra generation. Divergent synthesis begins with the core molecule and grows outwards, whereas convergent synthesis starts with the periphery. Convergent synthesis usually achieves a greater degree of purity compared to divergent synthesis, as divergent synthesis results in multiple reactions being performed on one molecule, whereas convergent synthesis uses a small number of reaction sites during each stage, limiting the number of side products generated . HoweverThe size of dendrimers is determined by the number of generations. There are reports of dendrimers constructed with as many as thirteen generations while retaining stability across changes in pH and temperature . ImportaDendrimer cytotoxicity is dependent on the number of generations, overall charge, and constituent dendrons. Cationic dendrimers and those with a large number of generations generally exert greater cytotoxicity compared to smaller, anionic, or neutral dendrimers . AlthougIn addition to their multifunctionality and capacity to transport a range of therapeutic agents, dendrimers can also exert anti-inflammatory effects. Neibert et al. showed that the hydroxyl terminal groups of small dendrimers could inhibit the active sites of the enzymes inducible nitric oxide synthase and cyclooxygenase-2, thereby inhibiting prostaglandin synthesis and inflammation . SeparatDendrimers can be classified according to their constituent core molecules and branching compounds. Several types of dendrimers exist, including polyamidoamine (PAMAM), poly-L-lysine (PLL), and polypropylene imine (PPI) dendrimers ,33. AlthPAMAM dendrimers contain ammonia or ethylenediamine at the core and have methyl acrylate and ethylenediamine added to create the branching architecture . These dLysine-based dendrimers, such as PLLs, also possess a favorable biodegradation and biocompatibility profile, along with many functional amino groups that allow for drug conjugation . These pPPI dendrimers are a third category of dendrimers commonly investigated for biological purposes. These dendrimers, synthesized using a divergent approach, generally contain 1,4-diaminobutane as the core, although variants can be used, such as an ethylenediamine core . PropyleDendrimers are routinely modified with functional groups that improve tissue targeting, reduce systemic effects, and carry therapeutic agents ,47. One Dendrimers can also be modified to alter the overall charge, thereby minimizing cytotoxicity and altering nanoparticle targeting and binding. For example, acetylation of PAMAM dendrimers can neutralize their cationic charge, thereby reducing the degree of cytotoxicity that results from the interactions of cationic polymers with negatively charged cellular membranes. Moreover, acetylation improves the delivery of genetic material from dendrimers to cells by decreasing interactions between the dendrimer and DNA, allowing for improved intracellular release . GabrielDendrimers can also be modified with surface-functional ligands that promote binding to cellular receptors and accumulation at target tissue, as will be discussed in later sections.In addition to conjugated agents that improve targeting and reduce systemic side-effects, dendrimers can carry a wide variety of therapeutic agents, either encapsulated within the dendrimer or attached covalently to the surface  56]. Tr. Tr56]. Chemotherapeutic agents that have been successfully conjugated to dendrimers include methotrexate, paclitaxel, doxorubicin, cisplatin, and 5-fluorouracil, which have been studied for efficacy against a variety of tumors ,61,62,63Beyond the capacity of dendrimers to deliver conventional chemotherapeutics, significant interest has been generated in the use of dendrimers as a delivery vehicle for genetic material, including DNA, RNA, small interfering RNA (siRNA), and microRNA (miRNA) . The fleEndocytosis of the dendriplexes is followed by endosomal destabilization of the complex, resulting in release of the genetic material . DNA canDendrimers can also be used to transport siRNA, which guides the RNA-induced silencing complex to target and cleave complementary RNA . SiRNA cOther studies have been carried out for the delivery of siRNA and miRNA to brain tissue. Posadas et al. showed that carbosilane dendrimers could deliver siRNA to target translation of the hypoxia-inducible factor-1-alpha protein involved in hypoxic signaling . By knocThe pharmacodynamics, pharmacokinetics, and biodistribution of dendrimers are dependent on their respective sizes, structures, charges, and surface functional groups. Small dendrimers undergo renal filtration. For example, PAMAM dendrimers are filtered through the kidneys up through generation-five compounds, and larger dendrimers cannot be filtered at the renal glomerulus and instead undergo hepatic clearance ,83,84. TDendrimers are usually administered intravenously or subcutaneously, and some studies have characterized an oral route that improves intestinal drug permeability . Their oSurface ligands that function as targeting moieties can improve dendrimer uptake by a selected tissue. These ligands include monoclonal antibodies, carbohydrates, peptides, and small-molecule receptor agonists that bind cellular receptors overexpressed on the target tissue ,85. For The toxicity of dendrimers is an important consideration in their synthesis and testing, and higher-generation dendrimers often confer greater toxicity compared to lower-generation dendrimers . DendrimAdditionally, cationic dendrimers have been associated with a pro-coagulant role and can induce platelet aggregation in vivo, resulting in a coagulation cascade that can produce a syndrome similar to disseminated intravascular coagulation. Jones et al., in a study also using embryonic zebrafish, illustrated that G7 PAMAM dendrimers can interact with a variety of blood components, including platelets, fibrinogen, and anionic blood proteins, producing a unique, multi-component, rapid coagulation cascade. These effects appear dependent on dendrimer size and charge . PAMAM dTargeting of dendrimers to gliomas requires dendrimers to either bypass or traverse the selective BBB, and to accumulate in the desired target tissue. Techniques that avoid the BBB include intracerebral implants, such as biodegradable polymer wafers that can deliver chemotherapeutics, and CED, which uses an external infusion pump to deliver drugs directly into the brain parenchyma via a pressure gradient ,101. IntSeveral of these drug delivery methods were analyzed by Albertazzi et al., who assessed G4 PAMAM dendrimer diffusion using confocal imaging after intraparenchymal, intraventricular, and subarachnoid injection . All thrAlternatively, nanoparticles can be delivered into the systemic circulation and cross the endothelial cells lining the BBB via paracellular diffusion, particularly with small nanoparticles, and/or transcellular transport mechanisms, including carrier-mediated transport, adsorptive-mediated transcytosis, and receptor-mediated endocytosis ,112. RecAfter dendrimers reach the CNS, the next step is targeting to the brain tumor to minimize side-effects from cytotoxicity to healthy nervous tissue. Nanoparticles can accumulate at the site of brain cancer via the EPR effect, a well-documented phenomenon reflecting the irregular and extensive neovascularization characteristic of fast-growing tumors with high metabolic and oxygen requirements. Permeability is increased along these blood vessels, owing to larger gaps between the endothelial cells, allowing for preferential accumulation of nanoparticles at the tumor site . ExpressHowever, the magnitude of the EPR effect can vary among CNS malignancies. Targeting of dendrimers to brain tumors can be improved by conjugating functional ligands that bind overexpressed receptors on the tumor cells . These fThe addition of sugar moieties to dendrimers can improve targeting of tumor tissues by exploiting the Warburg effect, in which cancer cells preference anaerobic glycolysis over oxidative phosphorylation . Cancer Folic acid and biotin are vitamins that can enhance targeting of brain tumors by dendrimers. Folic acid plays an essential role in nucleotide synthesis required for the division and proliferation of tumor cells, and consequently many cancer cells, including gliomas, significantly overexpress cysteine-rich folate receptors compared to healthy tissue . Xu et aSimilarly, biotin receptors are overexpressed in cancer cells, given the role of biotin in promoting cellular growth . FurtherMonoclonal antibodies can also improve dendrimer targeting while improving in vivo stability. Antibodies conjugated to dendrimers can target specific receptors on target tissue to promote dendrimer uptake . This stThere are a range of ways in which dendrimers are being used in the treatment and diagnosis of glioma . SeveralA logical way in which dendrimers can be applied to the treatment of glioma is as vehicles for delivering drugs from the periphery to the tumor target site . This isOther chemotherapeutics not normally used for the treatment of glioma—either due to poor BBB penetrance or intolerable systemic toxicity—have been conjugated to dendrimers and tested in rodent models. For instance, cisplatin-loaded dendrimers delivered intracranially via CED resulted in a pronounced antineoplastic effect accompanied by a tolerable toxicity profile in rats . SimilarIn addition to traditional chemotherapeutic agents, natural products with antineoplastic activity but nonspecific targeting can be salvaged for glioma therapy by shepherding them to their desired site of action using dendrimer complexes. Such an approach has recently been used to deliver α-mangostin—a xanthone with antineoplastic properties but poor water solubility and low selectivity for cancer cells—to glioma cells using a biotin-transport-targeting, polysaccharide-modified PAMAM G3 dendrimer . This drGene therapy is a promising approach for the treatment of brain diseases given its ability to manipulate defective genes along relevant pathways associated with disease . With thOne alternative to the delivery of free nucleic acids is to use a viral vector, such as adeno-associated virus (AAV), as a vehicle. Viral vectors are frequently used in laboratories as transfection agents, given their innate transduction efficiency; however, their clinical utility as delivery agents is more limited. Despite the now-widespread use and appreciable population-level benefits of several viral vector-based vaccines aimed at preventing and attenuating diseases such as COVID-19, this strategy can have the disadvantages of batch-to-batch vector variation, limited carrying capacity, and safety concerns depending on the vector used, such as rare but severe incidents of vaccine-induced thrombosis ,144,145.To avoid these potential safety and integration risks, and to decrease batch-to-batch vector variation and improve target specificity, non-viral vectors can be used for gene delivery. While viral vectors remain more efficient in their payload delivery and require less molecular engineering to ensure target internalization , non-virPlasmids encoding genes of interest, such as those capable of inducing apoptosis or stimulating the immune system, can be shuttled into tumor cells using dendrimers. As proof of this principle, Kuang et al. used intravenous injection of T7 peptide-functionalized dendrimers containing plasmid-encoded siRNA to successfully induce luciferase knockdown in a U87MG glioma nude mouse model treated with luciferin . In anotIn addition to the delivery of genes promoting apoptosis, dendrimers can be used to deliver biologics that elicit specific gene knockdown. In a recent study, dendrimer-siRNA conjugates were synthesized and shown to be capable of simultaneously extending the half-life of siRNA in plasma and significantly reducing GFP expression in vivo using a CX3CR-1GFP mouse orthotopic GL261 GBM model . EmployiIn addition to therapeutic delivery, dendrimers are also being explored as novel diagnostic and imaging agents given their low side-effect profiles, ability to breach the BBB/BBTB, and propensity to permeate and accumulate in tumor environments. Magnetic resonance imaging (MRI) is a vital noninvasive and nonradiative imaging tool for diagnosing and evaluating glioma ,156. The1 contrast agents to Gd-based agents, given that they also have paramagnetic properties to produce contrast but are organic species without the potential for toxicity from metal accumulation. In a recent study, an immunocompetent, orthotopic GL261 murine GBM model was used to test ex vivo and in vivo tumor contrast enhancement using a G3 water-soluble radical dendrimer with nitroxyl radicals anchored to its branches FDG. These results merit further study of the use of dendrimer platforms in glioma imaging.The use of dendrimer platforms in other imaging modalities, including radionuclide-based imaging techniques, has also been explored. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are extremely sensitive diagnostic strategies; however, some radionuclides have issues with specificity of localization. For instance,  imaging . This fi imaging . RemarkaOther potential applications for dendrimers will undoubtedly continue to be appreciated as the fields of nanotechnology and genetic engineering continue to advance. Imaging agents can be loaded onto dendrimers along with therapeutics to promote targeted theranostic approaches . MultiplImmunotherapy, a highly successful treatment option for many other types of aggressive cancer, is being actively pursued as a treatment option for GBM, which is characterized by an immunosuppressive environment . ImmunotClinicalTrials.gov), and there are no approved CNS nanomedicines [While there is strong interest in both academia and the pharmaceutical industry to translate dendrimers to the clinic for the treatment of patients with glioma, as of this writing, there are no registered clinical trials evaluating dendrimers in the context of glioma (edicines . Indeed,edicines ,170.Before this can happen, several preclinical objectives must be attained. Building upon promising previous work to identify targeting ligands for BBB access and glioma-homing ,171, denNext, before dendrimer-based therapies and diagnostics can advance to clinical trials, thorough in vivo studies must be performed to evaluate the biodistribution, toxicity, and efficacy of these interventions. Such studies on dendrimers in glioma are currently lacking. The majority of articles report strictly in vitro results, so there are limited pharmacodynamic assessments . These iThe design of future in vivo studies of dendrimer conjugates can be strengthened by incorporating systemic delivery of dendrimer agents via intravenous routes to best approximate delivery strategies used in patients and minimize complications, such as infection and BBB disruption. Additionally, such studies should strive to report the fractions of free drug and conjugated drug—versus only reporting the total drug concentration in the blood or brain—in order to extrapolate effects on toxicity and to determine the therapeutic index of the dendrimer nanocarrier . Only whIn summary, encouraging findings at the preclinical level indicate that further translational research efforts investigating the use of dendrimers in glioma contexts are well worth the investment and may even lay the groundwork for a new era of CNS-targeted oncologic interventions.Remarkably, as evidenced by a rapidly growing volume of preclinical studies, dendrimer conjugates can be designed to effectively bypass the BBB/BBTB, target glioma cells, and contribute to cell death or specific gene knockdown. The unique branching structure and binding capacity of dendrimers allow them to be exploited for novel, multi-step journeys through the peripheral circulation into the brain parenchyma and into individual tumor cells. However, these findings remain firmly in the preclinical realm, as few such approaches have advanced to clinical trials. Dendrimers hold promise to be effective therapeutic delivery and imaging tools for the treatment and diagnosis of glioma, but only if these preclinical results can be effectively translated. Building upon solid and reproducible methodologies for dendrimer conjugate synthesis, future work must focus on validating in vitro results using well-controlled experiments with in vivo tumor models. Additionally, studies investigating the effects of dendrimers and dendrimer conjugates on unloaded cargo must be carried out to demonstrate not only effective targeting, but non-interference with the therapeutic effects. Finally, studies comparing the current standard of care with combination treatments involving dendrimer complexes must be conducted to determine the most appropriate ways in which to incorporate this technology into the care of glioma patients.


Delayed diagnosis, gaps in services and subsequent delays in specialist care and treatment lead to poorer health outcomes for individuals with eating disorders (EDs) and drive significant government healthcare expenditure. Given the significant disease burden associated with EDs, it is imperative that current implementation research is summarised to identify gaps in care and enable refinement for optimal patient outcomes. This review aimed to provide an updated synthesis on models of care for EDs in developed healthcare systems.This paper was conducted as part of a series of Rapid Reviews (RRs) to be published in a special series in the Journal of Eating Disorders. To provide a current and rigorous review, peer-reviewed articles published in the English language between 2009 and 2021 across three databases  were searched, with priority given to higher level evidence ). The current review synthesises data from included studies investigating models of care for people with EDs.Sixty-three studies  were identified, which included several diagnostic populations, the most common being Anorexia Nervosa (AN) (30.51%). Across EDs, specialist care was found to improve patient outcomes, with many patients effectively being treated in outpatient or day programs with multi-disciplinary teams, without the need for lengthy inpatient hospitalisation. Few studies investigated the interaction of different ED services , however stepped care models emerged as a promising approach to integrate ED services in a targeted and cost-effective way. Issues surrounding low treatment uptake, underdiagnosis, long waiting lists and limited hospital beds were also evident across services.Findings suggested further research into alternatives to traditional inpatient care is needed, with partial and shorter ‘hospitalisations’ emerging as promising avenues. Additionally, to tackle ongoing resource issues and ensure timely detection and treatment of EDs, further research into novel alternatives, such as active waiting lists or a greater role for primary care clinicians is needed.This paper is part of a larger Rapid Review series carried out to guide Australia’s National Eating Disorders Research and Translation Strategy 2021–2031. Rapid reviews aim to thoroughly summarise an area of research over a short time period, typically to help with policymaking in this area. This Rapid Review summarises the evidence relating to how we care for people with eating disorders in Western healthcare systems. Topics covered include inpatient/hospital care, residential care, day programs, outpatient/community care, and referral pathways. Findings suggested specialist eating disorder services may enhance detection, referral, and patient care. Stepped care models presented as a cost-effective approach which may help with linkage between different eating disorder services. There was a trend towards shorter hospital stays and approaches which allow for greater connection with the community, such as day programs. Evidence was also found of treatment delays, due to system issues  and patient-related barriers . Upskilling and involving primary care clinicians in diagnosis and referral as part of a stepped care model may help to address some of these concerns. Further efforts to improve mental health literacy and de-stigmatise help-seeking for eating disorders are needed.The online version contains supplementary material available at 10.1186/s40337-022-00671-1. Eating disorders (EDs), including Anorexia Nervosa (AN) and Bulimia Nervosa (BN), are serious mental illnesses, characterised by severe disturbances in eating behaviours  and are Similar to other complex conditions, those with EDs benefit from clearly defined referral pathways and comprehensive care provided by multidisciplinary teams (MDTs), 26. MDTReviews of current service delivery for EDs have typically explored different models of care for particular ED subtypes, including primary care [in AN, BN, BED; The aim of this Rapid Review (RR) is to synthesise the literature on models of healthcare delivery for EDs across a broad range of settings  and study types . This RR forms one of a series of reviews scoping the field of EDs commissioned to inform the Australian National Eating Disorders Research and Translation Strategy 2021–2031 . The objThe Australian Government Commonwealth Department of Health funded the InsideOut Institute for Eating Disorders (IOI) to develop the Australian Eating Disorders Research and Translation Strategy 2021–2031  under thA RR protocol  was utilThe RR is a narrative synthesis and adheres to the PRISMA guidelines . It is dn > 50); moderately sized controlled-cohort studies (n > 50), and population-based studies (n > 500). However, the diagnoses ARFID and UFED necessitated less stringent eligibility criteria, due to a paucity of published articles. As these diagnoses are newly captured in the DSM-5 , the evidence base is emerging, and fewer studies have been conducted. Thus, smaller studies (n = < 20) and narrative reviews of these two disorders, were also included. Grey literature, such as clinical or practice guidelines, protocol papers (without results) and Masters’ theses or dissertations, was excluded. Other sources (which may not be replicable when applying the current methodology) included the personal libraries of authors, yielding 4 additional studies . This extra step was conducted in line with the PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews [The RR had a translational research focus with the objective of identifying evidence relevant to developing optimal care pathways. Searches therefore used a Population, Intervention, Comparison, Outcome (PICO) approach to identify literature relating to population impact, prevention and early intervention, treatment, and long-term outcomes. Purposive sampling focused on high-level evidence studies such as: meta-analyses; systematic reviews; moderately sized randomised controlled studies (RCTs) , BN , ARFID , BED , and Night Eating Syndrome (NES) . A number of studies included multiple ED populations , including those with Other Specified Feeding and Eating Disorder (OSFED), and Unspecified Feeding or Eating Disorder (UFED), previously Eating Disorder Not Otherwise Specified (EDNOS) in the DSM-IV. Three studies included participants without a formal ED diagnosis (4.8%). Results are structured into the following subsections: (1) inpatient/hospital care, (2) residential care, (3) day programs, (4) outpatient/community care, and (5) referral pathways. Findings relating to full threshold EDs  have been group together where possible within subsections.Sixty-three studies are included in this RR , 45 (71.4%) of which are primary articles. Fifty-nine of the articles related to Models of Care were identified by the original RR scoping the field of eating disorders , represeInpatient options are mostly reserved for acutely ill patients with AN and ARFID experiencing severe malnutrition, as it is considered the most practical for weight restoration in severely ill patients . There wThe diverse presentation characteristics of people with EDs influences whether they receive inpatient treatment and for how long. Kennedy et al. (2017) found that in a patient sample of adolescents with AN and atypical AN (A-AN), those with past obesity, despite greater percentage weight loss and similar duration of illness compared to other patients, were less likely to receive hospitalisation for medical stabilisation . This fiIndividuals with severe and enduring forms of ED often require hospital care with modifications to treatment that de-emphasise weight gain  and place a greater importance on QoL and individual functioning . PromisiEvidence suggests that hospitalisation is helpful for improving weight and reducing core ED pathology, although it is unclear whether it conveys a clear advantage over less intensive care. Naab et al. reported significant improvements in ED and depressive symptoms in a large sample of adolescents and adults with AN at a specialist inpatient ED service . In a reShorter inpatient stays may achieve similar remission  and readmission rates as that of longer inpatient stays , 59. In Any benefit of hospitalisation is likely to be apparent early on in hospitalisation, although there is mixed evidence as to whether this results in better longer-term outcomes post-discharge. In a secondary analysis of the Madden et al. (2015) RCT, early weight gain at 4-weeks predicted higher percent (%)EBW and remission at 12-month follow-up . SimilarHigher calorie diets during admission may be used to safely reduce the length of hospitalisation and improve weight gain outcomes , 63. PreCompared with AN, we found fewer publications on the treatment of BN in hospital settings . DiedricAs in AN, hospitalisation for ARFID has a primary objective of weight and nutritional restoration. Evidence from a systematic review of inpatient care for children with ARFID indicated inpatient care was able to produce positive outcomes in terms of increased food consumption following discharge . FurtherGenerally, the required length of hospitalisation for patients with ARFID, compared to those with AN is relatively long. Stranjord et al., (2015) found that patients with ARFID required longer inpatient stays than those with AN and had a greater reliance on enteral feeding to promote WR , 70.CompEvidence relating to inpatient care has been identified for AN, BN and ARFID, with little mention of other diagnoses, representing a gap in our understanding. One study identified an inpatient weight loss program incorporating psychoeducation, diet and exercise for those with NES , a type of OSFED . The stuThere has been relatively little evaluation of residential care for individuals with EDs . For adoDay programs may also assist in ED recovery , providiDay programs appear to be promising for individuals with AFRID. A systematic review on care for children with ARFID found day programs to produce positive outcomes in terms of increased food consumption following discharge, similar to inpatient programs . An obseEvidence also suggests that day programs may be a promising alternative to inpatient treatment. A 3-year follow-up study comparing individuals with BN who received inpatient care or day program was unable to find any differences in effectiveness in terms of core ED symptoms, remission rates and general psychopathology . Day proOutpatient or community care for EDs is recommended for most mild-to-moderate presentations, with the vast majority of evidence-based psychological therapies primarily provided in such settings. Implementation of an outpatient Maudsley FBT program had a substantial positive impact on patient outcomes in one Australian hospital following inpatient discharge . BetweenEvidence suggests that EDs can be effectively treated in the community, achieving outcomes on par with inpatient services , 56, 72.Generally, enteral  feeding is administered in inpatient settings, although recently outpatient services have been piloting tube feeding interventions to treat binge/purge symptoms in individuals with BN. Enteral feeding has the objective of breaking down the binge/purge cycle by exclusively NGT followed up with gradual reintroduction of meals, allowing patients to ‘withdraw’ . Daniel From the preliminary evidence available, engagement of an MDT team in the care of ED patients in outpatient settings compared with psychotherapy alone is associated with more appropriate referrals and treatment completion . A progrEvidence suggests that the availability of specialist ED services within local health care systems improves identification and care. Access to specialist care pathways in the United Kingdom (UK) led to increased detection of EDs at rates two to three times higher than in areas without a specialist ED clinic . LinkageThere are several barriers to optimal care within specialist ED services in Western countries as a result of both system and patient-related factors, such as long waiting lists for therapy due to high demand for services and stigma surrounding help seeking , 85, 86.Evidence relating to increased healthcare costs surrounding untreated EDs further underscores the importance of early identification and referral to specialist ED services. Significant healthcare utilisation and expenditure in prescription medication fills, outpatient and inpatient care for conditions associated with EDs are evident up to 7 years prior to BED diagnosis . Costs pThere is evidence supporting the value of a stepped-care model for improved outcomes and highly cost-effective ED treatment. Under the stepped-care model, patients first receive self-help, then can be “stepped up” to outpatient and then further to inpatient care if they do not respond to the preceding step , in their systematic review of ED treatment in primary care suggest that primary care clinicians could have a greater role in service delivery as part of a stepped care model - which begins with self-help and brief intervention - if a standardised protocol for EDs was developed . Bryan eThis RR synthesised the literature on models of care for EDs across a wide range of healthcare settings , drawing on different levels of evidence  and considering multi-disciplinary care along with emerging models of care . This RR was part of a series of reviews scoping the field of EDs , which iThe findings of this RR suggest the presence of specialist ED services in the system may help optimise patient outcomes , 98 by aDespite a substantial amount of literature relating to the effectiveness of outpatient settings on their own , 80–83, The findings also suggested a greater role for primary care clinicians in the assessment and diagnosis of EDs . GreaterEvidence addressing inpatient care suggests it may be used effectively to take care of especially medically unwell patients  with longer hospitalisation , 56, 67.Day programs may constitute a promising middle ground between outpatient and inpatient care, providing all the daytime support of inpatient care, but allowing the patient to stay connected to their community. Evidence from this review suggests it aids in WR , 37 and Evidence from this review suggests delays in treatment remain, from long waiting lists , 85, 86,Advances within the last decade have been made in developing both evidence-based treatments  and leadThis RR has several strengths, including its’ broad breadth, covering different healthcare settings, from outpatient to inpatient services, and synthesising evidence from a range of different study designs. It aimed to provide a current review  drawing on high quality data relating to models of care which would be applicable for policy making in Western contexts. Potentially relevant articles which were (a) conducted in non-Western countries, (b) with small sample sizes (except for studies examining ARFID and OSFED), (c) using qualitative methodologies and/or published in (d) non-peer-reviewed journals, (e) prior to 2009 were not included in the methodological approach and important evidence in these studies were outside the scope. Similarly, articles not published in the English language and/or unpublished data were excluded. Further, as this RR was conducted as part of a series of RRs, the search strategy was carried out in three major databases, using broad terms  due to time constraints. Hence, lack of nuance  means some articles may have been missed. Additionally, very few included studies focused on individuals with EDs other than AN and BN, this was particularly true for the evidence relating to inpatient care. Lastly, the search strategy includes a timeline which overlaps with the use of DSM-IV and DSM-5. DSM-5 made a number of changes to ED diagnoses  which meant more of those who would be classified as OSFED or UFED are given a formal ED diagnosis . HoweverFuture research should investigate cost-effective ways to increase treatment uptake and quality of care with minimal interruption to the daily lives of individuals with EDs, such as stepped care models and day programs. It is important that care is individualised and limits the burden on the individual and their family, where removing them from work/school or their community  can negaThis RR has identified key gaps in our care for EDs, including the integration of different healthcare services and the limited role of primary care clinicians in ED services. Promisingly, findings suggest specialist ED services can effectively treat EDs in both outpatient and day programs, with inpatient services reserved for particularly symptomatic patients. Further, for most patients, only relatively short inpatient hospitalisation is required, especially when paired with appropriate referrals to evidence-based outpatient services.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3