With the gradual demographic shift toward an aging and obese society, an increasing number of patients are suffering from bone and cartilage injuries. However, conventional therapies are hindered by the defects of materials, failing to adequately stimulate the necessary cellular response to promote sufficient cartilage regeneration, bone remodeling and osseointegration. In recent years, the rapid development of nanomedicine has initiated a revolution in orthopedics, especially in tissue engineering and regenerative medicine, due to their capacity to effectively stimulate cellular responses on a nanoscale with enhanced drug loading efficiency, targeted capability, increased mechanical properties and improved uptake rate, resulting in an improved therapeutic effect. Therefore, a comprehensive review of advancements in nanomedicine for bone and cartilage diseases is timely and beneficial. This review firstly summarized the wide range of existing nanotechnology applications in the medical field. The progressive development of nano delivery systems in nanomedicine, including nanoparticles and biomimetic techniques, which are lacking in the current literature, is further described. More importantly, we also highlighted the research advancements of nanomedicine in bone and cartilage repair using the latest preclinical and clinical examples, and further discussed the research directions of nano-therapies in future clinical practice. Nanomedicine combines nanoscience and medicine, aiming to understand the process and mechanism of biological activities from a microscopic level and apply nanotechnology to solve medical problems. Since most biomolecules exist and function at the nanoscale 1–100 nm), nanomaterials can impact cellular behaviours, which further regulates organ functions, playing a role in preventing and treating disease –100 nm, . To dateDue to the demographic shift to an aging and obese society, the risk of cartilage , 5 and bThe utilization of nanomedicine in cartilage and bone repair may offer improved therapeutic effects by replacing diseased osteochondral tissue with native biological tissue, potentially restoring joint function. For instance, nanoparticle-based targeted labelling technology can rapidly assess bone quality and identify early cartilage defects that cannot be easily detected using existing monitoring approaches . In addiThe commonly accepted definition of nanomaterials refers to “A natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in size range 1–100 nm” . Due to Nano-diagnostics typically involve using nanomaterials for labelling, tracing, detection, signal enhancement or conversion in living organisms, and detecting biologically active molecules to achieve rapid diagnosis and point⁃of⁃care testing (POCT) of early diseases. The main research directions include bio-barcode assay (BCA) , nanofluMolecular imaging is a popular direction in medical imaging research in recent years, aiming at the qualitative and quantitative study of biological processes at the cellular and molecular levels via imaging methods in the living state, thus enabling early, in vivo and targeted detection of diseases . To dateNanoscale drug carriers refer to nanoparticles that use polymers  or inorNovel biomimetic tissue repair nanomaterials and functionalized traditional materials have been developed for regenerative medicine Fig. A. For exThe ideal treatment should be the precise drug delivery to lesion sites with controlled-release so as to improve the pharmacokinetics and biodistribution of drugs and minimize the impact on non-target tissues. Nano drug delivery systems (NDDSs) are considered highly efficient targeted therapeutic carriers. Taking advantage of their high surface-to-volume ratio, drug loading capacity and stability, NDDSs can be distributed and retained in target tissues to exert therapeutic effect via the binding of ligands to specific receptors expressed on the surface of target cells, resulting in the reduction of the dose administered and alleviated side effects on the premise of ensuring drug efficacy, overcoming the limitations of conventional drug delivery methods , 34. OftNanoparticles (NPs) are microscopic particles manufactured from inorganic or organic materials up to 100 nm in size , which cDcore (the diameter of the gold core) > 15 nm of AuNPs have been proven to be comparatively nontoxic ..223].Poly (methyl methacrylate) (PMMA) is the basis of bone cement, which consists of radial particles of 1 ~ 3 μm in size. The incomplete dispersion of these particles forms agglomerates of 50–200 μm diameter, where large voids reduce the fracture toughness of PMMA. Studies have shown that replacing micrometre size radiopacifying particles with aluminium oxide particles resulted in a significant reduction in the volume of bone cement and a significant increase in tension properties, making PMMA nano-cements a promising alternative to conventional bone cement in orthopedic practice .Since it is difficult for a single type of material to adequately meet the specific needs of bone repair in complex environments, researchers have synthesized organic/inorganic, ceramic/polymer composites by combining several materials appropriately, taking into account the advantages and disadvantages of each component, in order to achieve optimal outcomes in practical applications.Studies have shown that synthetic composites that approximate the size and morphology of inorganic particles and organic phases of bone can achieve better osteoconductivity, evidenced by the improved osteoblast function in PLA/calcium metaphosphate composite developed by Jung et al., compared to PLA scaffolds alone . Besides2PO4 solution (2.5 wt.%) as the liquid phase of the cement, which exhibited significant enhancement in proliferation and adhesion of MG63 cells [CPC is a self-setting synthetic bone implant material composite of CaP, which can be surgically implanted into the human body or injected directly into the cavity of bone defects (the paste can self-harden in-situ to form HA with similar structure and composition to human hard tissues), with the characteristics of arbitrary shaping and good biocompatibility. Due to its pH-neutral composition and absence of polymers or plasticizers, it can be used in long-term contact with surrounding tissue without toxic reactions . However63 cells . Similar63 cells . In addi63 cells .Carbon nanostructures  have been widely studied and applied as reinforcing materials for orthopedic implants in recent years due to their generally ultra-high mechanical strength. For example, the physical properties of artificial bone were greatly enhanced by the addition of carbon NFs, which also improved the adhesion of osteoblasts, leading to an accelerated fusion between bone and the implant surface, with an improved cellular proliferation of osteoblasts as well as the synthesis of ALP, accumulating more ECM . In anotNano-coating modification of metallic substrates is an important current research direction in orthopedic implant materials. For example, researchers have successfully constructed a physiological transition layer that mimics the native bone tissue composition at the interface between the implants’ surface and surrounding host bone to enhance osteoblast function and promote bone regeneration, thereby improving the osseointegration . Nano-co2 nanotubes obtained by anodizing MWCNTs functionalized with -COOH groups and HA, which demonstrated an enhanced osteoblast response in terms of adhesion, viability and proliferation [3)/MWCNTs/CS nanocomposite coatings for surface modification of Ti6Al4V alloy via electroless deposition and reported improvement in bioactivity as well as corrosion resistance [2 composite coating on Ti alloy. Electrochemical studies showed a significant improvement in the corrosion resistance of the substrate after coating deposition [In order to synthesize coatings of implant materials with more desirable biological properties, an increasing number of researchers have turned their attention to the study of composite coatings. Prodana et al. developed a composite ceramic coating on Ti plates using TiOferation . In anotsistance . In the position . Shim etposition . In addiposition  as well position  had beenArticular cartilage is a dense connective tissue covering the joint surface composed of one single cell type (chondrocytes) with its ECM, which plays an essential role in cushioning and minimizing friction during joint movements . Due to The term “repair” in cartilage tissue engineering encompasses two separate concepts, one of which is a replacement, such as mosaicplasty , a common resurfacing technique that restores the partial function of osteochondral units by removing cylindrical plugs of healthy cartilage with subchondral bone and implanting them into the defective area like a mosaic pattern . This meAmong numerous biomaterials, hydrogel is considered an ideal material for cartilage repair due to its similar properties to ECM . When inMetal oxide NPs: Adedoyin et al. obtained an injectable nanocomposite hydrogel using inorganic iron oxide (Fe3O4) nanoparticles covalently combined with pNiPAAm and PAMAMs, which not only reduced the gelation time, but also responded to external magnetic fields to stimulate cellular activity and in situ regeneration [3O4, which exhibited excellent superparamagnetic properties, and sufficient mechanical strength with high biocompatibility. In vitro co-culture of this hydrogel with BMSCs under pulsed electromagnetic fields promoted the differentiation of BMSCs into chondrocytes, and in vivo experiments with rabbits also showed improved cartilage repair effects [neration . In anot effects .Carbon-based NPs: The addition of carbon-based nanoparticles can enhance the mechanical properties, lubrication and biocompatibility of nanocomposite hydrogels. Specifically, Cao et al. successfully fabricated GO homogeneously covered with HA particles via the dual-anchoring effect of PEG, and further encapsulated them into PVA hydrogels. The experimental results showed that HA with sharp edges of GO coating significantly improved the compressive deformation resistance and the lubrication property of the composite. More importantly, improved cell (mouse BMSCs) proliferation and cytocompatibility were observed, demonstrating the potential in cartilage replacement [lacement .Inorganic NPs: Inorganic clays are often used to prepare nanocomposite hydrogels with enhanced mechanical properties due to their layered structure and large specific surface area, facilitating the entry of polymer molecules into the nanoparticle lamellae to form a hybrid system with an intercalation structure. For example, Bonifacio et al. used mesoporous silica and sodium-calcium bentonite to modify the gellan gum-based hydrogels, which significantly improved their mechanical properties and showed excellent performance cytocompatibility as well as antibacterial properties in vitro and in vivo [ in vivo . In addi in vivo .Polymeric NPs: Liao et al. developed a novel injectable 3D alginate hydrogel using PCL − PEG − PCL (PCEC) microspheres as carriers for calcium gluconate  manufactured by electrospinning, self-assembly, and phase separation processes, which are implanted into cartilage defects to simulate the highly porous and pore-connected microenvironment of the human tissue, providing suitable mechanical support and physicochemical stimulation for the binding of seed cells along with growth factors. However, normally, it is difficult for a single material to mimic the components of natural ECM. Hence, most of the relevant research is on the composite application of several materials to meet the optimal conditions for cartilage regeneration, including:Favourable biocompatibility: Synthetic polymeric materials are widely used in cartilage tissue engineering scaffolds due to their superior controllability over physicochemical properties. That being said, the surface of synthetic polymers lacks certain receptor-specific binding bioactive molecules of natural materials, such as RGD sequences that are important for cell adhesion and growth migration, and functional differentiation [ntiation . Therefontiation . Chen etntiation .Fig. 7A Controllable degradation rate: The ideal degradability requires an excellent initial morphology of the scaffold after implantation, which is conductive to cell ingrowth, and rapid degradation of the material after 4 weeks to prevent stress shielding. During this process, the scaffold will be gradually replaced by the newly generated ECM until it is finally completely degraded and reabsorbed, maintaining the overall structural integrity [ntegrity . Materiantegrity .Suitable pore size and porosity: Studies have shown that proper pore size and porosity allow for cell migration and intercellular signalling, thus contributing to the maintenance of chondrocyte function [function . For insfunction . In anotfunction . Moreovefunction . Furtherfunction .Appropriate mechanical properties: Since articular cartilage is under constant loading, the mechanical mismatch between the implanted scaffolds and surrounding tissues may impede cartilage regeneration at the defective area. Therefore, in addition to pursuing the highest possible pore size and porosity, giving the scaffolds mechanical properties similar to those of native cartilage is another important task in cartilage tissue engineering. Li et al. fabricated a composite 3D scaffold with biomimetic structure and bioactivity using electrospun gelatin-PCL NFs and decellularized cartilage extracellular matrix (DCECM). The scaffold had an improved mechanical properties and structural stability as compared to DCECM scaffolds with enhanced chondrocyte proliferation rate. More importantly, in vitro and in vivo results showed the enhanced cartilage regeneration  that regulate cellular responses. Growth factors, such as BMPs, VEGF, and transforming growth factor-β (TGF-β), play a significant role in regulating chondrocyte metabolism and ECM formation . Howevere repair . In anote repair . In addie repair , which iAs previously mentioned, nano-scaffolds and -hydrogels have achieved some remarkable results as temporary extracellular matrices for therapeutic purposes, but the direct implantation of seed cells (MSCs) still involves challenges such as immune rejection  and pote2O2-induced apoptosis, resulting in enhanced proliferation and chondrogenesis [As intercellular and extracellular communicators, exosomes can directly activate or deactivate certain signalling in the target cells through binding to relevant receptors Fig. C. They cogenesis . Similarogenesis . In anotogenesis . In addiogenesis , miR-140ogenesis , where eIn addition to being used directly as biological agents for cartilage repair, or as bioactive coatings to functionalize the material surface for improved cell-implant interaction , 199, exThe development of nanomedicine has significantly changed the orthopedic surgery landscape. As outlined in this review, nanomedicine has been applied in different areas preclinically and clinically, including diagnosis, imaging, pharmaceutics and regenerative medicine Table . The varAlthough nanocomposite hydrogels have made a significant impact in tissue engineering, they are often deficient in macroscopic pores and complex microvascular systems, which impacts the transport of nutrients and discharge of metabolites, leading to a considerable loss in the viability and function of seeded cells. 3D porous nanostructured scaffolds with high porosity and suitable pore size overcome the limitation of hydrogels, but most of their internal pores are closed pore structures with limited pore connectivity, resulting in reduced cell infiltration, migration and tissue growth. The development of 3D printing and biofabrication has brought landmark advances in tissue engineering for bone and cartilage repair compared to traditional process methods . Based oDecellularized extracellular matrix (dECM) is a new direction in developing biomimetic biomaterials. Decellularization refers to the effective removal of DNA, RNA and other components from tissues or organs while protecting the composition and structural integrity of the natural ECM, thus achieving the goal of avoiding rejection reactions caused by cellular antigens in xenografts and allografts , 328. ThGene-based therapy would be the future for cartilage and bone repair as it targets the mechanisms associated with a specific disease, treating the causes rather than the symptoms. In order to achieve this goal, a safe and efficient delivery system is necessary. Despite the high transfection efficiency of viral vectors used by most gene-based therapies, its limitations, such as immunogenicity and cytotoxicity , signifiAlthough nanomaterial-based therapeutic products have been emerging in orthopedic fields such as drug delivery, biosensors and tissue-engineered scaffolds, the sample size of related studies is currently insufficient with a lack of long-term follow-up. Given that previous studies have focused on blending different materials to optimize the quality of implant-host integration, issues related to nanotoxicity and inflammatory responses cannot be ignored and require more preclinical studies for safety verification. In addition to continuously improving the match between nano-design and manufacturing processes , it is more important to strengthen the cooperation between clinicians and laboratory staff, in order to provide solutions for the key problems in the practical application of tissue-engineered structures, accelerating the advancement of nanomedicine from the bench to the operating room or even the bedside.


Death by suicide is a global epidemic with over 800 K suicidal deaths worlwide in 2012. Suicide is the 10th leading cause of death among Americans and more than 44 K people died by suicide in 2019 in the United States. Patients with chronic pain, including, but not limited to, those with substance use disorders, are particularly vulnerable. Chronic pain patients have twice the risk of death by suicide compared to those without pain, and 50% of chronic pain patients report that they have considered suicide at some point due to their pain. The kappa opioid system is implicated in negative mood states including dysphoria, depression, and anxiety, and recent evidence shows that chronic pain increases the function of this system in limbic brain regions important for affect and motivation. Additionally, dynorphin, the endogenous ligand that activates the kappa opioid receptor is increased in the caudate putamen of human suicide victims. A potential treatment for reducing suicidal ideation and suicidal attempts is buprenorphine. Buprenorphine, a partial mu opioid agonist with kappa opioid antagonist properties, reduced suicidal ideation in chronic pain patients with and without an opioid use disorder. This review will highlight the clinical and preclinical evidence to support the use of buprenorphine in mitigating pain-induced negative affective states and suicidal thoughts, where these effects are at least partially mediated via its kappa antagonist properties. Suicide is a pressing public health issue that accounts for more than 800,000 deaths per year globally . In the Recently, there has been a dramatic increase in the prevalence of suicidal ideation during the COVID-19 pandemic and subsequent mitigation activities, including social distancing and stay-at-home orders , 8. In JSuicidal ideation occurs in a subset of individuals with major depressive disorder (MDD); however, emerging evidence suggests that suicidal ideation may also represent a distinct behavioral disorder . For exaAcute and chronic alcohol use also play major roles in suicidal behavior. Approximately 26% of suicide decedents who were tested for alcohol had intoxicating blood alcohol levels (>0.08%) . AccordiFinally, suicidal ideation is highly prevalent in chronic pain patients -26, evenChronic pain has both sensory and emotional/affective components that, while distinct, share many of the same neurobiological substrates. Chronic pain often induces a persistent negative affective state, or “emotional pain,” likely as a result of neuroadaptations in the brain’s reward processing circuitry -41. ChroThe relationship between AUD and suicidality also suggests that suicidal ideation may be an expression of emotional pain. That AUD is often a key risk factor for suicidal behavior is likely due, at least in part, to alcohol-induced exacerbations in negative emotionality and alcohol-related negative consequences, particularly in interpersonal domains . Hyper-nThe emotional pain caused by the disruption or loss of social attachments also plays an important role in suicidality. In particular, suicidal ideation shares neurobiological and psychological features with separation distress—the innate, emotionally painful, dysphoric response of animals and humans to social separation or rejection , 50. ConResearch in the field of affective neuroscience suggests that separation distress represents one of the ancestral primary-process emotional systems (referred to as PANIC/GRIEF) , 59, 60.The neuroanatomy of the PANIC/GRIEF system overlaps with the brain’s system for processing physical pain , suggestSustained activation of the PANIC/GRIEF system can also lead to reduced activity in the brain reward SEEKING system , perhaps as a means to protect against sustained emotional pain by reducing the overall arousal of emotions , 59, 66.This two-stage model then suggests that the anhedonia of depression may reflect, in part, an emotional shutdown that follows the behavioral agitation of separation distress or other emotional pain, with these behavioral states correlating with underactivity of the SEEKING network and overactivity of the separation distress PANIC/GRIEF network, respectively. Of course, depression is a complex disorder that likely has multiple etiologies involving changes in many neural substrates. However, this model suggests one possible framework for understanding the relationship between suicidal ideation and depression. Sustained activation of the PANIC/GRIEF network may produce both a state of dysphoria that leads to suicidal ideation as well as, indirectly, a reduction in motivation (anhedonia) through subsequent downregulation of the reward SEEKING system . In thisUltimately, painful experiences  likely engage shared brain systems which produce negative affective states  and may subsequently disrupt downstream reward processing (anhedonia–implicated in depression), leading to a complex relationship between pain, separation/social distress, and motivation , 67, 68.Pain is a multidimensional experience comprised of sensory, cognitive, and emotional components. The sensory aspects of pain are relayed from peripheral nociceptors, which detect noxious sensory stimuli, along primary afferent neurons that have central terminals in the spinal cord . The secThe emotional and motivational aspects of pain  are carried to limbic structures such as the amygdala, hypothalamus, striatum, insula, and anterior cingulate cortex by the medial spinothalamic tract -74 Figu. A key sThe anterior cingulate has also been shown to be a critical brain region for the modulation of the subjective affective experience of pain . PatientEmotional pain also activates brain regions associated with physical pain including the PAG, insula, and anterior cingulate ; similarWhile a painful event serves an adaptive function and provides salience to a harmful stimulus that can support escape and avoidance learning, chronic pain can become pathological (serving no useful purpose). Although, it was recently proposed that this type of pain perhaps serves to provide hypervigilance . ChronicMuch of the same neurocircuitry described above is also engaged by separation distress, suggesting that the emotional pain elicited by separation distress is a result of the activation of circuits underlying physical pain. Specifically, the separation distress circuitry starts in the PAG and ascends through the dorsomedial thalamus, terminating in various basal forebrain regions including the anterior cingulate cortex , 59, 65 Reward and motivation, while often considered opponent processes to pain, are also processed within many of the same brain structures, in particular the mesolimbic system, which includes the VTA and nucleus accumbens . In neurTogether, the circuitry underlying pain, separation distress, and motivation provides a neuroanatomical substrate for the transition from physical or emotional pain to suicidality and possibly depression. Activity in pain/nociceptive circuitry  is correlated with the distress PANIC/GRIEF system, while activity in the mesolimbic circuit, particularly dopamine transmission in the nucleus accumbens, is correlated with the SEEKING system , 60, 66.The opioid system, which modulates pain, social distress, and reward circuitry, may be a promising target for the treatment of behavioral disorders caused by disruptions in this circuitry, including suicidal ideation. Opioid receptors belong to the G-protein coupled receptor family and are divided into four families: the mu (MOR), delta (DOR), kappa (KOR) and nociceptin (NOR). These receptors are activated by four classes of endogenous opioid peptides, beta-endorphin, dynorphin, enkephalin and nociceptin. MORs have a high affinity for beta-endorphin and enkephalins, but low affinity for dynorphin. Conversely, dynorphin primarily acts through the KOR. Here we focus on the role of the MOR and, particularly, the KOR, as both have been implicated in the mediation of suicidal ideation by opioid drugs.Opioid receptors are distributed throughout the central and peripheral nervous system and are present in many of the major structures involved in the pain circuitry, including the peripheral nociceptors, spinal cord, PAG, thalamus, anterior cingulate cortex, and other limbic regions . The MORWhile KOR and MOR expression widely overlaps throughout the brain, their activation produces opposing effects on mood . ActivatOpioids and their receptors can modulate both the sensory and emotional (bothersome) components of pain. For example, when injected into the dorsomedial thalamus (a key region for processing both the sensory and affective components of pain), the MOR agonist DAGO elevated rats’ sensory pain thresholds and induced a positive affective state, while the KOR agonist U50,488 reduced rats’ pain thresholds and induced a negative affective state . HoweverIn addition to their role in the sensory/affective components of pain, it is hypothesized that opioids constitute a major neurochemical underpinning of social bonding and isolation distress , 116. FoHigh expression levels of KOR have been also detected in brain areas responsible for reward and motivation, including the VTA and nucleus accumbens , 121 Fi. The abiStudies in rat brain slices show that KOR agonists  are capable of suppressing mesolimbic dopamine release via receptors expressed on dopamine neuronal terminals as well as neuronal cell bodies -125, whiActivation of KORs also contributes to the dopamine hypofunction observed in chronic pain states. Given that hypo-dopaminergic states contribute to chronic pain , 134 andThe role of KORs in dysfunctions of reward and motivation is particularly well-characterized with respect to AUD. KOR-mediated reductions in dopamine release in the nucleus accumbens have been hypothesized to mediate negative emotional states associated with alcohol withdrawal, particularly pain associated with acute alcohol withdrawal . At the The ability of opioids to modulate both sensory/affective pain circuits as well as reward/motivation circuits suggests these compounds have the capability to counteract multiple features of suicidality and depression. Opioids are able to produce dopamine-independent positive affective states through their influence on pain and social distress circuits, including areas such as the anterior cingulate cortex, PAG, and dorsomedial thalamus. Opioids can also counteract negative affective states by promoting increased motivational drive through their downstream influence on dopaminergic reward circuits, especially in the nucleus accumbens. Thus, since opioids can restore deficits in both pain and reward circuits, they may be particularly useful in treating suicidal ideation, as they would be able to blunt suicidality whether it was caused primarily by a disruption in dopaminergic motivational circuity or a disruption in non-dopaminergic pain/social distress circuits. Other treatments which primarily target reduced motivation (anhedonia) may not be effective in treating the subset of individuals experiencing suicidal ideation without a concomitant reduction in motivation .Given the above understanding of the opioid system, there has been a renewed interest in the use of opioid analgesics, particularly buprenorphine, for the treatment of suicidality. A retrospective 24-months study reported buprenorphine had the lowest incidence of suicide intent and deaths compared to other opioid analgesics . BuprenoBuprenorphine is an analgesic derived from oripavine that acts as a partial MOR agonist and KOR antagonist, as well as an antagonist at the DOR and an agonist at the NOR . BuprenoThe potential anti-suicidal effects of buprenorphine were first described in a case report of a 61-year-old woman suffering from treatment-resistant depression, chronic back pain, severe opioid use disorder, and ongoing suicidal ideation . While tBased on these case reports and anecdotal findings, clinical trials have begun to explore the anti-suicidal potential of buprenorphine. A multisite randomized double-blind placebo-controlled trial of ultra-low-dose  buprenorphine found that severely suicidal patients showed a reduction in Beck Scale for Suicidal Ideation (BSSI) scores after 2 and 4 weeks of treatment compared to patients that received placebo . AnotherOther studies have examined the effects of buprenorphine in combination with other drugs. A randomized double-blind placebo-controlled trial in adults with treatment-resistant depression showed that treatment with 2 mg/2 mg buprenorphine/samidorphan significantly improved scores on multiple depression measures compared to placebo controls . AntidepIn addition to the clinical findings described above, pre-clinical studies also support the potential anti-suicidal treatment effects of buprenorphine. While no behavioral assays for suicidal ideation exist for rodents, several behavioral assays have been validated to screen for depressive-like behaviors, including the forced swim test and the novelty-induced hypophagia test. The forced swim test is considered a measurement of behavioral despair  and is oIn mice, administration of buprenorphine produced significant reductions in forced swim test immobility (at doses ranging from 0.065–2 mg/kg) and reduced approach latencies in the novel environment of the novelty-induced hypophagia test (at a dose of 0.25 mg/kg) . In WistA better understanding of the specific pharmacological underpinnings of the anti-suicidal and anti-depressive effects of buprenorphine would be valuable as it could inform the development of even more targeted therapeutics which might avoid side effects, including abuse potential. As discussed previously, buprenorphine is both a partial agonist at the MOR and an antagonist at the KOR, but which receptor type is primarily responsible for the anti-suicidal and anti-depressive effects of the drug is uncertain. A review of preclinical studies can help to shed light on this question. In general, the data are conflicting, and both MOR partial agonist and KOR antagonist activity likely play a role in the anti-suicidal effects of buprenorphine. However, the data supporting the importance of KOR antagonism appear slightly more consistent (discussed in more detail below).Studies combining buprenorphine with opioid antagonists suggest that the MOR is not necessary for the behavioral effects of buprenorphine. In mice, the anti-depressive effects of buprenorphine described above (reduction in forced swim test immobility and reduced approach latency in the novelty-induced hypophagia test) were maintained when buprenorphine (1 mg/kg) was co-administered with the opioid antagonist naltrexone (1 mg/kg), suggesting that activation of MORs is not necessary for the expression of buprenorphine’s anti-depressive effects . Co-admi−/−) or KOR (Oprk1−/−), buprenorphine (0.25 mg/kg)-induced decreases in latency in the novelty-induced hypophagia test were blocked in Oprm1−/− but not Oprk1−/− mice [The use of selective knockout mice provides evidence that the behavioral effects of buprenorphine may be mediated by both MOR and KOR. In mice with genetic deletion of the MOR  , suggestWe can also examine the behavioral effects of other KOR and MOR drugs to further explore the potential role of opioid receptor subtype in the behavioral effects of buprenorphine. Since buprenorphine is an antagonist at the KOR, if activity at this receptor is primarily responsible for the anti-suicidal effects of buprenorphine, we would expect manipulations that increase activity at KOR to be pro-depressive while manipulations that decrease activity at KOR to be anti-depressive  threshold is a commonly used measure of dysphoria in rodents, and the KOR agonists U69,593 inorin A  have beeinorin A . Note thinorin A  and ratsinorin A , 181, aninorin A , a behavinorin A . Given tConversely, KOR antagonists tend to have the opposite effect, producing antidepressant effects in multiple behavioral assays. In particular, a number of studies indicate that KOR antagonists, including norBNI , 183-187MOR agonists have been shown to produce antidepressant-like effects, though their efficacy depends on the particular behavioral assay employed see . For exaThe effects of MOR antagonism on depressive-like behaviors are less conclusive see . The selOverall, it appears that the evidence for MOR activation underlying buprenorphine’s anti-suicidal effects is less convincing than the evidence for KOR antagonism underlying these effects. This conclusion is based primarily on: 1) the inability of MOR antagonists to block the anti-depressive and anti-suicidal effects of buprenorphine in humans , 165 andThis review has summarized the human and preclinical studies that support further investigation of the potential of buprenorphine treatment for reducing suicidal ideation. The unique pharmacology of buprenorphine that includes partial MOR agonism and KOR antagonism likely contributes to its potential therapeutic effects, where there is strong support for KOR antagonism in alleviating anhedonia and depression. Given the high rate of suicidal ideation and death by suicide in both chronic pain and substance use disorder patients, further research should focus on the development of novel KOR antagonists that do not possess the potential for abuse. Buprenorphine is a potent opioid analgesic (more potent than morphine), and while it is an effective treatment for opioid use disorder, it can be used illicitly where there is evidence of misuse, abuse and diversion . Thus, i


Substantial variation in the delivery of hip fracture care, and patient outcomes persists between hospitals, despite established UK national standards and guidelines. Patients’ outcomes are partly explained by patient-level risk factors, but it is hypothesised that organisational-level factors account for the persistence of unwarranted variation in outcomes. The mixed-methods REducing unwarranted variation in the Delivery of high qUality hip fraCture services in England and Wales (REDUCE) study, aims to determine key organisational factors to target to improve patient care.Quantitative analysis will assess the outcomes of patients treated at 172 hospitals in England and Wales (2016–2019) using National Hip Fracture Database data combined with English Hospital Episodes Statistics; Patient Episode Database for Wales; Civil Registration (deaths) and multiple organisational-level audits to characterise each service provider. Statistical analyses will identify which organisational factors explain variation in patient outcomes, and typify care pathways with high-quality consistent patient outcomes. Documentary analysis of 20 anonymised British Orthopaedic Association hospital-initiated peer-review reports, and qualitative interviews with staff from four diverse UK hospitals providing hip fracture care, will identify barriers and facilitators to care delivery. The COVID-19 pandemic has posed a major challenge to the resilience of services and interviews will explore strategies used to adapt and innovate. This system-wide understanding will inform the development, in partnership with key national stakeholders, of an ‘Implementation Toolkit’ to inform and improve commissioning and delivery of hip fracture services.This study was approved: quantitative study by London, City and East Research Ethics Committee (20/LO/0101); and qualitative study by Faculty of Health Sciences University of Bristol Research Ethics Committee (Ref: 108284), National Health Service (NHS) Health Research Authority (20/HRA/71) and each NHS Trust provided Research and Development approval. Findings will be disseminated through scientific conferences, peer-reviewed journals and online workshops. A mixed-methodology approach will aid identification of hospital-level organisational factors which explain adverse patient outcomes following hip fracture, and which are amenable to improvement across the UK.This study is novel in terms of its scale and the unique datasets used, which gives a rare opportunity to robustly assess a complex system of care and the impacts this system has on patients with hip fracture and National Health Service (NHS) budgets.Use of quantitative, economic and qualitative analysis will provide a system-wide understanding of the hip fracture care pathway, which will inform development of an Implementation Toolkit, in partnership with key national stakeholders, to improve future service design.While multiple organisational datasets exist relevant to patient care in NHS hospitals, linking this NHS activity to comprehensive social care data is not viable, hence, social care sequalae following hip fracture admission does not form part of this protocol.Currently the NHS is experiencing unprecedented pressures; the REducing unwarranted variation in the Delivery of high qUality hip fraCture services in England and Wales study will determine the most efficient management pathways for high cost patients, to improve patient outcomes and free NHS resources for use elsewhere.Each year in the UK more than 70 000 older adults sustain a fragility fracture of the hip.4Patients sustaining hip fractures almost invariably require an operation, but patient care has many complexities requiring contributions from various healthcare professionals at different time-points during an often-lengthy treatment journey. Many guidelines have been published trying to ensure all components of the care of patients sustaining hip fractures (hip fracture care) are provided consistently and to a high standard in all hospitals.Substantial variation exists in how well patients recover after a hip fracture. Across the 172 hospitals currently providing hip fracture care in England and Wales, 1 month after hip fracture the proportion of patients who have died varies from 2% to 14% between hospitals,It is important to understand how the set-up and organisation of healthcare services affects patient recovery and outcomes after hip fracture. These services can vary in many ways, for example, types and grade of clinical staff; capacity to perform prompt operations; access to suitable rehabilitation services. It is expected these factors will explain variation in quality of care, patient outcomes and associated health costs. Understanding these will enable us to inform changes in healthcare services to minimise avoidable variation in fracture care and improve the quality of care for all patients across the country.The 2020 COVID-19 pandemic has had an unprecedented impact on health service delivery across the NHS.The aim of this mixed-methods study is to determine the components of hospital service delivery of hip fracture care that predict patient outcomes post hip fracture, and the direct health costs attributable to these organisational factors. Furthermore, to understand factors that act as barriers and facilitators to the delivery of hip fracture care, including strategies that hospitals used to adapt and innovate hip fracture care delivery during the COVID-19 pandemic. Using these results, and working with key stakeholders, a toolkit will be developed, suitable for use by hospital managers, clinical leads and healthcare system leads across the country, to improve organisational delivery of high-quality hip fracture services. Understanding strategies hospitals used to reconfigure care during the COVID-19 pandemic will inform development of more resilient services in the future.Using a wide range of publicly available organisational-level service data, available at a hospital/trust provider level in England and Wales, including eight national audits and nine data series/ratings resources , data wiUsing routinely collected Hospital Episodes Statistics (HES) Admitted Patient Care (APC) data, that includes admissions to all English hospitals within the NHS , patients will be linked by NHS Digital, the national health and social care data provider, to Office for National Statistics (ONS) Civil Registrations (deaths) mortality data for the same period. Similarly, in Wales the NHS Wales Informatics Service will link patients with hip fractures in the Patient Episode Database for Wales (PEDW) to ONS mortality data. The resulting HES-ONS and PEDW-ONS patients’ data extracts will then be linked to data from the UK’s National Hip Fracture Database (NHFD) for the admission. The NHFD, active since 2007, is a clinically led web-based audit of hip fracture care and secondary fracture prevention in England, Wales and Northern Ireland, data collected have informed the Best Practice Tariff (BPT) for hip fracture care since 2010.20 21HES/PEDW provide information on patient demographics, admission, discharge, clinical diagnoses using International Classification of Diseases Tenth Revision (ICD-10) disease codes, and Classification of Interventions and Procedures version 4 codes.Hip fracture admissions will be identified using ICD-10 codes for fractured neck of femur (S72.0), pertrochanteric fracture (S72.1), subtrochanteric fracture (S72.2) and unspecified fracture of femur (S72.9). The study population will consist of index cases of hip fracture , among English or Welsh residents  aged 60 years or more, admitted to an English or Welsh hospital between 1 April 2016 and 31 March 2019.For each patient with an index hip fracture, all HES APC, outpatient clinic and emergency department (ED) attendance data in England, and similar PEDW data in Wales, will be analysed for the subsequent 12 months enabling post-fracture follow-up (thus the last follow-up will complete 31 March 2020). Patient outcome measures will include: (i) cumulative mortality at 30 days and 1 year, (ii) acute NHS ‘super-spell’ , (iii) return to original residence at discharge, (iv) emergency 30-day readmissions , (v) mobility at 120 days, (vi) return to original residence at 120 days, (vii) osteoporosis treatment to reduce future fracture risk, (viii) re-fracture/re-operation, (ix) the total number of days spent in hospital in the year following hip fracture, informing (x) total direct health costs attributable to hip fracture (see below).HES data reports Healthcare Resource Groups assigned to each finished consultant episode in a hospital spell via the Casemix Grouper Software (HRG4+).25Using a systematic approach, organisational factors will be identified which predict patient-level outcomes including associated health costs. Using a ‘top-down’ approach, defining a priori indicator groupings (domains), informed by NHFD BPT variables with stakeholder consensus, key indicators will be identified predicting patient outcomes. Clinicians will undertake expert panel review to select potential explanatory organisational-level variables. The flow diagram  illustraFurther expert-driven data reduction will involve examining the prevalence and correlation of selected organisational variables with each outcome, to finalise the dataset for multi-level models. Those variables selected for inclusion will be mapped to one or more domains of hip fracture care , nested within hospitals (level 2). Multilevel regression models will describe the association of organisational-level factors on patient-level outcomes, while adjusting for patient case-mix, and allow assessment of interactions between patient-level and organisational-level factors. Case-mix adjustment will be the same as that used in the NHFD clinical audit30Having identified the proportion of variance in a given patient-level outcome, not explained by patient-level factors , the between-hospital variability explained by fixed organisational effects will be quantified, that is, the proportion of between-hospital variance explained by the configuration of specific services. For each outcome, domains added sequentially to a multi-level model (after case-mix adjustment) will be fitted to identify those domains which have the greatest effect and predict patient-level outcomes. From the selected domains the most influential organisational variables will be identified.Patient costs will be adjusted for baseline costs  and patient case-mix as detailed earlier. Adjusted estimates of patient costs will be reported as aggregate costs and costs disaggregated by initial hospital superspell and readmissions/further NHS care. Different pathways of care following hip fracture will be identified by expert consensus agreement for comparative cost analyses.The multi-level model will be used to determine how health costs relate to organisational factors and patient outcomes, identifying organisational factors associated with highest/lowest costs. Cost profiles will be calculated for different hip fracture care pathway models, facilitating budget impact analyses . Costed scenarios will inform the Implementation Toolkit cost-benefit calculator.For the qualitative interviews four hospitals will be selected and approached. For English hospitals, BPT 2017–2019) and Key Performance Indicators (2018) will be collated, and 25 hospitals with the most and 25 with the least variable scores selected.7–2019 anA qualitative interview study will characterise the organisation of hip fracture services and identify barriers and facilitators to the implementation of key components of fracture care. In addition, strategies that hospitals used to adapt and innovate hip fracture care delivery, during the COVID-19 pandemic, along with barriers and facilitators to the reorganisation of services in 2020 will be ascertained. Four hospitals have been identified that encompass variation in a range of characteristics as listed above, aiming to identify varied service configurations.At the four participating hospitals, 1:1 in-depth interviews will be conducted with stakeholders involved in the organisation and delivery of hip fracture services, including orthogeriatricians, orthopaedic surgeons, anaesthetists, emergency medicine physicians, physiotherapists, occupational therapists, trauma nurses and discharge and service managers. Interviews will be carried out either remotely or in person (according to infection control constraints) with informed consent, including consent to audio-recording. An estimated 10–15 professionals will be interviewed at each hospital site, totalling around 40–60 professionals across the study. However, final sample size will be determined when data saturation is achieved; that is, when no new themes or subthemes are identified in the data.Interviews will be audio-recorded, transcribed and anonymised. Transcripts will be imported into NVivo qualitative software and analysed using an inductive thematic analysis to identify key themes and subthemes in the data.To complement the qualitative interviews and to understand the common themes and solutions (‘lessons learnt’) in relation to provision of hip fracture care, qualitative content analysis will be conducted of anonymised detailed hospital-initiated peer-review process (PRP) reports from 22 hospitals . PRP reports, produced by the BOA over the period 2013–2019, were delivered when UK hospital service leads requested a BOA ‘peer-review’ to improve their hip fracture service. Each PRP report includes interviews with a range of staff . PRP reports are structured encompassing appraisal of the full hip fracture care pathway: ED, orthopaedics, anaesthetics, theatre activity, orthogeriatrics, nursing, therapies, discharge planning, collection of NHFD audit data and governance structures. Reports list all areas of good practice and highlight issues where improvements are achievable. PRP reports include a series of recommendations made by the multi-disciplinary assessment team with numerated action points. Reports will be imported into NVivo qualitative analysis software and will be analysed thematically to identify barriers and facilitators to implementation of quality hip fracture services.In 2015 the Royal  Osteoporosis Society (ROS), developed a Fracture Liaison Service (FLS) Toolkit to aid FLS commissioning of new or improved services.Working with the ROS, the BOA and other stakeholders, a Hip Fracture Implementation Toolkit will be codeveloped, focusing on inpatient hip fracture services, prioritising organisational factors identified from our quantitative and qualitative results which contribute to poor and/or highly variable patient outcomes post hip fracture. All acute NHS hospitals currently have a hip fracture care pathway; hence, the toolkit will include a step-by-step guide to improve and implement changes to current services. It will be made available online and provide a series of instructions and guides  for managers, clinical leads and healthcare system leads to use to improve their hospital hip fracture services, encompassing service redesign/restructuring, organisational cultural change, and approaches to improve efficient use of limited healthcare resources. Tools will include a service improvement guide, business case resources, a cost calculator and a project plan.This study has been developed in collaboration with the University of Bristol Musculoskeletal Research Unit (MRU) PPI group comprising members who have had/are having treatment for osteoporosis and/or fractures, who meet  every 3 months to input into the design and conduct of MRU research projects. They have guided development of the project proposal, informing prioritisation of research questions, drafting plain English text, changing language and wording within study texts; they have informed methods adaptation in response to COVID-19 in 2020. The group will provide ongoing support throughout the study, addressing (i) key patient and carer questions and priorities, (ii) the interpretation and relevance of results and (iii) communication of findings. ‘Taking the research’ to patients in the involvement group rather than asking patients to attend research management meetings has improved engagement and fosters strong collaboration and respect.The quantitative study has research approvals from NHS Health Research Authority—London City and East Research Ethics Committee ; Royal College of Physicians (RCP) Falls and Fragility Fracture Audit Programme (FFFAP)  and Healthcare Quality Improvement Partnership approval ; NHS Wales Informatics Service (NWIS)  and an NHS Digital Data Sharing Agreement . The qualitative study has been approved for conduct by the Faculty of Health Sciences University of Bristol Research Ethics Committee  and by the NHS Health Research Authority . Each NHS Trust has provided Research and Development approval.Findings will be disseminated through scientific conferences, peer-reviewed publications and online implementation workshops. Results will be fed back to the scientific committee with oversight of the NHFD as well as the BOA. Reports will be provided to each hospital in England and Wales summarising findings, and the PPI group will be involved in all stages of dissemination. Working with the ROS, dissemination materials will be developed for its membership network (n=20 000). The Implementation Toolkit will be hosted and made freely available by the ROS website.Through the use of mixed methodology, this study will determine the components of hospital service delivery which account for poor patient outcomes post hip fracture and identify which service configurations are most efficient and successful. Quantitative analyses will allow us to distinguish patient outcomes explained by the health of the patient themselves, versus outcomes attributable to the hospital services which they encounter. Domains of hip fracture care which are most critical for a wide range of patient outcomes over 12 months, will be identified. The direct health costs ascribed to each patient in the year after hip fracture, accounting for costs in the year prior to fracture, will be calculated. Thus, hospital expenditure attributable to different components of hip fracture service delivery will be calculated. These financial calculations will inform cost calculators in the Implementation Toolkit. The Toolkit will be a novel, freely available online resource for managers, clinical leads and healthcare system leads to use to improve their hip fracture service.The qualitative analysis will aid understanding of the organisational processes that help or hinder the implementation of key components of hip fracture services. In addition, it will identify strategies that hospitals have used to adapt and innovate hip fracture care delivery during the COVID-19 pandemic. Knowledge gained will inform toolkit development, aiming to assist services in overcoming organisational barriers when designing and implementing sustainable high-quality fracture services, and improve patient care. Understanding strategies hospitals used to reconfigure care during the COVID-19 pandemic will provide learning towards the development of more robust and resilient hip fracture services in the future. This information is likely to be transferrable to other services.In conclusion, a system-wide understanding of sources of variation in hip fracture care delivery and the effects on patient outcomes will inform service-level interventions to reduce unwarranted variation, maximise health equity and ultimately improve patient experience. The study aims to show effective hip fracture care is more efficient, realising cost-savings in hospital bed-days potentially re-directable to other services. This project is novel in terms of its scale and the unique datasets which gives us a rare opportunity to robustly assess what is a complex system of care and the very real impacts this system has on patients. Findings will inform future commissioning/service planning priorities for hip fracture care, inform national review processes for hip fracture services and, together with a new online toolkit, this programme aims to minimise avoidable variation in hip fracture care and improve the quality of care for patients across the UK.


Hantavirus can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome (HPS) in America, with high mortality and unknown mechanisms. Innate immunity is the host’s first-line defense to bridge the acquired immunity against viral infections. However, hantavirus has evolved various strategies in both molecular and cellular aspects to evade the host’s natural immune surveillance. The Interferon-I (IFN-I) signaling pathway, a central link of host defense, induces various antiviral proteins to control the infection. This paper summarizes the molecular mechanisms of hantavirus evasion mechanisms of the IFN signaling pathway and cellular processes such as regulated cell death and cell stress. Besides, hantavirus could also evade immune surveillance evasion through cellular mechanisms, such as upregulating immune checkpoint molecules interfering with viral infections. Understanding hantavirus’s antiviral immune evasion mechanisms will deepen our understanding of its pathogenesis and help us develop more effective methods to control and eliminate hantavirus. In recent years, the repeated outbreaks of diseases caused by hantavirus have seriously threatened human health. Hantavirus syndrome is caused by hantaviruses infection and is a type of emerging zoonosis. Hantavirus has been found in Europe, Asia, North America, and parts of South America. It is a pathogen sometimes transmitted from animals to humans. Through gene sequence alignment and serodiagnosis, hantaviruses are categorized into more than 20 types; some have different geographical distributions and unique rodent hosts. Old World Hantavirus, including Hantaan virus (HTNV), Dobrava virus (DOBV), Puumala virus (PUUV), and Seoul virus (SEOV), mainly targets human kidneys, causing hemorrhagic fever with renal syndrome (HFRS). New World Hantavirus, including Sin Nombre virus (SNV) and Andes virus (ANDV), mainly targets the lungs, causing hantavirus cardiopulmonary syndrome (HCPS). However, more and more studies have shown that many clinical manifestations overlap between HFRS and HCP . HantaviHantavirus is in the Bunyaviridae family. + T cells in patients at the acute phase of severe HFRS harbored HTNV nucleocapsid protein, and then confirmed that primary human CD8+ T cells were not only permissive to HTNV infection in vitro but also supported the complete viral replication cycle using electoral microscopy. The study revealed a cross-talk between virus and host factors and suggested some observed changes related to innate immune response. Exemplified by the current COIVD-19 pandemic, zoonotic infections can cause havoc to human society. We reasoned that lessons learned from studying a specific zoonotic viral infection, hantavirus infection, can be helpful in the understanding of virus-host interaction in general.The incubation period of HFRS is approximately 12–16days; however, this can vary from 5 to 42days. Typical HFRS clinical courses include five phases: febrile, hypotensive, oliguric, diuretic, and convalescent. Stages may occasionally overlap . AlthougThe innate immune system, characterized by interferon (IFN) responses and innate immunocyte activation, provides the first line of defense against hantavirus infection. IFN signaling is activated by different mechanisms. It has been demonstrated that the virus RNA rather than the virion proteins acts as pathogen-associated molecular patterns (PAMPs) to trigger innate immune activation during hantavirus infection . In the −/− mice can show symptoms similar to patients characterized by thrombocytopenia, renal tubular dilatation, and hemorrhage, which can be a potential disease research model. Besides the classical pathogen recognition receptors (PRRs), long noncoding RNAs (lncRNAs), and miRNAs also regulate innate immunity. Nucleotide-binding oligomerization domain-like receptors (NLRs) were also reported to be involved in anti-hantavirus infection. Virus-induced interferon expression is not only a critical part of the innate cellular immune response but also the first defense against virus invasion, thus limiting viral replication . StudiesIn contrast to pathogenic hantaviruses, the non-pathogenic hantaviruses-Prospect Hill (PHV) elicits robust interferon response by inducing IRF-3 activation early after infection within human endothelial cells simultaneously. It directs high-level ISG56 and MxA compared with NY-1V or HTNV, and the degree of STAT-1/2 phosphorylation in PHV-infected cells was considerably higher than that in ANDV , which aHantavirus escapes the immune response by regulating cell death, mainly including autophagy, apoptosis, and pyroptosis. Cells and organisms can utilize autophagy to remove damaged organelles, degrade toxic proteins, and achieve bioenergetic materials recycling, which is necessary for survival . With coThere are accumulating studies showing that hantavirus infection inhibits apoptosis in the infected cell through extrinsic or intrinsic pathways to support viral replication and survival. For example, Jonas Klingström et al. demonstrated that six different orthohantaviruses all showed an inhibitory effect of apoptosis and function of cytotoxicity of lymphocyte on infected cells, and the NP of different orthohantaviruses can inhibit granzyme B and caspase-3 activity . In addiHowever, some researches showed that hantaviruses could also induce apoptosis in some cell lines. Whether induction of apoptosis is for virus evasion of host anti-viral effect is still inconclusive. For example, cultured Vero E6 cells exhibited characteristic features of apoptosis, including condensation and segmentation of nuclei and internucleosomal cleavage of nuclear DNA when infected by the HTNV or the PHV . HantaviOnly one study has reported pyroptosis associated with hemorrhagic fever disease, but that was in Zebrafish Larvae. Using zebrafish larvae as a viral hemorrhagic diseases model, The ability of the virus to cause cell death is directly related to its pathogenicity. Studying whether and how cells die after virus infection is important for us understanding the interaction between virus and cells and host immunity and providing unique insights for potential therapeutic intervention. In 2019, Kanneganti et al. proposed the concept of “PANoptosis.” PANoptosis is an interplay of three different cell death pathways – pyroptosis, apoptosis, and necroptosis. When pathogens or other blockers destroy one or more programmed death pathways, PANoptosis provides an alternative cell death defense mechanism for the host to coordinate adaptive immune responses to promote pathogen elimination . In turnThe link between miRNAs and viruses has been shown in recent studies. miRNA released from virus target cells is reported to regulate virus infection and replication. Studies have found that HTNV infection and HTNV NP/GP can promote the production of miR-146a in human umbilical vein endothelial cells (HUVECs), which can negatively regulate the NF-κB pathway. Therefore, using miR-146a mimic could reduce the expression of pro-inflammatory cytokines, thus escaping the host immune response. It was also discovered that viral proteins (NP/GP) could increase the transcriptional activity of the miR-146a promoter . Latest Virus infection could induce cell stress in both target cells and lymphocytes. However, whether the hantavirus would benefit from cells is still controversial. It might be relevant to different cell models. The study confirmed that TULV infection caused ER stress, which mediated the death program in Vero E6 cells . They th+T cells activation is bypassing the checkpoint inhibition. However, they did not test the cytokines production and cell killing ability of the activated T cells in their study. The outcome of their battle needs to be further determined.The battle between viruses and host cells is complex and fierce. This review summarizes the molecular and cellular mechanisms on how hantavirus engages several strategies to evade innate immune responses, as illustrated in Although the host cells defeat the hantavirus finally, in most cases, the hantaviruses struggled their way to survive. In our perspective, these strategies used to regulate hantavirus immune response negatively could also help maintain a balance between immune activation and inhibition. Further research focusing on various immune responses induced by hantavirus infection will enhance our understanding of hantavirus pathogenesis and develop more effective methods to control infection and fine-tune the activation, strength, and duration of the antiviral immunity.YZ, YW, ZY, WS, and RM wrote the manuscript. MH and TH drew a diagram. RL, YZ, and XW edited, reviewed, and approved the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation Grants  and Key Research and Development Project of Shaanxi Province (No. 2019ZDLSF02-03).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The influence of social media among adolescent peer groups can be a powerful change agent.Our scoping review aimed to elucidate the ways in which social media use among adolescent peers influences eating behaviors.A scoping review of the literature of articles published from journal inception to 2019 was performed by searching PubMed , Embase, CINAHL, PsycINFO, Web of Science, and other databases. The review was conducted in three steps: (1) identification of the research question and clarification of criteria using the population, intervention, comparison, and outcome (PICO) framework; (2) selection of articles from the literature using the PRISMA  guidelines; and (3) charting and summarizing information from selected articles. PubMed’s Medical Subject Headings (MeSH) and Embase’s Emtree subject headings were reviewed along with specific keywords to construct a comprehensive search strategy. Subject headings and keywords were based on adolescent age groups, social media platforms, and eating behaviors. After screening 1387 peer-reviewed articles, 37 articles were assessed for eligibility. Participant age, gender, study location, social media channels utilized, user volume, and content themes related to findings were extracted from the articles.Six articles met the final inclusion criteria. A final sample size of 1225 adolescents (aged 10 to 19 years) from the United States, the United Kingdom, Sweden, Norway, Denmark, Portugal, Brazil, and Australia were included in controlled and qualitative studies. Instagram and Facebook were among the most popular social media platforms that influenced healthful eating behaviors  as well as unhealthful eating behaviors related to fast food advertising. Online forums served as accessible channels for eating disorder relapse prevention among youth. Social media influence converged around four central themes: (1) visual appeal, (2) content dissemination, (3) socialized digital connections, and (4) adolescent marketer influencers.Adolescent peer influence in social media environments spans the spectrum of healthy eating  to eating disorders . Strategic network-driven approaches should be considered for engaging adolescents in the promotion of positive dietary behaviors. Adolescent peer groups have been recognized to influence individuals’ health behaviors, including diet . During Six Degrees—short for Six Degrees of Separation—and it launched in 1997. In 2018, YouTube, Instagram, and Snapchat were identified as the most popular online platforms utilized by teens 13 to 17 years of age [Social media has been defined as any social networking site that enables interactive, user-generated content that allows sharing of images, ideas, videos, music, or commentary on internet forums , blogs and microblogs , and photograph- or video-hosting platforms  . Individs of age . User-geviral among peers on social media platforms—has been recognized as an effective way to promote health behaviors [r=–0.065) and was strongly correlated with fast food and junk food intake (r<0.200) [Social media is an effective channel for engaging adolescents , a targeehaviors -15. Behaehaviors -18. Exter<0.200) . In a rer<0.200) , an examA social network analysis of adult, in-person peer relationship influences indicated that maladaptive eating behaviors  may be influenced by friendships . Social Social media platforms  and mobile gaming nutrition-intervention apps  demonstrate utility among young adult populations to raise awareness, increase knowledge, influence intrinsic beliefs, and motivate attitudes . Social The following databases were searched in October 2017 and updated in October 2019: PubMed , AgeLine, BIOSIS Citation Index, CINAHL, the Cochrane Library, Embase, ERIC (Education Resources Information Center), Food Science and Technology Abstracts, Google Scholar, Inspec, PubMed Central, PsycINFO, SciELO (Scientific Electronic Library Online), and Web of Science. PubMed’s Medical Subject Headings (MeSH) and Embase’s Emtree subject headings were reviewed along with specific keywords to construct a comprehensive search strategy. Grey literature was searched for in The New York Academy of Medicine Grey Literature Report and the OAIster database from the OCLC (Online Computer Library Center). An extensive electronic journal hand search was conducted in the following journals: American Journal of Health Promotion, American Journal of Preventive Medicine, Appetite, Childhood Obesity, Eating Behavior, Ethnicity & Disease, Ethnicity & Health, International Journal of Eating Disorders, International Journal of Obesity (London), Journal of the American Dietetic Association, Pediatrics, Obesity (Silver Spring), and Public Health Nutrition. In consultation with the first author (AC), a clinical librarian (DV) trained in systematic literature reviews conducted the literature search and managed the information tools. The project was conducted in accordance with the PRISMA  guidelines . A comprInclusion criteria for articles to be included in the review were as follows: study sample included adolescents 10 to 19 years of age; study examined a social media app; study had a cross-sectional, qualitative, observational, and experimental design; study had a social media component; study examined adolescent peer communications in a social media environment; and study examined eating behaviors. Studies were required to be written in English and were published from journal inception to October 2019. Conversely, studies related to the impact of social media on body image, related to gastric bypass, or conducted in animal models were excluded. EndNote X9  was used to manage the bibliographic data. All references were downloaded to Google Sheets for screening. Full texts were retrieved and a Google Form was created for data extraction.Two independent researchers (NT and AS) screened the articles, assessed them for eligibility, and extracted the data from the search results. The extracted data were exported to Microsoft Excel 2016 for data analysis. Specifically, extracted data included author names; year of publication; country of study; study time frame; participant ages and genders; total number of participants; total number of user accounts; racial and ethnic groups, including percentage or whole number by group; study design; type of social media; behavior influence on food; and primary study outcomes measured. Reviewer agreement was reached through discussion with the senior author and review of the abstracts. Reviews of the study titles, abstracts, and full text, where needed, were completed to ensure agreement with study inclusion parameters to confirm eligibility. Tiebreakers were decided by DV.A total of 1225 adolescents ranging in age from 10 to 19 years who participated in studies across the United States, the United Kingdom, Sweden, Norway, Denmark, Portugal, Brazil, and Australia were represented in the sample. Social media platforms included Facebook and Facebook Messenger, YouTube, Instagram, Twitter, self-made blogs, school websites, and researcher-moderated forums. Each study examined how youth utilized such social media platforms to communicate ideas regarding food and diet.A total of 2074 articles were identified through electronic databases and manual hand searching of articles from systematic review reference lists. After removing duplicates, 1412 articles remained and were evaluated according to our inclusion criteria. Of the 32 full-text articles that were reviewed further, 26 did not meet the inclusion criteria and were removed. A total of six studies met the full inclusion criteria and were included in the final sample . Table 1Instagram and Facebook were among the most popular social media platforms that influenced healthful eating behaviors  as well as unhealthful eating behaviors related to fast food advertising. Online forums served as accessible channels for eating disorder relapse prevention among youth. However, self-made blogs on anorexia also promoted content about self-harming behavior in support of the eating disorder.Both positive and negative influences were found in eating behavior content among adolescents. Holmberg et al ,27 were marketer influencers. Social media not only served as a communication channel to a target cohort but also allowed for interaction through a platform that allowed for user autonomy on a specific topic.Thematically, results of the six studies included in the scoping review revealed several core themes related to engagement and dissemination of food-related content in a social media environment among adolescent users across eight developed countries. Social media influence converged around four central themes: (1) visual appeal, (2) content dissemination, (3) socialized digital connections, and (4) adolescent First, communicating eye-catching visual imagery of food, fitness, and body ideals among adolescent peers played a primary role of influence in several modalities. Videos and pictures allow for creative design feature elements that may increase engagement. Entertaining videos with appealing graphics, relatable scenarios, and music were employed effectively in Quick et al’s development of food safety videos. These videos increased food safety practices  among 332 preadolescent peer groups in an experimental design study within the United States . Similarlikes or other affirmative visual icons, such as hearts and smiley emojis, connote positive agreement and affirm approval of what is depicted by a statement or image. Food brands with positive associations among peers that signified social status and generated likes and positive comments were viewed as favorable among teens in Sweden. In a qualitative study with Swedish teens, one 14-year-old participant described her reasoning for sharing a Starbucks image as follows: “Even if one has never had a Starbucks beverage or visited the place, one still loves it, because one knows that everyone else loves it” [Similarly, oves it” .Peer group reinforcers may influence in both directions of the pendulum. Findings of semistructured interviews with 20 Swedish adolescent boys and girls enrolled in a pediatric obesity clinic revealed that they avoided posting unhealthy “fattening” foods in fear of this behavior being viewed as unacceptable from their peers with the potential to elicit criticism and bullying . Postingvirality or viral marketing of a topic faster than a formal broadcasting channel, indicating the speed of dissemination by sharing unique, entertaining messages on one’s pre-existing social network [Second, posting images and videos with friends allows for quick dissemination of health-related ideas, products, and practices. Social media has the ability to be circulated worldwide instantly. Rapid dissemination allows for contagion  network . Quick cviral messages may influence person-to-person well-being. Social media dissemination of harmful ideas may have negative consequences on adolescent mental health, thereby influencing nonpathological eating disorders. Social media contagion passed between individuals may have mental health implications contributing to unique social norms that affect anxiety levels due to viral messaging of negative eating behaviors.The emotion conveyed behind Third, digital platforms facilitate peer-to-peer interactions in ways that are quicker and more convenient than traditional in-person support networks, potentially influencing peer social norms. Social media interactions occur at a speed, engagement, and influence level beyond in-person communication. Their reach and scale could effectively influence adolescent beliefs, attitudes, and norms around eating behaviors at a broad scale. Digital communities have been leveraged by the food industry as a marketing tool to advertise directly to consumers. Thaichon and Quach  reportedSocialization of digital connections builds online community relationships that connect individuals based on shared experiences, including eating behaviors. Social media digital communities have had positive and negative effects on eating disorder behaviors among adolescents. Castro and Osório  were ablImages shared by adolescents with one another may be more influential than commercial advertising. Adolescent user-generated food content on social media was presented and received differently than food advertisements, but still mimicked that of food advertisers. Holmberg et al  examinedThematic review of the selected articles also revealed a mixed pattern of effect of peer influence on eating behavior of adolescents in social media environments. Social media channels were found to be used as social support for both positive and negative eating patterns. Peer-to-peer support for overweight or obese female adolescents who used Facebook Messenger increased their positive perception about social support and, thus, their online social interactions compared to a group that only received large-group face-to-face support . PositivThe literature on peer-enhanced social media interventions for eating behaviors is in its nascent stages. This scoping review aims to fill the gap in the literature and to review the evidence on the influence of peer-to-peer enhanced social media environments on eating behaviors among adolescent youth aged 10 to 19 years. Self-reported, user-generated eating behavior content on social media, supplanted with image recognition, food diaries, nutrient-intake mobile apps, or data synced to wearable devices, such as cameras embedded in eyeglasses, allows for passive data collection with minimal user burden; this data could be integrated into social media in order to build medical evidence to support decision making. Our paper demonstrates that peer social media influence on dietary behaviors warrants a robust amount of additional work to add to the body of scientific medical evidence in the field.likes among user networks in social media environments, may represent reinforcement of positive—or any valence—nutrition behaviors as positive, well-liked behaviors [Holmberg and colleagues  reportedehaviors .Commercial advertising on Facebook and Twitter, as described by Thaichon and Quach , may detPeer influence via social media could be an effective channel to engage this typically hard-to-reach population on health topics, including health behaviors. Social media networks were a consistent setting for engaging adolescents with healthy eating messages . Visual Facebook was the most common social media network reported, despite the rising popularity of Instagram and Snapchat over Facebook among adolescents . Only onjunk food posts on Instagram and Facebook [Healthy eating posts may reflect an aspirational lifestyle change among people in the contemplation phase toward healthy eating. Kinard  and HolmFacebook . SimilarFacebook  commenteAs social norms are modified in a digital milieu, cautionary monitoring of peer pressures may be needed. Social media peer pressures may affect body image ideals  that couMultipronged interventions with in-person and social media components have reported successful weight loss among participants  and an iNutrition information may raise awareness and promote nutrition literacy when content is verified. Mixed messages in the media on the healthfulness of certain foods may be misleading to the public . AdditioSocial media may influence poor eating habits and maladaptive eating behaviors. Thaichon and Quach  reportedUnfortunately, these studies do not help in understanding the role of social media influence or impact in real-world dietary behavior change in adolescent peer groups. Measurements of actual behavior change need to be studied in conjunction with social media marketing campaigns . Hawkins et al  reportedFuture research should emphasize methodological rigor to elucidate peer influence on dietary behavior change. An extensive amount of research is needed in the field, including objective measures of actual dietary intake with social media interventions and social network analysis of peer influence change agents on food behavior outcomes. In a pilot study that examined whether promoting red peppers via a social media influencer on Instagram would increase actual vegetable intake among adolescents in the Netherlands, no effect was found on users’ actual dietary intake . AdditioAdditionally, fact checking of user-generated content and use of credible dietary sources on social media may be questionable. Content verification of nutrition information  may alsoFuture research may also include Snapchat and other novel platforms that are now pervasively used by youth . TikTok Racial and ethnic youth of color are underrepresented in studies of this kind. Only Kulik et al, who conducted a study in the United States, included minority youth; in their study of Facebook as a complement to an in-person weight loss intervention, 20% of the sample was African American and 21% were participants from other groups of color . Since nRacial and ethnic health disparities experienced by people of color give rise to a heightened need for targeted healthful marketing via social media channels to engage youth. Racial and ethnic minority youth are heavily targeted for fast food marketing ,50, and Future research should evaluate the role of social media engagement with peer influencer change agents in dietary behavior change interventions. The pervasiveness of social media usage among adolescents calls attention to a communication channel that cannot be ignored. Moreover, the cell phone technology that allows touchscreen access to social media may enhance the capacity of peer influencer change agents that could be more powerful than prior print or television media. In the social media realm, evidence from social network analysis indicates that peer influencers are effective health behavior change agents based on leadership styles by peers, social network connectedness, and communication patterns between the peer influencer change agent and end recipient . Even prSocial media offers the potential of a hand-held change agent. Social media use on cell phones has become a global mainstay in contemporary culture, particularly for adolescents. Adolescent youth can serve as digital beacons of influence on health topics, including eating behaviors. Drawing from influencer marketing strategies in the digital landscape, tailored for culture and audience, adolescents could have a significant influence on the health behaviors of their peers. Health promotion initiatives to influence adolescent youth should consider the integration of social media channels.