Trends in Childhood Anaphylaxis in Singapore: 2015-2022.

BACKGROUND: There has been limited data regarding the incidence of anaphylaxis in Asia. We aim to describe patterns in patient characteristics, triggers and clinical presentation of childhood anaphylaxis in Singapore. METHODS: This was a retrospective review of emergency electronic medical records of children with anaphylaxis. Patients with the allergy-related diagnoses of anaphylaxis, angioedema, allergy and urticaria based on ICD-9 codes were screened. Cases fulfilling the World Allergy Organization criteria for anaphylaxis were included. RESULTS: A total of 1188 cases of anaphylaxis were identified with a median age of 6.3 years. Extrapolating data from the study sites, from 2015 to 2022, the incidence rate of childhood anaphylaxis emergency visits in Singapore doubled from 18.9 to 38.8 per 100,000 person-years, with an incidence rate ratio (IRR) of 2.06 (95% confidence interval [CI] 1.70-2.49). In 2022, the incidence rate of food anaphylaxis was 30.1 per 100,000 person-years, IRR 2.39 (95% CI 1.90-3.01) and drug anaphylaxis was 4.6 per 100,000 person-years, IRR 1.89 (95% CI 1.11-3.25). The incidence rate in children aged 0-4 years quadrupled during the study period. Common triggers were egg (10.4%), peanut (9.3%), tree nut (8.8%), milk (8%), shellfish (7.8%) and non-steroidal anti-inflammatory drug (4.4%). The majority (88.6%) of patients were treated with intramuscular adrenaline. Total number of allergy-related visits did not increase over time between 2015 and 2019. Rates of severe anaphylaxis, namely anaphylactic shock and admission to high-dependency and intensive care, did not increase over time, with a mean incidence of 1.6, IRR 0.85 (95% CI 0.40-1.83) and 0.7, IRR 1.77 (95% CI 0.54-5.76) per 100,000 person-years, respectively. CONCLUSION: While the number of emergency visits due to childhood anaphylaxis has increased, the number of cases of allergy-related visits, anaphylactic shock and anaphylaxis requiring high-dependency and intensive care did not rise.

Functional Polymorphisms of the Arachidonic Acid Pathway Associate with Risks and Clinical Outcomes of Allergic Diseases.

INTRODUCTION: The arachidonic acid (AA) pathway plays a crucial role in allergic inflammatory diseases; however, the functional roles of allergy-associated single nucleotide polymorphisms (SNPs) in this pathway remain incompletely illustrated. METHODS: This study belongs to a part of an ongoing Singapore/Malaysia cross-sectional genetics and epidemiological study (SMCSGES). We performed population genotyping on n = 2,880 individuals from the SMCSGES cohort to assess the associations of SNPs in the AA pathway genes with asthma and allergic rhinitis (AR). Spirometry assessments were performed to identify associations between SNPs and lung function among n = 74 pediatric asthmatic patients from the same cohort. Allergy-associated SNPs were functionally characterized using in vitro promoter luciferase assay, along with DNA methylome and transcriptome data of n = 237 peripheral blood mononuclear cell (PBMC) samples collected from a subset of the SMCSGES cohort. RESULTS: Genetic association analysis showed 5 tag-SNPs from 4 AA pathway genes were significantly associated with asthma (rs689466 at COX2, rs35744894 at hematopoietic PGD2 synthase (HPGDS), rs11097414 at HPGDS, rs7167 at CRTH2, and rs5758 at TBXA2R, p < 0.05), whereas 3 tag-SNPs from HPGDS (rs35744894, rs11097414, and rs11097411) and 2 tag-SNPs from PTGDR (rs8019916 and rs41312470) were significantly associated with AR (p < 0.05). The asthma-associated rs689466 regulates COX2 promoter activity and associates with COX2 mRNA expression in PBMC. The allergy-associated rs1344612 was significantly associated with poorer lung function, increased risks of asthma and AR, and increased HPGDS promoter activity. The allergy-associated rs8019916 regulates PTGDR promoter activity and DNA methylation levels of cg23022053 and cg18369034 in PBMC. The asthma-associated rs7167 affects CRTH2 expression by regulating the methylation level of cg19192256 in PBMC. CONCLUSIONS: The present study identified multiple allergy-associated SNPs that modulate the transcript expressions of key genes in the AA pathway. The development of a "personalized medicine" approach with consideration of genetic influences on the AA pathway may hopefully result in efficacious strategies to manage and treat allergic diseases.

An online survey of clinical practice for allergic rhinitis among the Asia-Pacific representatives.

BACKGROUND: Physicians' knowledge and practice which are consistent with evidence-based guidelines can improve allergic rhinitis (AR) patients' care. Compared with western countries, the available literature about Asian doctors' perceptions and clinical practices regarding Allergic Rhinitis and its Impacts on Asthma (ARIA) guidelines is limited. OBJECTIVE: To collect detailed information about the practical management patterns specific for AR patients and investigate compliance with ARIA in the clinical practice of Asian physicians and elucidate the possible inadequacy in the existing ARIA guidelines. METHODS: An e-mail with a structured questionnaire was sent to members of the Asia-Pacific Association of Allergy, Asthma and Clinical Immunology. The questionnaire consisted of doctors' characteristics, environment of medical practice, routine clinical practice following ARIA guidelines and patients' adherence to the prescription. RESULTS: Physicians from 14 countries and regions sent valid questionnaires back, 94.12% of whom were senior doctors with more than 10 years of experience. 88.24% of doctors diagnosed AR depending on the history combined with allergy tests. 82.35% of participants employed the classification criteria by ARIA. 94.12%, 88.24% and 41.8% of respondents recommended intranasal corticosteroids, oral antihistamines and leukotriene receptor antagonists as first-line medications. 5.88% treated perennial AR by intranasal corticosteroids alone. 11.76% of clinicians recommended no allergen immunotherapy (AIT) or biologics and 58.82% of interviewees reported AR patients occasionally or sometimes agreed with the recommendation of AIT. CONCLUSIONS: There was high compliance with ARIA guidelines in Asian senior physicians' actual notion and practice in the management of AR. New-generation ARIA guidelines are imperative for unmet needs.

A synbiotic intervention modulates meta-omics signatures of gut redox potential and acidity in elective caesarean born infants.

BACKGROUND: The compromised gut microbiome that results from C-section birth has been hypothesized as a risk factor for the development of non-communicable diseases (NCD). In a double-blind randomized controlled study, 153 infants born by elective C-section received an infant formula supplemented with either synbiotic, prebiotics, or unsupplemented from birth until 4 months old. Vaginally born infants were included as a reference group. Stool samples were collected from day 3 till week 22. Multi-omics were deployed to investigate the impact of mode of delivery and nutrition on the development of the infant gut microbiome, and uncover putative biological mechanisms underlying the role of a compromised microbiome as a risk factor for NCD. RESULTS: As early as day 3, infants born vaginally presented a hypoxic and acidic gut environment characterized by an enrichment of strict anaerobes (Bifidobacteriaceae). Infants born by C-section presented the hallmark of a compromised microbiome driven by an enrichment of Enterobacteriaceae. This was associated with meta-omics signatures characteristic of a microbiome adapted to a more oxygen-rich gut environment, enriched with genes associated with reactive oxygen species metabolism and lipopolysaccharide biosynthesis, and depleted in genes involved in the metabolism of milk carbohydrates. The synbiotic formula modulated expression of microbial genes involved in (oligo)saccharide metabolism, which emulates the eco-physiological gut environment observed in vaginally born infants. The resulting hypoxic and acidic milieu prevented the establishment of a compromised microbiome. CONCLUSIONS: This study deciphers the putative functional hallmarks of a compromised microbiome acquired during C-section birth, and the impact of nutrition that may counteract disturbed microbiome development. TRIAL REGISTRATION: The study was registered in the Dutch Trial Register (Number: 2838 ) on 4th April 2011.

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation.

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.

Correction: Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cause and Clinical Presentation of Anaphylaxis in Singapore: From Infancy to Old Age.

BACKGROUND: The study objective was to compare age-related differences in the cause and clinical presentation of anaphylaxis. METHODS: We conducted a prospective study of patients visiting the emergency department for anaphylaxis. Data were collected from 3 emergency departments from 1 April 2014 to 31 December 2015. Patient electronic records with the diagnoses of allergy, angioedema, urticaria, and anaphylaxis (ICD-9 codes 9953, 9951, 7080, 9950, 7089) were screened and cases fulfilling World Allergy Organisation criteria for anaphylaxis were included. RESULTS: A total of 426 cases of anaphylaxis were identified with a median age of 23 years (range 3 months to 88 years and 9 months). The causes of anaphylaxis were food (n = 236, 55%), drugs (n = 85, 20%), idiopathic (n = 64, 15%), and insect bites or stings (n = 28, 7%). The most common food was shellfish (n = 58, 14%) and the most common drugs were non-steroidal anti-inflammatory drugs (n = 26, 6%). There were more cases of food anaphylaxis in children than in adults (72 vs. 42%, p < 0.001) and more cases of drug anaphylaxis in adults than in children (28 vs. 10%, p < 0.001). Compared to patients of other ages, infants and young children had more gastrointestinal symptoms (adjusted odds ratio [aOR] 2.1, 95% CI 1.1-3.9), while schoolchildren and adolescents had more respiratory symptoms (aOR 2.7, 95% CI 1.4-5.2). Adults had more cardiovascular symptoms (aOR 2.9, 95% CI 1.8-4.6) and hypotension (aOR 3.7, 95% CI 2.1-6.8) compared to children. However, 42% of the infants lacked blood pressure measurements. CONCLUSIONS: Knowledge of age-related variation in the cause and clinical presentation of anaphylaxis aids in diagnosis and acute management.

Anaphylaxis to cow's milk formula containing short-chain galacto-oligosaccharide.

BACKGROUND: On the basis of the proven prebiotic effects of oligosaccharides in cow's milk formula (CMF) in infants, CMFs are supplemented with oligosaccharides. OBJECTIVE: We present a series of 5 cases of cow's milk-tolerant but atopic patients with a history of respiratory allergies. All had anaphylaxis after the ingestion of CMF supplemented with short-chain galacto-oligosaccharide (scGOS). The allergen trigger was investigated. METHODS: Clinical histories were collated. Skin prick tests (SPTs) and basophil activation tests (BATs) were carried out with the eliciting CMF that triggered anaphylaxis, with or without supplemented prebiotics (scGOS) and with scGOS fractions containing oligosaccharides of different chain lengths. RESULTS: The median age of presentation was 6 years (range, 5-38 years). Anaphylaxis occurred within 30 minutes of the first known exposure to CMF supplemented with prebiotics in all patients. Only 1 patient was subjected to oral challenge, which resulted in an anaphylactic reaction. All patients demonstrated IgE sensitization through SPTs and BATs to scGOS and fractions of scGOS containing 3 sugar units or greater but not to cow's milk or long-chain fructo-oligosaccharide. Eight child control subjects tolerant to regular ingestion of scGOS-supplemented CMF and 1 adult volunteer were found to have negative results to scGOS through SPTs and BATs. In addition, in vitro BATs with donor basophils sensitized with sera from 2 of the 3 reported cases showed reactions to scGOS. The scGOS-induced basophil activation was inhibited in the presence of wortmannin, a phosphatidylinositol 3-kinase inhibitor. CONCLUSIONS: This study describes an unusual form of IgE-mediated anaphylaxis triggered by low-molecular-weight oligosaccharides in scGOS. The primary sensitizer for this phenomenon requires further investigation.

An Evaluation of the Mechanisms of Galacto-Oligosaccharide (GOS)-Induced IgE Cross-Linking on Basophils in GOS Allergy.

The prebiotics, galacto-oligosaccharides (GOS), are small carbohydrate molecules with 1-7 galactose units linked to glucose and have been shown to trigger IgE-mediated anaphylaxis in some cases following ingestion. It is still an unresolved question of how GOS cross-links IgE on basophils. In this study, we examined whether human galectins, a class of lectins that bind specifically to ß-galactoside carbohydrates, are involved in GOS-induced basophil activation. Basophil activation test to GOS and control allergen, Blomia tropicalis (Blo t) extract were performed in the presence or absence of four sugar-based galectin inhibitors (lactose, thiodigalactoside [TDG], TD139, and GB1107) and one peptide-based inhibitor, G3-C12. Results showed that TD139, GB1107, and G3-C12 did not display a specific inhibitory effect on GOS-induced basophil activation as compared to control allergen. An inhibitory effect of lactose and TDG on GOS-induced basophil activation was observed and varied between subjects with up to 100% inhibition at low doses of GOS. The results of competitive ELISA suggest that the inhibitory effects of high dose lactose and TDG on the basophil activation is likely due to the cross-reactivity of GOS-specific IgE to lactose and TDG. Basophil activation is performed using purified basophils suggested that cell surface receptors on other blood cells were not required to induce basophil activation. In conclusion, our results suggest that GOS, a low molecular weight sugar, is able to cross-link IgE independently.

Mite component-specific IgE repertoire and phenotypes of allergic disease in childhood: the tropical perspective.

Sensitization to perennial aeroallergens correlates with the risk of persistent asthma (AS) in children. In tropical Singapore, multiple codominant species of mites abound in the indoor environment, and preferential species-specific sensitization has been associated with different phenotypes of allergic disease. We investigated the pattern of mite component-specific IgE (mcsIgE) in children with different phenotypes of clinical allergic disease in an environment with multiple mite species exposure. A prospective evaluation of newly diagnosed patients with clinical diagnosis of allergic rhinitis (AR), atopic dermatitis (AD), or AS and sensitization to one or more aeroallergens were performed. Sera were tested for specific IgE against an extensive panel of Dermatophagoides pteronyssinus and Blomia tropicalis allergens. A total of 253 children were included, mean age 7.3 yr, 79% fulfilled criteria for AR, 46% AS, 71% AD, and 31% for all three. Sensitization to one or both mites was observed in 91% of children, 89% were sensitized to D. pteronyssinus, and 70% to B. tropicalis. The most common mite allergens recognized by these atopic children were Der p 1 (64%), Der p 2 (71%), Blo t 5 (45%), Blo t 7 (44%), and Blo t 21 (56%). Specific IgE responses to an increased number of distinct mite allergens correlated with the complexity of the allergic phenotype. In multivariate analysis, an increased risk for the multi-systemic phenotype (AR + AS + AD) was associated with sensitization to an increased repertoire of mite components (three or more) (OR 4.3, 95% CI 2.1-8.8, p = 0.001) and a positive parental history of AS (OR 2.4, 95% CI 1.2-2.9, p = 0.013). A highly pleiomorphic IgE response to the prevalent indoor mites is associated with the presence of a multi-systemic allergic phenotype in childhood in a tropical environment.

Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity.

BACKGROUND: Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence. OBJECTIVE: To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity. METHODS: A retrospective study of patients who completed BL DPT from 1 August 2016 to 31 December 2017 at a paediatric allergy centre in Singapore. Suspected hypersensitivity reactions were classified as immediate (onset ≤1 hour) or delayed (onset > 1 hour). Patients with immediate reactions underwent skin prick test (SPT) followed by DPT if SPT was negative. Patients with delayed reactions underwent DPT directly. RESULTS: We identified 120 children who reported 121 suspected hypersensitivity reactions. The median age at reaction was 2.0 years (interquartile range [IQR], 1.0-5.0 years) and the median age at DPT was 7.4 years (IQR, 4.2-11.1 years). The timing of suspected hypersensitivity reaction was immediate in 21% (25 of 121), delayed in 66% (80 of 121), and uncertain in 13% (16 of 121). Commonly implicated drugs were amoxicillin in 45% (54 of 121), amoxicillin-clavulanate in 37% (45 of 121), and cephalexin in 8% (10 of 121). Commonly reported symptoms were maculopapular rash 44% (53 of 121), urticaria 34% (41 of 121), and angioedema 22% (27 of 121). All SPTs (n = 26) were negative. There were 118 diagnostic DPTs to index drug and 3 DPTs to alternative drug. A negative challenge result was obtained in 93% (110 of 118) of diagnostic DPTs: 92% (96 of 104) and 100% (14 of 14) of DPTs to penicillin group and cephalosporins respectively. All challenge reactions were mild. CONCLUSION: Our study supports the opinion that prior skin tests may not be necessary for children who report nonsevere reactions and directly performing diagnostic DPT is a safe approach in the evaluation of suspected childhood BL hypersensitivity.

Childhood vaccinations: Hidden impact of COVID-19 on children in Singapore.

Although the direct health impact of Coronavirus disease (COVID-19) pandemic on child health is low, there are indirect impacts across many aspects. We compare childhood vaccine uptake in three types of healthcare facilities in Singapore - public primary care clinics, a hospital paediatric unit, and private paediatrician clinics - from January to April 2020, to baseline, and calculate the impact on herd immunity for measles. We find a 25.6% to 73.6% drop in Measles-Mumps-Rubella (MMR) uptake rates, 0.4 - 10.3% drop for Diphtheria-Tetanus-Pertussis-inactivated Polio-Haemophilus influenza (5-in-1), and 8.0-67.8% drop for Pneumococcal conjugate vaccine (PCV) across all 3 sites. Consequent herd immunity reduces to 74-84% among 12-month- to 2-year-olds, well below the 95% coverage that is protective for measles. This puts the whole community at risk for a measles epidemic. Public health efforts are urgently needed to maintain efficacious coverage for routine childhood vaccines during the COVID-19 pandemic.

Erratum to "IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper" [World Allergy Organ J 13/2 (2020) 100080].

[This corrects the article DOI: 10.1016/j.waojou.2019.100080.].

Phenomic Analysis of Chronic Granulomatous Disease Reveals More Severe Integumentary Infections in X-Linked Compared With Autosomal Recessive Chronic Granulomatous Disease.

Background: Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI), characterised by recurrent bacterial and fungal infections. It is inherited either in an X-linked (XL) or autosomal recessive (AR) mode. Phenome refers to the entire set of phenotypes expressed, and its study allows us to generate new knowledge of the disease. The objective of the study is to reveal the phenomic differences between XL and AR-CGD by using Human Phenotype Ontology (HPO) terms. Methods: We collected data on 117 patients with genetically diagnosed CGD from Asia and Africa referred to the Asian Primary Immunodeficiency Network (APID network). Only 90 patients with sufficient clinical information were included for phenomic analysis. We used HPO terms to describe all phenotypes manifested in the patients. Results: XL-CGD patients had a lower age of onset, referral, clinical diagnosis, and genetic diagnosis compared with AR-CGD patients. The integument and central nervous system were more frequently affected in XL-CGD patients. Regarding HPO terms, perianal abscess, cutaneous abscess, and elevated hepatic transaminase were correlated with XL-CGD. A higher percentage of XL-CGD patients presented with BCGitis/BCGosis as their first manifestation. Among our CGD patients, lung was the most frequently infected organ, with gastrointestinal system and skin ranking second and third, respectively. Aspergillus species, Mycobacterium bovis, and Mycobacteirum tuberculosis were the most frequent pathogens to be found. Conclusion: Phenomic analysis confirmed that XL-CGD patients have more recurrent and aggressive infections compared with AR-CGD patients. Various phenotypic differences listed out can be used as clinical handles to distinguish XL or AR-CGD based on clinical features.

Clinical characteristics and genotype-phenotype correlation in 62 patients with X-linked agammaglobulinemia.

INTRODUCTION: X-linked agammagobulinemia (XLA) is a primary immunodeficiency disorder caused by Bruton's tyrosine kinase (Btk) gene mutation. Recent studies suggested genotype-phenotype correlation in XLA, but a definitive association remains controversial. PATIENTS AND METHODS: We examined the relationship between specific Btk gene mutations and severity of clinical presentation in 62 patients with XLA. Disease severity was assessed by the age of disease onset and the presence of severe infections, while mutations were classified into severe and mild based on structural and functional consequence by bioinformatics analysis. RESULTS: Fifty-six Btk mutations were identified in 62 patients from 57 kindreds. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset as well as occurrence of severe infections. CONCLUSION: A critical analysis of the circumstances upon presentation also revealed that under-recognition of recurrent infections and relevant family history are important hurdles to timely diagnosis of XLA.

Serological and clinical characteristics of children with peanut sensitization in an Asian community.

In the past two decades, peanut allergy prevalence has increased in the West but has been perceived as having remained low in Asia. To review the clinical presentation of Asian children with peanut hypersensitivity and measure their IgE responses to major peanut allergens. We enrolled 31 children presenting with various allergies and a positive skin prick test to peanut from the Children's hospital outpatient allergy clinic in Singapore. A detailed questionnaire was completed by parents. The children's serum IgE specific to native Ara h 1, native Ara h 2, and recombinant Ara h 3 were detected using ELISA. Of the 31 patients, 19 had previously documented reactions to peanuts, while 12 had no previous clinical reaction. Most, 89.5% (17/19) of first reactions featured skin changes (urticaria, erythema, angioedema), but only 36.8% (7/19) involved skin symptoms alone. Respiratory symptoms and GI symptoms occurred in 42.1% and 26.3% of patients respectively and did not occur as the sole manifestation of reaction. The most common GI manifestation was emesis, present in 26.3% (5/19) of subjects. Two children experienced impaired consciousness with systemic, anaphylactic events. Although most sought treatment for their first peanut reaction only one patient received epinephrine. Half of our patients reported a subsequent accidental ingestion after the diagnosis of peanut allergy, with a median time from diagnosis to first accidental ingestion of 4 months and a reported increased severity of reaction in approximately half of the repeat exposures. Eighty-seven percent of children had specific IgE directed against at least one of the major peanut allergens. Among all patients, 87.1% had IgE specific to both Ara h 1 and Ara h 2 and 54.8% to rAra h 3. Asian children with peanut sensitization have clinically similar presentations and respond to the same major allergenic proteins as their Western counterparts. The perceived differences between the populations in this context do not stem from divergent clinical or immunological responses.

A 5-year retrospective review of children with peanut allergy in the largest paediatric hospital in Singapore.

BACKGROUND: The prevalence of peanut allergy (PA) among children has increased significantly over the past decade. Even though the prevalence of PA in Singapore is considered low, peanut is the top trigger for food-induced anaphylaxis in Singaporean children. OBJECTIVE: To describe the demographic characteristics and clinical features of children with PA. METHODS: This is a 5-year retrospective review of children diagnosed with PA based on clinical history coupled with a positive skin prick test to peanut or positive oral food challenge results. RESULTS: There were 269 patients (53.9% males) with a clinical diagnosis of PA. The median age at first allergic presentation for the PA group was 24 months old, with interquartile range of 13-39 months. The most common form of peanut introduced was roasted peanut. The rate of peanut anaphylaxis was 7.1%. Concomitant tree nut sensitization was found in 32.3% of this cohort, predominantly to cashew nut. Majority of them have a personal history of atopy - 75.8% with eczema, 63.6% with allergic rhinitis, and 19.7% with asthma. CONCLUSION: This is the first large review of peanut-allergic children in Singapore. Prospective population-based studies are needed to establish the true prevalence and risk factors associated with the development of this potentially life-threatening condition.

Retraction Note to: Partially hydrolysed, prebiotic supplemented whey formula for the prevention of allergic manifestations in high risk infants: a multicentre double-blind randomised controlled trial.

[This retracts the article DOI: 10.1186/2045-7022-5-S3-P30.].