Asia Pacific Allergy最新文献

{"title":"Philippine guidelines on the dietary primary prevention of allergic diseases in children.","authors":"Roxanne J Casis Hao, Maria Lourdes G Genuino, Carol Stephanie C Tan-Lim, Regina D Capulong, Mary Anne R Castor, Phorenice D Francisco, Valerie T Guinto, Aimee Lou M Nano, April P Padua-Zamora, Marysia Stella T Recto, Jossie M Rogacion, Marilou G Tan, Maribel Vitug-Sales","doi":"10.5415/apallergy.0000000000000158","DOIUrl":"https://doi.org/10.5415/apallergy.0000000000000158","url":null,"abstract":"<p><strong>Background: </strong>In response to the continual increase in the prevalence of pediatric allergic diseases in the Philippines, the Philippine Society of Allergy, Asthma, and Immunology (PSAAI) and the Philippine Society of Pediatric Gastroenterology, Hepatology, and Nutrition (PSPGHAN) have published guidelines on the dietary prevention of allergic diseases in children.</p><p><strong>Objective: </strong>This guideline aims to update the previous guideline recommendations for clinicians on the use of dietary interventions for the prevention of allergic disease in children.</p><p><strong>Methods: </strong>Following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach specified in the Department of Health Manual for Clinical Practice Guidelines development, we systematically searched for and appraised clinical practice guidelines and systematic reviews on topics formulated and prioritized by a Steering Committee, which comprised of members of the PSAAI and PSPGHAN. In the absence of an existing systematic review, a de novo systematic review was conducted. A multisectoral consensus panel reviewed the evidence summaries and formulated recommendations through a formal consensus method.</p><p><strong>Results and conclusion: </strong>The recommendations made by the consensus panel were based on the available evidence on the benefits and harm of the intervention, as well as the cost, feasibility, acceptability, and availability. Several research gaps exist, resulting in low levels of certainty of evidence on most dietary recommendations for the prevention of pediatric allergic diseases.</p>","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 4","pages":"191-213"},"PeriodicalIF":1.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differences in the direct effects of various type 2 cytokines on functions of blood eosinophils from healthy subjects.","authors":"Yutaka Ueda, Kazuyuki Nakagome, Kazuki Katayama, Hidetoshi Iemura, Sachiko Miyauchi, Toru Noguchi, Takehito Kobayashi, Tomoyuki Soma, Toshiko Itazawa, Makoto Nagata","doi":"10.5415/apallergy.0000000000000157","DOIUrl":"https://doi.org/10.5415/apallergy.0000000000000157","url":null,"abstract":"<p><strong>Background: </strong>Eosinophil inflammation often persists in the airways of severe asthmatics, even under treatment with high-dose inhaled corticosteroids. Biologics for various type 2 cytokines have been recently developed for corticosteroid-resistant, eosinophil-dominant, severe asthma. However, it is unclear whether these biologics act directly on eosinophils.</p><p><strong>Objective: </strong>In this study, we examined whether various type 2 cytokines targeted by biologics can directly modify the functions of eosinophils obtained from the peripheral blood of healthy individuals.</p><p><strong>Methods: </strong>Peripheral eosinophils of healthy subjects were purified by conventional negative-depletion methods using anti-CD16 beads to avoid the priming effect (i.e., stimulation <i>in vitro</i>) to the maximum extent possible. Eosinophils were stimulated with interleukin (IL)-4, IL-5, IL-13, or thymic stromal lymphopoietin (TSLP), and eosinophil adhesiveness to recombinant human-intercellular adhesion molecule (ICAM)-1 was evaluated by eosinophil peroxidase assays. The effect of these cytokines on eosinophil superoxide anion (O₂ ^-) generation was evaluated by the superoxide dismutase-inhibitable reduction of cytochrome C. To determine whether eosinophil degranulation was induced, the concentration of eosinophil-derived neurotoxin (EDN) in the supernatant was measured using enzyme-linked immuno sorbent assay.</p><p><strong>Results: </strong>As reported previously, at 100 pM, IL-5 increased eosinophil adhesiveness to ICAM-1, O₂ ^- generation, and EDN release. Conversely, at concentrations up to 10 nM, IL-4, IL-13, and TSLP did not induce eosinophil adhesiveness, O₂ ^- generation, or EDN release.</p><p><strong>Conclusion: </strong>Type 2 cytokines other than IL-5 do not directly affect the functions of eosinophils from healthy individuals when used at clinical concentrations. These findings suggest that eosinophils play little, or no, direct role in the effects of anti-IL-4 receptor α or anti-TSLP antibody on severe asthma.</p>","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 4","pages":"183-190"},"PeriodicalIF":1.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dermatological dichotomy: Atopic dermatitis or mycosis fungoides?","authors":"Helena P Pereira, Inês G Nunes, Inês C Farinha, Sofia Pereira, Ana Todo-Bom","doi":"10.5415/apallergy.0000000000000166","DOIUrl":"10.5415/apallergy.0000000000000166","url":null,"abstract":"<p><p>The presence of atopic dermatitis (AD) and mycosis fungoides (MF) presents diagnostic challenges due to their shared clinical features. AD, a chronic skin disorder characterized by pruritic and inflamed lesions, shares these features with MF, which is the most common cutaneous T-cell lymphoma. A 19-year-old male, who had a history of childhood AD, developed eczema-like lesions on his forearms, neck, and head. Initially, allergic contact dermatitis was suspected due to his occupational metal exposure. However, despite treatment with topical therapies, his condition worsened, requiring 3 cycles of oral corticotherapy. Notably, his lesions appeared atypically, affecting areas such as the scalp and nonflexural regions. Histopathological examination played a crucial role in the diagnostic process. While the initial biopsy suggested parapsoriasis, a second scalp biopsy confirmed MF. Despite their clinical similarities, AD and MF require distinct diagnostic approaches. This case emphasizes the need to consider MF as a diagnostic possibility, even in individuals with a history of AD. Early MF diagnosis enables tailored treatment, including topical therapies and narrowband ultraviolet B phototherapy. A multidisciplinary approach, advanced techniques such as immunophenotyping, and early identification are essential for providing optimal patient care. The shared clinical features of AD and MF suggest potential common mechanisms, underscoring the need for further research to enhance treatment strategies and patient care.</p>","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 4","pages":"226-228"},"PeriodicalIF":1.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stepping down of treatment in Chronic Spontaneous Urticaria: A retrospective study comparing tapering vs abrupt discontinuation of antihistamines in patients having well-controlled disease.","authors":"Sukhdeep Singh, Anuradha Bishnoi, Muthu Sendhil Kumaran, Davinder Parsad","doi":"10.5415/apallergy.0000000000000153","DOIUrl":"https://doi.org/10.5415/apallergy.0000000000000153","url":null,"abstract":"","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 4","pages":"229-231"},"PeriodicalIF":1.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tattoo-induced immunologic reaction to red inks.","authors":"João Vieira, João Marcelino, Sofia Farinha, Miguel Proença, Joana Guimarães, Rui Bajanca, Elza Tomaz","doi":"10.5415/apallergy.0000000000000165","DOIUrl":"https://doi.org/10.5415/apallergy.0000000000000165","url":null,"abstract":"<p><p>A 43-year-old male presented with pruritic nodular lesions in the red dye area of his leg tattoo, which developed 4 weeks after its application. Patch tests were performed using a standard series, and the inks used by the tattooist were tested semi-open. Tests identified a sensitization to 2 inks containing an azo-organic dye (Pigment Red 170), diketopyrrolopyrrole (Pigment Red 254), and copper phthalocyanine (Pigment Blue 15). Histopathological findings suggested a pseudolymphoid reaction, likely driven by T-cell hypersensitivity to the red pigments. Although the utility of patch testing in the assessment of tattoo reactions is not consensual, it can be useful in identifying the offending inks, helping to guide future tattoo choices and prevent recurrences. Patch testing including the suspected ink should not be disregarded from the diagnostic workup.</p>","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 4","pages":"223-225"},"PeriodicalIF":1.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the protocol for rush subcutaneous immunotherapy with birch pollen extract.","authors":"Masaaki Hamada, Masakazu Kagawa, Ichiro Tanaka","doi":"10.5415/apallergy.0000000000000164","DOIUrl":"https://doi.org/10.5415/apallergy.0000000000000164","url":null,"abstract":"<p><p>We previously reported the effectiveness of rush subcutaneous immunotherapy with birch pollen extract (Birch rSCIT) for pollen-food allergy syndrome (PFAS) and the high rate of systemic reactions (SR) during the rapid escalation phase. In this study, we examined whether modifying the dose escalation protocol of Birch rSCIT would reduce SR and maintain therapeutic effects. Birch rSCIT was introduced in 20 patients with PFAS who experienced systemic symptoms upon ingestion of soybeans. Birch rSCIT was implemented using 3 protocols: 2 protocols (nonstep-up group) increased the target dose to more than 1:2 × 10² (w/v) in 0.05 mL, while 1 protocol (step-up group) increased the target dose to 1:2 × 10³ (w/v) in 0.3 mL, and then increased to 1:2 × 10² (w/v) in 0.05 mL using the conventional method in the following week. In the nonstep-up group, 4 out of 5 patients (80%), and in the step-up group, 2 out of 15 patients (13.3%) developed SR during rapid escalation. During the rapid escalation phase, the step-up group had significantly fewer SR than the nonstep-up group (<i>P</i> = 0.014). The median ingestible dose of soy milk in the oral food challenge was 3.5 mL before the treatment and increased significantly to 200 mL 1 year after initiating Birch SCIT (<i>P</i> < 0.01). We confirmed that reducing the target antigen dose in Birch rSCIT improved safety and maintained the therapeutic effect for soybean allergy with PFAS.</p>","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 4","pages":"214-219"},"PeriodicalIF":1.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-IL-4Rα monoclonal antibody (CM310) in patients with chronic rhinosinusitis with nasal polyps (CROWNS-2): Rationale and design of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study.","authors":"Shen Shen, Bing Yan, Ming Wang, Di Wu, Chengshuo Wang, Luo Zhang","doi":"10.5415/apallergy.0000000000000156","DOIUrl":"10.5415/apallergy.0000000000000156","url":null,"abstract":"<p><strong>Background: </strong>Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease that affects a large proportion of the global population. The treatment of CRSwNP, especially eosinophilic CRSwNP (ECRSwNP), has always been of great obstacle. Our previous phase 2 trial showed that CM310, a monoclonal antibody that targets interleukin-4 receptor alpha, was both safe and effective in reducing the size of nasal polyps, improving symptom scores, and increasing the quality of life for those with severe ECRSwNP.</p><p><strong>Objective: </strong>This phase 3 trial aims to evaluate the efficacy, safety, pharmacokinetic, pharmacodynamic, and immunogenicity of CM310 in participants with CRSwNP.</p><p><strong>Result: </strong>The CROWNS-2 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial. The study consisted of a screening/run-in period (up to 4 weeks), a treatment period (24-week double-blind treatment period plus 28-week maintenance period), and a safety follow-up period (8 weeks). The study planned to enroll 180 participants with CRSwNP (at least 60% of ECRSwNP) to receive CM310 300 mg/placebo every 2 weeks (Q2W) subcutaneously for a total of 12 doses in double-blind treatment period and 300 mg CM310 Q2W subcutaneously for a total of 14 doses in maintenance period. Enrolled participants continued to use mometasone furoate nasal spray throughout the study. The primary endpoints are a change from baseline in nasal polyp score and nasal congestion score at week 24 between CM310 and placebo in both ECRSwNP and CRSwNP.</p><p><strong>Conclusion: </strong>The CROWNS-2 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical study to evaluate the efficacy and safety of CM310 in patients with CRSwNP.</p><p><strong>Trial registration: </strong>NCT05436275.</p>","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 3","pages":"118-123"},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Food-dependent exercise-induced anaphylaxis (FDEIA) suspected triggered by lipid transfer protein in a Chinese child: A case report.","authors":"Nannan Jiang, Kai Guan, Li Xiang","doi":"10.5415/apallergy.0000000000000154","DOIUrl":"10.5415/apallergy.0000000000000154","url":null,"abstract":"<p><p>Lipid transfer protein (LTP) has been documented as the dominant protein involved in food-induced anaphylaxis and food-dependent exercise-induced anaphylaxis (FDEIA) patients from Mediterranean European countries. To date, there is no report of FDEIA triggering by LTP in China. A 12-year-old Chinese boy experienced recurrent anaphylaxis during intense exercise for 3 months. Specific immunoglobulin E was performed using ImmunoCAP (Thermo Fisher Scientific, Sweden) and Euroline (EUROIMMUN, Germany). He was sensitized to several pollens, mainly mugwort (62 KUA/L), and was found to have detectable immunoglobulin E in multiple foods: cereal (wheat, barley, oat maize, rice, buckwheat, and common millet), fruits (peach, apple, grape, cherry, and orange), vegetables (lettuce, cabbage, broccoli, cauliflower, tomato, and celery), and legumes and nuts (soybean, peanut, and walnut). He also showed sensitization to LTP components from mugwort Art v3 (79.7 KUA/L) and wheat Tri a14 (12.4 KUA/L), but negative to gluten, gliadin, and omega-5 gliadin. We advised our patient to carry an epinephrine auto-injector, not to exercise alone, and to avoid wheat and fruit/vegetable ingestion for at least 4 hours before exercise or when taking non-steroidal anti-inflammatory drugs. After a 6-month follow-up, the patient has experienced no episode of anaphylaxis. We reported the first documented FDEIA case suspected triggered by LTP in a Chinese child. Clinicians should be aware of LTP sensitization when anaphylaxis occurs during exercise in individuals with multiple pollen and food sensitization.</p>","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 3","pages":"148-150"},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From tumor to tolerance: A comprehensive review of immune checkpoint inhibitors and immune-related adverse events.","authors":"Henry Sutanto, Ardea Safira, Deasy Fetarayani","doi":"10.5415/apallergy.0000000000000146","DOIUrl":"10.5415/apallergy.0000000000000146","url":null,"abstract":"<p><p>The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape for various malignancies by harnessing the body's immune system to target cancer cells. However, their widespread use has unveiled a spectrum of immune-related adverse events, highlighting a critical balance between antitumor immunity and autoimmunity. This review article delves into the molecular immunology of ICIs, mapping the journey from their therapeutic action to the unintended induction of immune-related adverse events. We provide a comprehensive overview of all available ICIs, including cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1, programmed death-ligand 1 inhibitors, and emerging targets, discussing their mechanisms of action, clinical applications, and the molecular underpinnings of associated immune-related adverse events. Special attention is given to the activation of autoreactive T cells, B cells, cytokine release, and the inflammatory cascade, which together contribute to the development of immune-related adverse events. Through a molecular lens, we explore the clinical manifestations of immune-related adverse events across organ systems, offering insights into diagnosis, management, and strategies to mitigate these adverse effects. The review underscores the importance of understanding the delicate interplay between enhancing antitumor responses and minimizing immune-related adverse events, aiming to guide future research and the development of next-generation ICIs with improved drug safety profiles.</p>","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 3","pages":"124-138"},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of cross-reactive IgE-binding proteins from Philippine allergenic grass pollen extracts.","authors":"Mary Anne R Castor, Maria Katrina Diana M Cruz, Gregg Austine M Balanag, Krystal M Hate, Roche Dana C Reyes, Maria Socorro Agcaoili-De Jesus, Cherie C Ocampo-Cervantes, Leslie Michelle M Dalmacio","doi":"10.5415/apallergy.0000000000000155","DOIUrl":"10.5415/apallergy.0000000000000155","url":null,"abstract":"<p><strong>Background: </strong>Respiratory allergies are one of the most common allergic diseases that affect Filipinos. Grass pollen accounts for the majority of the outdoor allergens triggering these respiratory allergies. Cross-reactivity among the Philippine grass pollen grains has not been extensively studied.</p><p><strong>Objective: </strong>This study aims to investigate the cross-reactivity of our local grasses and identify the cross-reactive allergens.</p><p><strong>Methods: </strong>Grass pollen grains were collected and processed into crude allergenic extracts. The IgE-reactivity of these crude allergenic pollen extracts was studied using sera from patients who tested positive for the mentioned extracts. The proteins from the immunoblots of cross-reactive pollen allergen extracts were sequenced and identified.</p><p><strong>Results: </strong>Allergenic pollen proteins were identified as cross-reactive among the grass pollen extracts. Four of these have not been listed yet as grass allergens in the World Health Organization/International Union of Immunological Societies allergen nomenclature database.</p><p><strong>Conclusion: </strong>Local grass pollen allergens are cross-reactive with probable new allergens identified.</p>","PeriodicalId":8488,"journal":{"name":"Asia Pacific Allergy","volume":"14 3","pages":"108-117"},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}