Joint contracture is reduced by intra-articular implantation of rosiglitazone-loaded hydrogels in a rabbit model of arthrofibrosis. Because fibrosis is caused by an imbalance in cytokine production activated by high levels of TNF-α, IL-1,139 TGF-β and other mediators an effective therapeutic approach may involve regulating cytokines and mediators to favour resolution. Basu RK, et al. Kendall RT, Feghali-Bostwick CA. Yeranosian MG, Petrigliano FA, Terrell RD, Wang JC, McAllister DR. Marks PH, Donaldson ML. Halofuginone ameliorates inflammation in severe acute hepatitis B virus (HBV)-infected SD rats through AMPK activation. The https:// ensures that you are connecting to the a Side view cross-section showing a healthy knee. Such biomarkers will be essential for the development and testing of therapies.89 Ideally tests should be minimally invasive, for example, serum parameters and imaging, and applicable before surgery and during treatment to follow progress.90. It promotes SMAD 2 phosphorylation and expression of α-SMA, collagen type 1, MMP-2 and TIMP-1.200 The lower pH created by increased levels of lactic acid may be important in activating TGF-β and myofibroblasts.201 Furthermore, fibrotic tissue has reduced vascularity, resulting in permanently hypoxic tissues and another positive feedback cycle where lactic acid and fibrotic mediators are continuously expressed.198,201, Many of the effects of hypoxia are driven by hypoxia-inducible factor-1 (HIF-1), a protein that is a key regulator of genes in hypoxic tissue.202,203 It is upregulated and stabilised in response to ROS179 and in tissue with low oxygen levels200 and is important in both normal wound healing and in fibrosis.198 HIF-1 increases SMAD3 signalling and thereby TGF-β signalling,204 and upregulates connective tissue growth factor198 and genes involved in ECM deposition.205 Inhibiting HIF-1 inhibits myofibroblast differentiation201 and reduces transcription of collagen type 1.203,206 HIF-1 is known to be upregulated in cardiac fibrosis202 and contributes to the progression of liver disease to liver fibrosis.207. Inclusion in an NLM database does not imply endorsement of, or agreement with, Kisseleva T, et al. Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines. Early intervention to prevent fibrosis is likely to be important,14 halting the process before extensive epigenetic modifications occur and a significant amount of ECM has formed and become strongly cross-linked. Chu SJ, Zhang ZH, Wang M, Xu HF. Pathological mechanisms and therapeutic outlooks for arthrofibrosis Another target for early intervention is substance P. Recent research has found that knockout of the receptor for substance P attenuates liver fibrosis in animal models,213,254 while other animal studies found that a receptor antagonist for substance P downregulated some pro-fibrotic genes in joints214 and reduced fibrosis and inflammation of the colon.255 Substance P antagonists are routinely used to alleviate nausea.214, Although anti-inflammatory medications do not halt fibrosis of organs,107 they are nonetheless the only currently prescribed medications for treating arthrofibrosis. Levi-Schaffer F, Nagler A, Slavin S, Knopov V, Pines M. Inhibition of collagen synthesis and changes in skin morphology in murine graft-versus-host disease and tight skin mice: effect of halofuginone. Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. Induces production of SMPs. Qiu W, et al. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Early arthrofibrosis research found increased collagen accumulation in the IFP,230,231 with later studies reporting high numbers of myofibroblasts positive for the presence of α-SMA232–234 and a proliferation of fibrotic connective tissue.234 Later, Freeman et al.13 found that fibrotic tissue from the knees of arthrofibrosis patients contained heterotrophic ossification, limited vascularity and increased numbers of mast cells expressing fibroblast growth factor. Scholtes SA, Khoo-Summers L, Damico KJ. Ao M, et al. In addition to proteins the ground substance of the ECM is comprised of proteoglycans, and these bind and inhibit or enhance a range of growth factors, proteases, protease inhibitors and TGF-β (for review see ref. l-proline production can be upregulated by arginine metabolism, resulting in macrophage switching and promoting Th2 cells and fibrosis.319. IL-17 acts as a pain sensitiser,67 induces monocyte migration and activates monocyte-derived macrophages to produce IL-1, TNF-α and PGE2.178, A number of other chemokines and cytokines including IL-13, IL-4 and IL-5 are associated with a higher risk of fibrosis, while IL-10 and IL-12 are protective.62,116,161 There is conflicting evidence for the role of interferon-γ.161, NF-κB is a family of proteins that occur in the cytoplasm of cells in an inactive form. Mas E, Croft KD, Zahra P, Barden A, Mori TA. Accessibility Benefits and risks not established for treating fibrosis. Metformin prevents peritendinous fibrosis by inhibiting transforming growth factor-β signaling. Collagenase nanocapsules: an approach to fibrosis treatment. Lipid mediators in immune dysfunction after severe inflammation. Itoi E, et al. Reduced levels of TGF-β and lung fibrosis in rats. Smad3 as a mediator of the fibrotic response. Modulate the immune system, inhibit the production of inflammatory cytokines. The .gov means it’s official. Received 2018 Jul 27; Revised 2019 Feb 17; Accepted 2019 Feb 26. The formation of ECM may be localised, for example, cyclops lesions on tendons or generalised to involve much of the joint6,12 (Fig. Recent research shows that it is possible to reverse fibrosis but it is still not understood how this occurs. The myofibroblast: one function, multiple origins. Fibrous scar in the infrapatellar fat pad after arthroscopy: MR imaging. Duong BH, et al. IL-6 also appears to be involved in the “memory” of inflammation163 and the development of chronic fibrosis.161, Recently, Schafer et al. A number of dietary additions may assist those about to undergo surgery to avoid arthrofibrosis, or reduce symptoms in those with an existing condition, although data is lacking. The different disorders that are diagnosed as arthrofibrosis need to be clarified and defined. The number of participants in CPM trials is particularly important because only a small proportion of patients develop post-operative arthrofibrosis, and it is only in these patients that a significant gain in ROM would be anticipated. Indeed, TGF-β is understood to be a key factor that recruits MSCs to damaged tissue, and the demonstrated differentiation of MSCs into myofibroblasts94 suggests that MSCs are often involved in the pathology of fibrosis. Sharma K. Obesity oxidative stress, and fibrosis in chronic kidney disease. While some of the confusion about the rates of post-operative arthrofibrosis are due to the lack of an agreed definition,32 other factors most likely come into play too. Attention should be focused on assessing levels of pain, inflammation and functional scores. Downregulates inflammation and possibly TGF-β. Gut bacteria produce short-chain fatty acids which counter inflammation. Over tid bygger arrvev seg opp inne i kneet, noe som får kneleddet til å krympe og stramme. Almost all types of immune cells are involved in fibrosis110 and the pathways are extremely complex. Liu X. Sequenced response of extracellular matrix deadhesion and fibrotic regulators after muscle damage is involved in protection against future injury in human skeletal muscle. The lack of well controlled studies makes it difficult to draw conclusions. Kayley M. Usher, Phone: +618 6457 2739, Email: ua.ude.awu@rehsu.yelyak. Kieran, N. E., Maderna, P. & Godson, C. Lipoxins: Potential anti-inflammatory, proresolution, and antifibrotic mediators in renal disease. Can encourage tumours. The complex role of vitamin D in autoimmune diseases. Elucidation of this mechanism may indicate the best timing and most appropriate treatment targets to prevent post-operative arthrofibrosis. Risk of adverse outcomes from the inflammatory response and worse fibrosis. However, despite the understanding of the pathogenesis of fibrosis, there are no effective therapies to halt fibrosis, and none to cure it.16,107 This situation may soon change, with a range of pharmacological therapies in clinical trials for the treatment of fibrosis of organs.17. Mummidi S, et al. Sanjabi S, Oh SA, Li MO. Scanzello CR, Goldring SR. NF-κB regulates genes and cells involved in inflammatory responses,179 including the activation, differentiation and function of inflammatory T cells and inflammasomes.120,134 It directly and indirectly promotes Th17 differentiation, and dysregulated production of NF-κB is associated with a range of autoimmune and inflammatory diseases.120, NF-κB upregulates the transcription of chemokines and inflammatory cytokines including TNF-α, IL-1β and IL-6 in a range of innate immune cells, inducing inflammation.120,157 NF-κB in macrophages and fibroblasts is activated by TGF-β-activated kinase 1, as well as many of the inflammatory cytokines induced by it,120 leading to another feedback loop of inflammation and fibrosis. Cardinale JP, et al. Badalamente MA, Wang ED. Carlson CM, et al. Zhang Y, Lee TC, Guillemin B, Yu MC, Rom WN. Kolahian S, Fernandez IE, Eickelberg O, Hartl D. Immune mechanisms in pulmonary fibrosis. Histone deacetylase inhibitors have been effective in treating liver and kidney fibrosis in rodents,218 and Schuetze et al.279 demonstrated that diverse histone deacetylase inhibitors were able to suppress proliferation of cardiac fibroblasts in vitro. Risk factors for total knee arthroplasty aseptic revision. The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype. Cheuy VA, et al. Epigenetic alterations, Persistent pain and restricted ROM, with typically mild swelling. Complex regional pain syndrome. Essent. Presence of IL-17 in synovial fluid identifies a potential inflammatory osteoarthritic phenotype. Careers, Unable to load your collection due to an error. Evaluation and treatment of disorders of the infrapatellar fat pad. Akdis M, et al. Scanzello CR, et al. 103). Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. Kundenfrage. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. Sanders TL, et al. Li J, Qu X, Ricardo SD, Bertram JF, Nikolic-Paterson DJ. Liu RM, Gaston Pravia KA. Gut bacteria produce short-chain fatty acids from non-digestible dietary fibre, which counter inflammation and suppress the cleavage of protease caspase-1 and secretion of IL-18.302, In addition, consumption of soy products may help reduce the levels of inflammatory cytokines. Shi YF, et al. Halofuginone also suppresses TGF-β, but does not have the well-known safety profile of metformin. Johnson ZI, Schoepflin ZR, Choi H, Shapiro IM, Risbud MV. Ricard-Blum S, Baffet G, Theret N. Molecular and tissue alterations of collagens in fibrosis. Die dauerhafte Bewegungseinschränkung des Kniegelenks führt längerfristig zur Pangonarthrose. This peaks at 6 months, but after a year is no longer present in half of patients,253 suggesting that fibrosis is a frequent reaction to surgery that often resolves without treatment. J. Physiol. Verjee et al.287 demonstrated that TNF-α antibodies inhibited the contractions of myofibroblasts taken from patients with Dupuytren’s disease, which involves progressive fibrosis of the palm. An NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice. Another medication that is currently available may also assist in treating arthrofibrosis. IL-11 is a crucial determinant of cardiovascular fibrosis. Unfortunately, the efficacy of CPM is difficult to determine as trials differ in their duration, timing and length of CPM treatment. El Agha E, et al. For example, Evans et al.195 demonstrated that the hypermethylation of a COX-2 transcriptional regulator in lung fibrosis resulted in suppressed COX-2 expression and a fibrotic phenotype. Hinz B, et al. For example, a young female patient with minimal loss of ROM but considerable pain underwent three surgeries to lyse ECM and adhesions, however, each surgery appeared to worsen the pain and inflammation despite a focus on decreasing inflammation. Agrawal K, Das V, Vyas P, Hajduch M, Nucleosidic DNA. Yang YM, Seki E. TNFalpha in liver fibrosis. Copple BL, Bai S, Burgoon LD, Moon JO. Nonsteroidal anti-inflammatory drugs and the kidney. A number of cell types contribute to the initiation and maintenance of chronic inflammation and fibrotic diseases, including macrophages, myofibroblasts and Th2 cells.62 In addition to these factors, protein complexes within the cytoplasm of cells called inflammasomes produce inflammatory cytokines, and which serve as a type of “memory” of insult (see below). Therapeutic targets for treating fibrotic kidney diseases. Other factors can also come into play. 141). Until these research priorities are addressed risk factors such as many previous surgeries, pre-existing stiffness or inflammation, early onset OA, childhood adversity and female gender should be considered prior to surgery. This review highlights current progress in understanding the pathogenesis of sterile arthrofibrosis, focusing on arthrofibrosis of the knee to illustrate the condition. Unfortunately, as with research publications, these forums are largely silent on the long-term outcomes for patients with permanent active arthrofibrosis. Kajihara I, et al. Sterile activators include nuclear factor kB (NF-κB)134 and stimuli generated by cell death or damage, referred to as damage-associated molecular patterns (DAMPS), which signal the inflammasome via cell receptors. Dysregulation and positive feedback loops (curved yellow arrows) result in persistent pathological fibrosis. Reduces pain, inflammation, fibrosis and serum TGF-β in animals. Bitte nennen Sie mir Ihr Alter, Geschlecht und Medikamente, die Sie einnehmen. Photo: Clicsouris, CC BY-SA 2.5. Zeplin P, Larena-Avellaneda A, Schmidt K. Surface modification of silicone breast implants by binding the antifibrotic drug halofuginone reduces capsular fibrosis. Das Wachstum der Fibroblasten wird durch mechanischen und emotionalen Stress hervorgerufen oder zumindest begünstigt. Kundenfrage. Pines M, Spector I. Halofuginone—the multifaceted molecule. Inflammasomes serve as an inflammatory memory, however, it is not yet clear how they remain active in chronic fibrotic diseases.2, Inflammasomes are present in immune cells and a wide variety of cells in tissues, including myofibroblasts and fibroblasts, and are activated by an array of different signals from wounds and infection. Sentez et voyez combien l'Eternel est bon! Deng YQ, et al. Raison CL, Capuron L, Miller AH. This suggests that the mechanical forces created by CPM reduce inflammation and pain, and may reduce damage to cartilage. Presentation and management of arthrofibrosis of the knee: a case report. List of existing and potential new therapies for treating arthrofibrosis, with a summary of the associated benefits and risks, For other potential therapies, including those that inhibit TGF-β signalling, see main text. a pharmaceutical therapy that is currently used to other conditions, which has potential for treating arthrofibrosis, Post-operative use of continuous passive motion (CPM) is sometimes prescribed to increase ROM,52,235 but remains controversial, most likely due to the associated expense and inconvenience.236,237 This results in many patients not having access to regular CPM.235. Although the results from arthrofibrosis studies have been variable,19 possibly due to differences in the type of biopsy tissue and the location and extent of fibrosis of donor patients, these studies have nonetheless provided important information. This study showed that rates of arthrofibrosis requiring surgical treatment were significantly higher for ACL reconstruction compared to meniscectomy and microfracture.5 However, even exploratory arthroscopies are capable of causing arthrofibrosis.12. Brito HO, et al. New therapeutic targets include epigenetic modifications, TGF-β and its downstream signalling, IL-1β, NLRP3 inflammasomes, mast cells, substance P and hypoxia-inducible factor-1. TGF-β, IL-1 and TNF-α stimulate ROS production from a range of cell types including fibroblasts, and TGF-β can also suppress the production of antioxidant enzymes.208 TGF-β promotes ROS production209,210 and in a feedback effect, high levels of ROS stimulates TGF-β production94 and causes more damage, cell death198 and the release of cell fragments that act as DAMPs, causing activation of NF-κB and increased expression of inflammatory cytokines. However, MSCs from the IFP are also capable of differentiating into fibroblasts25 in a similar wasy to MSCs from bone marrow.113 Furthermore, MSCs from the synovial membrane are positive for the TGF-β receptor CD 105,299 raising the possibility that these cells may induce fibrosis under inflammatory conditions. Zhang H, et al. Kalson NS, et al. Im schwarzwälder Gesundheitszentrum erhalten Sie professionelle Informationen und Hilfe rund um die Arthrofibrose-Themen: Entstehung (Ätiologie), Verlauf (Pathogenese) und Behandlungs ergebnisse innerhalb der vor 7 Jahren entwickelten Arthrofibrose-KombinationsTherapie (Original). Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Sulphoraphane has an anti-fibrosis effect via the activation of nuclear factor erythroid 2-related 2, which may be important in preventing fibroblast differentiation.301 A diet high in resistant fibre is also likely to be beneficial for preventing inflammation and fibrosis. Intermittent fasting has profound positive effects on many health measures and can improve functional outcomes for many diseases.313 Animal research shows that intermittent fasting is protective against fibrosis of organs,314 and it is also known suppress inflammation313,315 and downregulate the inflammatory cytokines IL-1, IL-6 and TNF-α in humans.316 Intermittent fasting suppresses the activity of NLRP3 inflammasomes,313 providing what appears to be a cumulative anti-fibrotic effect. Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Doz. However, there are no specific diagnostic tests for CRPS, and no clinical features that identify it.54,55 Consequently, the diagnosis of CRPS is made in the absence of other explanations for pain and swelling, and it remains a controversial diagnosis.54,55, Without publically available blood tests for arthrofibrosis, it seems likely that many patients that have been diagnosed with CRPS do in fact have active arthrofibrosis and a dysregulated inflammatory response. IL-6 is essential for host defence against bacterial and viral infections, controlling T cell functions and survival. Diarrhoea, GI symptoms and liver toxicity in some. Bravo pour votre travail remarquable. Increased risk of infections. Reactive oxygen species in cell signaling. Kim H, et al. Serhan CN, et al. Symptome sind starke Schmerzen an Gelenken und eingeschränkte Beweglichkeit . More research is needed to understand the difference between active and residual arthrofibrosis, as the response of patients within these groups to surgery and exercise may be significantly different. Giang T, et al. Arthrofibrosis (from Greek: arthro- joint, fibrosis - scar tissue formation) has been described in most joints like knee, hip, ankle, foot joints, shoulder ( frozen shoulder, adhesive capsulitis ), elbow (stiff elbow), wrist, hand joints as well as spinal vertebrae. Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway. It is likely that patients with active arthrofibrosis have a higher risk of the return of aggressive arthrofibrosis following surgical intervention or MUA, compared to those with residual arthrofibrosis. van der Linde D, et al. Morrey BF. Rehabilitation of the arthrofibrotic knee. New pathomechanistic insights into arthrofibrotic remodeling after knee replacement therapy. Disc in flames: roles of TNF-α and IL-1β in intervertebral disc degeneration. Khan MI, Rath S, Adhami VM, Mukhtar H. Targeting epigenome with dietary nutrients in cancer: Current advances and future challenges. Shoulder stiffness: current concepts and concerns. TGF-beta: the master regulator of fibrosis. During normal wound healing and resolution of inflammation some myofibroblasts become apoptotic, while others revert to the original cell type, however, the processes by which this occurs are not yet understood.90 In fibrosis epigenetic alterations in myofibroblasts increase the activity of inflammatory and pro-fibrotic genes118 (see below in Epigenetic alterations), and appear to serve as a type of memory of the insult.108 Myofibroblasts that have reverted back to fibroblasts are more likely to become re-activated when exposed to further insult.60,90 This has implications for repeated joint surgeries as fibrosis may resolve naturally and unnoticed, but the presence of reverted fibroblasts that serve as a store of pre-fibrotic cells may leave the patient susceptible to arthrofibrosis after subsequent surgeries, as discussed earlier. However, the potential benefits of surgery must be weighed against the risks, which include increased dysregulation of fibrogenesis in response to the surgical injury. Other cytokines known to have involvement are TNF-α, IL-17, IL-1β and the anti-inflammatory IL-10.139 A combination of inflammatory cytokines upregulates expression of TGF-β receptors, and inflammation plays an important role in the development of fibrosis.140. Arthrofibrose er også kjent som stiv knesyndrom. In addition, hypermethylation of micro-RNA promoter regions can result in the upregulation of genes normally supressed by micro-RNA, causing fibrosis.223, Demethylation is triggered by translocation enzymes, and these are downregulated in liver fibrosis, suggesting that an imbalance between methylation and demethylation enzymes contributes to fibrosis.219 In a similar fashion, sirtuins are natural enzymes that remove acetyl groups on histones, providing protection from a range of diseases including fibrosis.224. Robertson IB, et al. Complex regional pain syndrome: a comprehensive and critical review. Zhang Q, et al. IL-1 antibodies such as Rilonacept bind to and inactivate IL-1. Die Arthrofibrose ist eine schmerzhafte Beweglichkeitsstörung, die durch vermehrte Bildung von Bindegewebszellen (Fibroblasten) verursacht wird. Some patients are removed from studies of surgical outcomes after a diagnosis of “complex regional pain syndrome”, a condition with no established diagnostic criteria (see above). Patellofemoral problems after anterior cruciate ligament reconstruction. Evidence D, Standards Branch HQO. Mast cells and hypoxia drive tissue metaplasia and heterotopic ossification in idiopathic arthrofibrosis after total knee arthroplasty. These activate immune cells, causing more inflammation and a cascade of events that stimulates fibroblasts to differentiate into myofibroblasts, the key mediators of fibrosis. However, 4 weeks after full resolution of arthrofibrosis the patient became ill with suspected influenza. Stretching fibroblasts remodels fibronectin and alters cancer cell migration. Used to treat type II diabetes. Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor-1. Posttraumatic elbow contractures: targeting neuroinflammatory fibrogenic mechanisms. Goodman SB, Yao Z, Keeney M, Yang F. The future of biologic coatings for orthopaedic implants. Stone RC, et al. Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells—an experimental study. Flanders KC. Commonly used histological stains are easily applied and readily visualise fibrotic tissue and ECM,218 permitting patient diagnosis and visualisation of treatment efficacy in animal models. Sivakumar P, Kitson C, Jarai G. Modeling and measuring extracellular matrix alterations in fibrosis: challenges and perspectives for antifibrotic drug discovery. Xiao H, et al. Panni SA, Cerciello S, Vasso M, Tartarone M. Stiffness in total knee arthroplasty. Increased ROM is the primary reason for CPM treatment, and of the ten trials that reported short term (0–6 weeks) effects on ROM, only five used a blinded assessor.236 Even fewer studies used a blinded assessor for the reported medium term (6 weeks to 6 months) and long-term (over 6 months) ROM. Afonina IS, Zhong Z, Karin M, Beyaert R. Limiting inflammation-the negative regulation of NF-kappaB and the NLRP3 inflammasome. Intensity should be adapted according to resulting inflammation in individuals. TGF-β is known to start a cascade of other downstream regulatory effects including a reduction in ECM degradation via the downregulation of a family of matrix metalloproteinases (MMPs),152 which include collagenases. Snelling SJ, et al. Huang YP, et al. Metformin alleviates bleomycin-induced pulmonary fibrosis in rats: pharmacological effects and molecular mechanisms. Results of small trial for elbow arthrofibrosis shows no effect. Lipid mediator class switching during acute inflammation: signals in resolution. Downregulates NLRP3 inflammasomes. In addition, halofuginone inhibits the development of Th17 cells,44 decreasing Th17 cell numbers and inflammatory cytokines via AMP-activated protein kinase-mediated NF-κB p65 inactivation.275 Halofuginone has undergone clinical trials to treat Duchenne muscular dystrophy and several forms of cancer using an oral encapsulated form to prevent gastric bleeding. Inducible cyclooxygenase may have anti-inflammatory properties. The high numbers of fibroblasts in knee synovium can drive inflammation67 and become further activated following surgery. Arthrofibrosis is a fibrotic joint disorder characterised by excessive collagen production and adhesions that result in restricted joint motion and pain. Arthrofibrose - Verdacht auf Heilung! Teil II DOKU direkt aus der AF ... Anti-inflammatory agents: present and future. Capsaicin (found in chilli and peppers) and sulphoraphane (found in cruciferous vegetables) have been demonstrated to reverse differentiation of myofibroblasts in vivo. Pardo A, Selman M. Matrix metalloproteases in aberrant fibrotic tissue remodeling. Sullivan DE, Ferris M, Pociask D, Brody AR. DNA methylation regulated gene expression in organ fibrosis. Lee JS, Shin JH, Choi BS. Arthrofibrose | SpringerLink Direct activation of Nlrp3 inflammasome in hepatic stellate cells leads to upregulation of fibrotic markers. Have been successfully used to prevent post-operative arthrofibrosis in small studies.

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