Prevalence Of Contact Allergy Research Articles

Contact allergy to neomycin in consecutively patch tested Danish eczema patients from 2000 to 2023: A cross-sectional study.

Neomycin is an aminoglycoside antibiotic that may cause contact allergy. It was withdrawn as a medicine for human use in Denmark in October 2009 but is still found in some vaccines. To identify time trends in contact allergy to neomycin in the period from 2000 to 2023. A cross-section study of patients ≥18 years consecutively patch-tested with neomycin sulfate (20% in pet.) at Gentofte Hospital, Denmark, during the period 2000-2023 was conducted. The overall prevalence of contact allergy to neomycin was 1.4%. The prevalence was significantly lower in the period '2010-2023' (1.2%) than in '2000-2009' (1.8%) (p < 0.005). Contact allergy to neomycin was significantly positively associated with facial dermatitis and age >40 years, and significantly negatively associated with occupational dermatitis and hand dermatitis. No changes in sex, occupational dermatitis, atopic dermatitis, hand dermatitis, leg dermatitis, facial dermatitis, or age > 40/≤40 (the MOAHLFA-index) were identified when comparing neomycin contact allergic-patients in the two periods '2010-2023' and '2001-2009'. Neomycin is a rare cause of contact allergy in Denmark with a significantly lower prevalence following its withdrawal as a medicinal product for human use in Denmark in 2009.

Current frequency of contact allergy to isothiazolinones (methyl-, benz- and octylisothiazolinone) across Europe.

The use of methylisothiazolinone (MI) as a preservative in cosmetic products caused an alarming increase in MI contact allergy across Europe in the 2010s. This was followed by regulations of use with a total ban on leave-on (implemented in 2017) and reduced use concentrations in rinse-off cosmetics (2018). To follow-up on the prevalence of contact allergy to MI and the related benzisothiazolinone (BIT) and octylisothiazolinone (OIT) in consecutively patch-tested patients in Europe. A cross-sectional audit following the design of two previous audits on MI contact allergy from 1 May 2022 to 31 October 2022 included all patients patch tested with the European baseline series, including or supplemented with MI, BIT and OIT across 10 departments in eight European countries. A total of 2554 patients were consecutively patch tested with the three isothiazolinones during the study period. The prevalence of MI and BIT contact allergy was 2.9% (95% confidence interval [CI]: 2.3%-3.7%; range 1.1%-5.8%) and 3.1% (95% CI: 2.4%-3.9%; range 0.0%-6.6%), respectively; that of OIT was 0.7% (95% CI: 0.4%-1.1%; range 0%-3.2%). Rinse-off cosmetic (73.3%) and leave-on cosmetic products (13.3%) were still associated with eliciting allergic contact dermatitis to MI. We confirmed a positive impact of regulatory measures on the prevalence of MI contact allergy in Europe, which halved compared to 2015. However, our data suggest that consumers may still be exposed to older cosmetic products containing MI. BIT has superseded MI in causing contact allergy, despite not being allowed for use in cosmetic products.

Contact allergy to topical ophthalmic medications: A retrospective single-centre study of three decades.

The prevalence of contact allergy to various ophthalmic medications appears to be rare; however, data on culprits, clinical relevance of sensitizations, and changes in frequency within recent decades are limited. This study aimed to investigate the clinical relevance, risk factors, and prevalence of contact allergy to topical ophthalmic medications in patients suspected of allergic contact dermatitis to ophthalmic medication. We retrospectively analysed patch test results and clinical data for 754 patients patch-tested with an ophthalmic medication series at our tertiary referral centre between January 1992 and December 2022. In total, 37.5% (283/754) of patch-tested patients had a contact allergy to at least one ophthalmic allergen, with 87.3% (247) being clinically relevant sensitization. Phenylephrine (31.8%, 192/604), povidone-iodine (29%, 27/93), and tobramycin (23%, 46/200) were the most important sensitizers. The incidence of contact allergies increased significantly in a linear manner (p = 0.008) from 20% to 44.1% within the study period. Male sex and age above 40 were risk factors for contact allergy to ophthalmic medication. One third of patch tested patients had allergic contact dermatitis to ophthalmic medication, particularly phenylephrine. Male sex and age above 40 years were independent risk factors and drove the linear increase in contact allergy to ophthalmic medications within the past 31 years.

Contact Allergy to Allergens in the Swedish Baseline Series Overrepresented in Diabetes Patients with Skin Reactions to Medical Devices - A Retrospective Study from Southern Sweden.

Allergic contact dermatitis is reported among individuals using continuous glucose monitoring systems and insulin pumps. The aim of this study was to describe contact allergy patterns for allergens in the Swedish baseline series and medical device-related allergens among users. Contact allergy to baseline series allergens and isobornyl acrylate was compared between diabetes patients and dermatitis patients patch-tested at the Department of Occupational and Environmental Dermatology during 2017 to 2020. Fifty- four diabetes patients and 2,567 dermatitis patients were included. The prevalence of contact allergy to fragrance mix II and sesquiterpene lactone mix was significantly higher in diabetes patients compared with dermatitis patients. Of the diabetes patients 13.0% and of the dermatitis patients 0.5% tested positive to sesquiterpene lactone mix (p < 0.001). Of the diabetes patients 7.4% and of the dermatitis patients 2.3% tested positive to fragrance mix II (p = 0.041). Of the diabetes patients 70.4% tested positive to medical device-related allergens. Of the diabetes patients 63.0% and of the dermatitis patients 0.2% were allergic to isobornyl acrylate (p < 0.001). In conclusion, not only medical device-related contact allergies, but also contact allergy to baseline series allergens (fragrance mix II and sesquiterpene lactone mix), is overrepresented in diabetes patients who use medical devices.

Results of patch testing with five fragrance materials hitherto not tested: A dose-finding study in the clinical population.

Quantitative risk assessment (QRA) for skin sensitization is used to derive safe use levels of sensitising fragrance ingredients in products. Post-marketing surveillance of the prevalence of contact allergy to these ingredients provides relevant data to help evaluate the performance of these measures. To determine a suitable patch test concentration for five fragrance materials that had hitherto not been tested on a regular basis. These concentrations are then to be used in a surveillance study with patch testing consecutive patients over an extended monitoring period. Furaneol, CAS.3658-77-3; trans-2-hexenal, CAS.6728-26-3; 4,8-dimethyl-4,9-decadienal, CAS.71077-31-1; longifolene, CAS.475-20-7; benzaldehyde, CAS.10052-7, were patch tested with other fragrance allergens in four clinics. Patch testing was conducted in three rounds, starting with the lowest concentrations of the five ingredients. The doses were increased in the subsequent rounds if no late-appearing positive reactions and virtually no irritant reactions were reported. Overall, 373 patients were tested. No positive allergic reaction was reported to the five ingredients. Patch test results of other fragrance allergens are reported. The highest test concentrations are each considered safe for patch testing consecutive patients. Further surveillance based on these preparations will evaluate the hypothesis that QRA-driven consumer product levels of these fragrances can prevent sensitization.

Contact allergy to rubber accelerators in consecutively patch tested Danish eczema patients: A retrospective observational study from 1990 to 2019.

Rubber accelerators are used in the production of rubber gloves and may cause contact allergy. To estimate long-term trend and prevalence of contact allergy to rubber accelerators for a 30-year period in Denmark, high-risk occupations, and exposures. Data from all patients with contact dermatitis consecutively patch tested at the department of Skin and Allergy Gentofte hospital with the rubber accelerators from the European baseline series (EBS) from 1990 to 2019, were analysed. Further, patients under suspicion of rubber accelerator contact allergy were additionally patch-tested with rubber accelerators from the specialised rubber series from 2005 to 2019 and these were additional extracted. The overall prevalence of contact allergy to one or more of the rubber accelerators from the EBS series was 2.7% with a significant decline in the first 12-years, followed by a stable frequency in the past 18-years. Associations with occupational contact dermatitis, hand dermatitis, and leg/foot dermatitis were found. Wet-work occupations were most often affected and gloves the most frequent exposure. Contact allergy to one or more of the rubber accelerators from the EBS is frequent and has been unchanged for several decades, which calls for prevention.

The use of carvone in consecutive patch testing.

Carvone (l-carvone) is a mint-tasting flavour additive that most of us is exposed to and can cause allergic contact reactions. To analyse the frequency and the relevance of positive carvone reactions in a dermatitis population. A retrospective analysis of dermatitis patients consecutively tested with carvone from 2017 to 2021. Data were retrieved from the department's patch-test database. Of 3554 patients tested with carvone, 28 (0.79%) had a positive reaction. Carvone-positive patients had higher mean age, were significantly more likely female (p< 0.001) and had often an intraoral/lip involvement (p< 0.001). In the carvone-positive group, 50% (n= 14) had a relevant reaction, and in 4 of 14, the relevance was first revealed after test reading. Of the carvone-positive patients, 18 of 28 did not have a coexisting allergy to a fragrance/flavour allergen and of these 44% had a relevant allergy. The study suggests that a significant fraction of relevant carvone contact allergies may be overlooked if the allergen is not tested. Furthermore, as the exposure is widespread, inclusion of carvone in the Swedish baseline series may be justified even if the contact allergy prevalence is below 1%.

Use of sorbitan sesquioleate in patch test preparations and patch testing with the substance-What do our results mean?

Sorbitan sesquioleate (SSO) is a sorbitan fatty acid ester, an emulsifier used in topical products and certain patch test preparations. SSO may affect the patch test results. It has been debated whether to include the substance in the baseline series to avoid misinterpretation of the results. To report the prevalence and simultaneous reactions of SSO with other patch test preparations containing SSO as an emulsifier. A retrospective analysis of 3539 dermatitis patients who underwent patch testing from 2016 to 2020 was performed. The 5-year SSO contact allergy prevalence was 0.48%, and 1.3% had a doubtful reaction. Patients with a stronger positive reaction (2+, 3+) were more likely to react simultaneously to other allergen preparations containing SSO (p value=0.018). One patient with a strong reaction to SSO reacted positively to all SSO-containing patch test preparations. Definite fragrance allergens could not be identified in the patients who had simultaneous reactions to SSO and fragrance mix (FM) I. Patch testing with allergen preparations containing SSO affected the patch test interpretation. Fragrance contact allergy could not be ruled out when a patient simultaneously reacted to SSO and FM I. Changing emulsifiers in patch test preparations would be advantageous.

Systematic review on skin adverse effects of important hazardous hair cosmetic ingredients with a focus on hairdressers.

The burden of occupational hand eczema in hairdressers is high, and (partly strong) allergens abound in the hair cosmetic products they use. To systematically review published evidence concerning contact allergy to an indicative list of active ingredients of hair cosmetics, namely, p-phenylenediamine (PPD), toluene-2,5-diamine (PTD), persulfates, mostly ammonium persulfate (APS), glyceryl thioglycolate (GMTG), and ammonium thioglycolate (ATG), concerning the prevalence of sensitization, particularly in terms of a comparison (relative risk; RR) between hairdressers and non-hairdressers. Following a PROSPERO-registered and published protocol, eligible literature published from 2000 to February 2021 was identified, yielding 322 publications, and extracted in standardized publication record forms, also considering risk of bias. Based on 141 publications, the contact allergy prevalence to PPD was 4.3% (95% CI: 3.8-4.9%) in consecutively patch tested patients. Other ingredients were mostly tested in an aimed fashion, yielding variable, and partly high contact allergy prevalences. Where possible, the RR was calculated, yielding an average increased sensitization risk in hairdressers of between 5.4 (PPD) and 3.4 (ATG). Additional evidence related to immediate-type hypersensitivity, experimental results, exposures, and information from case reports was qualitatively synthesized. An excess risk of contact allergy is clearly evident from the pooled published evidence from the last 20 years. This should prompt an improvement in working conditions and product safety.

Prevalence of contact allergy to corticosteroids in a Danish patient population.

BackgroundAllergic contact dermatitis to corticosteroids can be a challenging diagnosis as corticosteroids are used in the treatment of dermatitis. The prevalence of contact allergy to corticosteroid varies between previous studies.ObjectiveTo study the prevalence of sensitization to budesonide, tixocortol‐21‐pivalate and hydrocortisone‐17‐butyrate in a Danish patient population from 2006‐2020, cross‐sensitization, risk factors and clinical relevance.MethodsA retrospective analysis of patch test data and MOAHLFA index was performed among 6823 patients consecutively patch tested with TRUE test as part of the baseline series.ResultsA positive patch test for corticosteroids was found in 185 patients (1.2% budesonide, 1.6% tixocortol‐21‐pivalate, 1.0% hydrocortisone‐17‐butyrate) without gender difference. For women, the prevalence of tixocortol‐21‐pivalate sensitization increased significantly from 1.3% in 2006–2008 to 2.9% in 2018–2020. Tixocortol‐21‐pivalate sensitization had more frequently clinical relevance in women (61.3%) compared to men (34.5%). Age above 40 years was positively associated to corticosteroid sensitization. Budesonide and hydrocortisone‐17‐butyrate accounted for 67.7% of co‐sensitizations.ConclusionsThe prevalence of corticosteroid sensitization was 2.7%. Age was the only risk factor for corticosteroid sensitization. The frequency of corticosteroid sensitization was stabile over time except for tixocortol‐21‐pivalate sensitization for women. About one third of sensitized patients had co‐sensitizations to other corticosteroid groups.

Contact allergy in children with and without atopic dermatitis: An Italian multicentre study.

BackgroundContact allergy and atopic dermatitis (AD) are both common inflammatory T cell‐mediated diseases and many factors may influence the prevalence of contact allergy in AD patients. In children, their possible correlation was debated with conflicting results.ObjectivesThe present study aimed to assess the prevalence of contact sensitivity in children and to investigate the association with AD.Materials and methodsA retrospective multicentre study on children aged from 0 to 14 years patch tested between January 2017 and December 2018 was performed. Children were consecutively patch tested with the SIDAPA (Società Italiana Dermatologia Allergologica Professionale Ambientale) baseline series.ResultsAmong the 432 children investigated for contact allergy, 125 (28.9%) showed a positive reaction to at least one of the allergens tested, with a higher prevalence of positive patch test reactions in girls (32.3%) than in boys (25.0%). The most frequent contact allergens were nickel sulphate (10.2%), cobalt chloride (6.7%), methylisothiazolinone (3.7%), fragrance mix‐2 (3.2%), potassium dichromate (2.8%), fragrance mix‐1 (2.1%) and methylchloroisothiazolinone/methylisothiazolinone (2.1%). One‐hundred‐three children (23.8%) suffered from AD showing a higher prevalence of positive patch test (36.9%) compared to children without AD (26.4%).ConclusionsDespite the topic being still controversial, the present study suggests a consistent prevalence of contact allergy among children with higher sensitivity rate among children with AD than without AD.

Nickel: Intrinsic Skin Sensitization Potency and Relation to Prevalence of Contact Allergy.

Nickel: Intrinsic Skin Sensitization Potency and Relation to Prevalence of Contact Allergy.

Prevalence of Contact Allergy to Nickel: A Retrospective Chart Review.

No recent studies reporting nickel sensitivity prevalence in Canadians exist. The aim of this study was to quantify nickel sensitivity prevalence in patients at a patch test clinic in Vancouver. Retrospective chart review of 3263 patients patch tested for nickel sensitivity at our clinic in Vancouver between 2008 and 2020. In total, 24.3% (n = 792 of 3263) of patients were sensitive to nickel. Nickel sensitivity significantly increased over time from 24.3% to 27.9% from 2008 to 2020. Nickel-sensitive patients were significantly more likely to be women (P < 0.001), between the ages of 19 and 64 years (P = 0.010), and have dermatitis affecting the face (P = 0.001) and hands (P = 0.001). Nickel-sensitive patients were significantly less likely to be 65 years or older (P = 0.001) and have dermatitis affecting the legs (P = 0.002). Approximately half of nickel-sensitive reactions were new positive reactions at the second reading. Nickel sensitivity occurred in approximately one quarter of patients and significantly increased over time. Nickel-sensitive patients were more likely to be women, aged 19 to 64 years, and have dermatitis affecting the face and hands; and less likely to be 65 years or older and have dermatitis affecting the legs.

Contact allergy to haptens in the Swedish baseline series: Results from the Swedish Patch Test Register (2010 to 2017).

Allergic contact dermatitis has considerable public health impact and causative haptens vary over time. To report the prevalence of contact allergy to allergens in the Swedish baseline series 2010 to 2017, as registered in the Swedish Patch Test Register. Results and demographic information for patients tested with the Swedish baseline series in 2010 to 2017 were analysed. Data for 21 663 individuals (females 69%) were included. Females had significantly more positive patch tests (54% vs 40%). The reaction prevalence rates were highest for nickel sulfate (20.7%), fragrance mix I (7.1%), Myroxylon pereirae (6.9%), potassium dichromate (6.9%), cobalt chloride (6.8%), methylchloroisothiazolinone/methylisothiazolinone (MCI/MI; 6.4%), MI (3.7%), colophonium (3.5%), fragrance mix II (3.2%), and formaldehyde (3.2%). Myroxylon pereirae reaction prevalence increased from 5% in 2010 to 9% in 2017 and that for methyldibromo glutaronitrile from 3.1% to 4.6%. MCI/MI and MI reactions decreased in prevalence after 2014. Nickel reaction prevalence decreased among females aged 10 to 19 years. Nickel remains the most common sensitizing agent, with reaction prevalence decreasing among females younger than 20 years. The changes in MCI/MI and MI reaction prevalence mirrored those in Europe. The register can reveal changes in contact allergy prevalence over time among patients patch tested in Sweden.

Occupational Allergic Contact Dermatitis in Wind Turbine Blades Production

Introduction: Epoxy resins, widely used in several industrial sectors, are among the main causes of allergic contact dermatitis. The wind turbine production industry is one of the sectors that uses these products widely. This study aimed to assess the prevalence of contact allergy to epoxy resin and its components among wind turbine blades production workers with suspected contact dermatitis.&#x0D; Methods: We performed a retrospective analysis of the patch test results performed between 2012 and 2019 in wind turbine blades production workers with dermatitis and characterized their demographic and clinical data, patch test results and the occupational impact of allergic contact dermatitis on these workers.&#x0D; Results: Out of the 3049 patients patch tested in the period 2012-2019, we identified thirteen wind turbine blades production workers, predominantly male (69.2%). All of them handled glues, resins and/or paints in their daily work activities. Seven (53.8%) had a combination of hand dermatitis and airborne dermatitis, two (15.4%) had exclusively hand dermatitis and four (30.8%) had predominantly airborne dermatitis. All patients had positive patch test for epoxy resin and ten patients (76.9%) had also reaction for 1,6-hexanediol diglycidylether. Two patients (15.4%) also had a reaction to the already hardened resin powder. Four (30.8%) patients had to quit their jobs due to allergic contact dermatitis and three (23.1%) were transferred to another workstation without exposure to epoxy resin. Avoidance of exposure resulted in a significant improvement.&#x0D; Conclusion: With this study, we confirmed that epoxy resin and its components are the main cause of dermatitis among wind turbine blades production workers, that eczema occurs by direct contact and by airborne exposure.

Trends in preservative allergy: Benzisothiazolinone emerges from the pack.

Preservatives are used widely in cosmetic, household, and industrial products to prevent microbial growth and spoiling of the products. There has been a recent epidemic of contact allergy to methylisothiazolinone (MI). To establish emerging trends in preservative contact allergy as MI is replaced. We performed a retrospective study on consecutively patch-tested patients at our center from January 2011 to December 2019. A total of 7846 consecutively patch-tested patients were included who were patch tested between January 2011 and December 2019. The prevalence of allergy to MI fell from a peak of 9.39% in 2013 to 1.98% in 2019. MI/methylchloroisothiazolinone (MCI) followed a similar trend, with a peak prevalence of 7.85% in 2014 and falling to 1.39% in 2018. The prevalence of contact allergy to benzisothiazolinone (BIT) has increased steadily increased in 2014 from 0.26% (confidence interval [CI] 0.03-0.93) to 3.42% (CI 2.43-4.66) in 2019. Our data show a significant increase in the prevalence of contact allergy to BIT over the last 6 years, probably as a consequence of increased use in household products. It is essential to continue to look for emerging trends in contact allergy to enable prompt preventative measures to be taken.

Contact allergy to fragrance mix I and its components in individuals with photocontact allergy to ketoprofen.

Contact allergy to fragrance mix I (FM I) is over-represented in patients photoallergic to ketoprofen. The prevalence of contact allergy to two components of FM I, cinnamal and cinnamyl alcohol, in ketoprofen-photoallergic patients is higher than in dermatitis patients. To explore the prevalence of contact allergy to FM I and its individual components in patients with photocontact allergy to ketoprofen, and to compare with a dermatitis and the general population. Data on patch and photopatch tests performed between 2009-2018 were collected. Ketoprofen-photoallergic patients were compared with dermatitis patients and published data on the general population regarding the prevalence and the distribution of contact allergy to FM I and its components. A higher prevalence of contact allergy to cinnamyl alcohol compared with cinnamal (23.3% vs 10.0%), and eugenol compared with isoeugenol (23.3% vs 6.7%), was observed in ketoprofen-photoallergic patients, while the relationship was the opposite in the dermatitis group (0.7% vs 1.05%; 0.4% vs 0.9%). The overall prevalence of contact allergy to several components of FM I was significantly higher in ketoprofen-photoallergic patients. Contact allergy to FM I and many of its components is over-represented in patients photoallergic to ketoprofen compared with dermatitis patients and the general population.

Should methyldibromo glutaronitrile continue to be used in the European baseline Series? A REIDAC national cross-sectional study.

Methyldibromo glutaronitrile (MDBGN) was one of the most frequent and relevant allergens found in patch testing at the beginning of this century. In 2008, this preservative was banned from cosmetics in Europe and ever since the prevalence of contact allergy to MDBGN has progressively decreased. Despite that gradual decline, MDBGN is still patch-tested in most baseline series. This study assessed the frequency of MDBGN sensitization, epidemiological characteristics of allergic patients, and the relevance of positive patch tests in a nationwide Spanish registry (REIDAC). We evaluated consecutively patch-tested patients in all participating centres. Using these data, we calculated the proportion of patients with positive patch tests to MDBGN from June 2018 to June 2020 and evaluated the relevance of the positive patch tests. One hundred and fourteen out of 5072 (2.24 %) tested patients were sensitized to MDBGN. Clinical current relevance was confirmed in only one case. Although the frequency of contact allergy to MDBGN remains high, no clinical significance was found in most of these patients (5072 tests needed to obtain one relevant positive result). The clinical usefulness of this allergen seems weak and its continued inclusion in the European baseline series is questionable.

Skin exposure to scented products used in daily life and fragrance contact allergy in the European general population - The EDEN Fragrance Study.

BackgroundFragrances are widely used in scented products used in daily life with the potential to induce skin sensitization.ObjectiveTo evaluate exposure to scented products and to explore associations between exposure and fragrance contact allergy.MethodsA cross‐sectional study on individuals from 18 to 74 years of age, who were randomly selected from the general population in five European countries. A random sample (N = 3119) was patch tested and interviewed on exposure to scented products.ResultsFemale participants were strongly associated with exposure to scented products relative to male participants. Participants age 40 years and older showed an inverse association with exposure to scented products. Compared to Sweden, The Netherlands followed by Germany showed the highest overall exposure to scented products. Sensitive skin was associated with exposure to scented products and with fragrance allergy. In univariable regression analysis, exposure to leave‐on products and to specific scented product subgroups was significantly associated with fragrance allergy.ConclusionExposure to scented products depends primarily on sex and age. Female sex and sensitive skin are relevant indicators for developing fragrance allergy. Because aggregate exposure, especially to scented leave‐on products, may enhance the prevalence of contact allergy to fragrances, further investigations into exposure amounts and frequencies is warranted.

Patch test results with the European baseline series and additions thereof in the ESSCA network, 2015-2018.

Clinical surveillance of the prevalence of contact allergy in consecutively patch tested patients is a proven instrument to continually assess the importance of contact allergens (haptens) assembled in a baseline series. To present current results from the European Surveillance System on Contact Allergies, including 13 countries represented by 1 to 11 departments. Anonymized or pseudonymized patch test and clinical data from various data capture systems used locally or nationally as transferred to the Erlangen data centre were pooled and descriptively analysed after quality control. In the 4 years (2015-2018), data from 51 914 patients patch tested with the European baseline series (EBS) of contact allergens were analysed. Contact allergy to nickel was most frequent (17.6% positive), followed by contact allergy to fragrance mix I (6.9%), methylisothiazolinone (MI; 6.2%), and Myroxylon pereirae resin (balsam of Peru; 5.8%). While the prevalence of MI contact allergy decreased substantially following regulatory intervention, the persistently high levels of allergy to metals, fragrances, other preservatives, and rubber chemicals point to problems needing further research and, potentially, preventive efforts. Results with national additions to the baseline series provide important information on substances possibly to be considered for inclusion in the EBS.