S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" - update 2023, part 2: epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Causes of irritant contact dermatitis after occupational skin exposure: a systematic review.

PURPOSE: Irritant contact dermatitis (ICD) is a major cause of occupational disease. The aim was to review the relation between exposure to occupational irritants and ICD and the prognosis of ICD. METHODS: Through a systematic search, 1516 titles were identified, and 48 studies were included in the systematic review. RESULTS: We found that the evidence for an association between ICD and occupational irritants was strong for wet work, moderate for detergents and non-alcoholic disinfectants, and strong for a combination. The highest quality studies provided limited evidence for an association with use of occlusive gloves without other exposures and moderate evidence with simultaneous exposure to other wet work irritants. The evidence for an association between minor ICD and exposure to metalworking fluids was moderate. Regarding mechanical exposures, the literature was scarce and the evidence limited. We found that the prognosis for complete healing of ICD is poor, but improves after decrease of exposure through change of occupation or work tasks. There was no substantial evidence for an influence of gender, age, or household exposures. Inclusion of atopic dermatitis in the analysis did not alter the risk of ICD. Studies were at risk of bias, mainly due to selection and misclassification of exposure and outcome. This may have attenuated the results. CONCLUSION: This review reports strong evidence for an association between ICD and a combination of exposure to wet work and non-alcoholic disinfectants, moderate for metalworking fluids, limited for mechanical and glove exposure, and a strong evidence for a poor prognosis of ICD.

Update "Systemic treatment of atopic dermatitis" of the S2k-guideline on atopic dermatitis.

This guideline is an update from August 2020 the S2k-guideline "Atopic dermatitis" published in 2015. The reason for updating this chapter of the guideline were the current developments in the field of systemic therapy of atopic dermatitis. The agreed recommendations for systemic treatment in atopic dermatitis of the present guideline are based on current scientific data. Due to the approval of dupilumab for the treatment of moderate to severe atopic dermatitis, which cannot be treated sufficiently with topical drugs alone, this part of the guideline has now been adapted and newly consented. The indication for systemic therapy and the therapeutic response to topical and systemic treatment should be recorded and documented in a suitable form in clinic and practice. A standardized documentation of the indication for system therapy in atopic dermatitis can be recommended and is also part of the updated chapter of this guideline.

No evidence of increased cancer incidence in children using topical tacrolimus for atopic dermatitis.

BACKGROUND: Long-term safety of topical calcineurin inhibitors is not well understood. APPLES (A Prospective Pediatric Longitudinal Evaluation to Assess the Long-Term Safety of Tacrolimus Ointment for the Treatment of Atopic Dermatitis; NCT00475605) examined incidence of lymphoma and other cancers in a pediatric population with atopic dermatitis. OBJECTIVE: To quantify incident malignancies during 10 years in children with atopic dermatitis who used topical tacrolimus for ≥6 weeks. METHODS: Standardized incidence ratios for cancer events were analyzed relative to sex-, age-, and race-matched control data from national cancer registries. RESULTS: There were 7954 eligible patients enrolled at 314 sites in 9 countries. During 44,629 person-years, 6 confirmed incident cancers occurred (standardized incidence ratio, 1.01; 95% confidence interval, 0.37-2.20). No lymphomas occurred. LIMITATIONS: Observational prospective cohort study. CONCLUSION: The cancer incidence was as expected, given matched background data. This finding provides no support for the hypothesis that topical tacrolimus increases long-term cancer risk in children with atopic dermatitis.

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma - short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators.

Actinic keratoses (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guideline is aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AK and cSCC. The guideline is also aimed at affected patients, their relatives, policy makers and insurance funds. In the first part, we will address aspects relating to diagnosis, interventions for AK, care structures and quality-of-care indicators.

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) - short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease.

Actinic keratoses (AKs) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guidelines for actinic keratosis and cutaneous squamous cell carcinoma were developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guidelines are aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AKs and cSCC. The guidelines are also aimed at affected patients, their relatives, policy makers and insurance funds. In the second part, we will address aspects relating to epidemiology, etiology, surgical and systemic treatment of cSCC, follow-up and disease prevention, and discuss AKs and cSCC in the context of occupational disease regulations.

Socioeconomic Status and the Prevalence of Skin and Atopic Diseases in Five European Countries.

The aim of this study was to investigate the association between socioeconomic status and the prevalence of self-reported skin and atopic diseases in the general population of 5 European countries. A random sample was drawn from the general population aged 18-74 years, based on electoral precincts. Socioeconomic status was estimated by combining net household income with the highest education of respondents. A total of 7,904 subjects were included in this analysis. The lifetime prevalence of "contact dermatitis" ranged from 13.1% (95% confidence interval (95% CI 11.8-14.4%) in subjects with low socioeconomic status, to 19.1% (95% CI 17.5-20.8%) in those with high socio-economic status. In younger subjects skin cancer was more prevalent in the middle or high socioeconomic status groups compared with the low socioeconomic status group (odds ratio 2.4; 95% CI 1.4-4.3); however, this effect was not found in elderly subjects. The lifetime prevalence for at least one atopic disease was 61.2% (95% CI 59.4-63.0%) in the low and 82.8% (95% CI 81.1-84.3%) in the high socioeconomic status group. Individuals with middle or high socioeconomic status reported an overall higher prevalence of skin and atopic diseases compared with those with low socioeconomic status. These findings may reflect differences in reporting, which are likely to result in an underdiagnoses, especially for skin cancer in the younger age groups with low socioeconomic status.

Interventions for hand eczema.

BACKGROUND: Hand eczema is an inflammation of the skin of the hands that tends to run a chronic, relapsing course. This common condition is often associated with itch, social stigma, and impairment in employment. Many different interventions of unknown effectiveness are used to treat hand eczema. OBJECTIVES: To assess the effects of topical and systemic interventions for hand eczema in adults and children. SEARCH METHODS: We searched the following up to April 2018: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, AMED, LILACS, GREAT, and four trials registries. We checked the reference lists of included studies for further references to relevant trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared interventions for hand eczema, regardless of hand eczema type and other affected sites, versus no treatment, placebo, vehicle, or active treatments. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes were participant- and investigator-rated good/excellent control of symptoms, and adverse events. MAIN RESULTS: We included 60 RCTs, conducted in secondary care (5469 participants with mild to severe chronic hand eczema). Most participants were over 18 years old. The duration of treatment was short, generally up to four months. Only 24 studies included a follow-up period. Clinical heterogeneity in treatments and outcome measures was evident. Few studies performed head-to-head comparisons of different interventions. Risk of bias varied considerably, with only five studies at low risk in all domains. Twenty-two studies were industry-funded.Eighteen trials studied topical corticosteroids or calcineurin inhibitors; 10 studies, phototherapy; three studies, systemic immunosuppressives; and five studies, oral retinoids. Most studies compared an active intervention against no treatment, variants of the same medication, or placebo (or vehicle). Below, we present results from the main comparisons.Corticosteroid creams/ointments: when assessed 15 days after the start of treatment, clobetasol propionate 0.05% foam probably improves participant-rated control of symptoms compared to vehicle (risk ratio (RR) 2.32, 95% confidence interval (CI) 1.38 to 3.91; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 8; 1 study, 125 participants); the effect of clobetasol compared to vehicle for investigator-rated improvement is less clear (RR 1.43, 95% CI 0.86 to 2.40). More participants had at least one adverse event with clobetasol (11/62 versus 5/63; RR 2.24, 95% CI 0.82 to 6.06), including application site burning/pruritus. This evidence was rated as moderate certainty.When assessed 36 weeks after the start of treatment, mometasone furoate cream used thrice weekly may slightly improve investigator-rated symptom control compared to twice weekly (RR 1.23, 95% CI 0.94 to 1.61; 1 study, 72 participants) after remission is reached. Participant-rated symptoms were not measured. Some mild atrophy was reported in both groups (RR 1.76, 95% CI 0.45 to 6.83; 5/35 versus 3/37). This evidence was rated as low certainty.Irradiation with ultraviolet (UV) light: local combination ultraviolet light therapy (PUVA) may lead to improvement in investigator-rated symptom control when compared to local narrow-band UVB after 12 weeks of treatment (RR 0.50, 95% CI 0.22 to 1.16; 1 study, 60 participants). However, the 95% CI indicates that PUVA might make little or no difference. Participant-rated symptoms were not measured. Adverse events (mainly erythema) were reported by 9/30 participants in the narrow-band UVB group versus none in the PUVA group. This evidence was rated as moderate certainty.Topical calcineurin inhibitors: tacrolimus 0.1% over two weeks probably improves investigator-rated symptom control measured after three weeks compared to vehicle (14/14 tacrolimus versus 0/14 vehicle; 1 study). Participant-rated symptoms were not measured. Four of 14 people in the tacrolimus group versus zero in the vehicle group had well-tolerated application site burning/itching.A within-participant study in 16 participants compared 0.1% tacrolimus to 0.1% mometasone furoate but did not measure investigator- or participant-rated symptoms. Both treatments were well tolerated when assessed at two weeks during four weeks of treatment.Evidence from these studies was rated as moderate certainty.Oral interventions: oral cyclosporin 3 mg/kg/d probably slightly improves investigator-rated (RR 1.88, 95% CI 0.88 to 3.99; 1 study, 34 participants) or participant-rated (RR 1.25, 95% CI 0.69 to 2.27) control of symptoms compared to topical betamethasone dipropionate 0.05% after six weeks of treatment. The risk of adverse events such as dizziness was similar between groups (up to 36 weeks; RR 1.22, 95% CI 0.80 to 1.86, n = 55; 15/27 betamethasone versus 19/28 cyclosporin). The evidence was rated as moderate certainty.Alitretinoin 10 mg improves investigator-rated symptom control compared with placebo (RR 1.58, 95% CI 1.20 to 2.07; NNTB 11, 95% CI 6.3 to 26.5; 2 studies, n = 781) and alitretinoin 30 mg also improves this outcome compared with placebo (RR 2.75, 95% CI 2.20 to 3.43; NNTB 4, 95% CI 3 to 5; 2 studies, n = 1210). Similar results were found for participant-rated symptom control: alitretinoin 10 mg RR 1.73 (95% CI 1.25 to 2.40) and 30 mg RR 2.75 (95% CI 2.18 to 3.48). Evidence was rated as high certainty. The number of adverse events (including headache) probably did not differ between alitretinoin 10 mg and placebo (RR 1.01, 95% CI 0.66 to 1.55; 1 study, n = 158; moderate-certainty evidence), but the risk of headache increased with alitretinoin 30 mg (RR 3.43, 95% CI 2.45 to 4.81; 2 studies, n = 1210; high-certainty evidence). Outcomes were assessed between 48 and 72 weeks. AUTHORS' CONCLUSIONS: Most findings were from single studies with low precision, so they should be interpreted with caution. Topical corticosteroids and UV phototherapy were two of the major standard treatments, but evidence is insufficient to support one specific treatment over another. The effect of topical calcineurin inhibitors is not certain. Alitretinoin is more effective than placebo in controlling symptoms, but advantages over other treatments need evaluating.Well-designed and well-reported, long-term (more than three months), head-to-head studies comparing different treatments are needed. Consensus is required regarding the definition of hand eczema and its subtypes, and a standard severity scale should be established.The main limitation was heterogeneity between studies. Small sample size impacted our ability to detect differences between treatments.

The significance of batch and patch test method in establishing contact allergy to fragrance mix I-EDEN Fragrance Study Group.

BACKGROUND: A fragrance mix consisting of eight separate fragrance ingredients (fragrance mix I [FM I]) is present in most baseline patch test series. Patch testing with the TRUE Test technique is considered to detect less contact allergy to FM I than testing with the Finn Chamber technique. OBJECTIVE: To investigate the possible significance of batch and patch test method in establishing contact allergy to FM I. METHODS: Three thousand one hundred and nineteen individuals representing a sample of the general population were patch tested with two batches of FM I with two patch test techniques at six dermatology clinics in five European countries. The TRUE Test technique and the Finn Chamber technique with pet. preparations were used. McNemar's test was used for statistical calculations. RESULTS: The contact allergy prevalences varied between 0.7% and 2.6%. The patch tests with the mixes containing Evernia prunastri (oak moss) with a high content of chloratranol/atranol resulted in substantially more positive reactions than the corresponding tests with the mixes containing oak moss with a low content of chloratranol/atranol. The Finn Chamber technique detected significantly more contact allergic reactions than the TRUE Test technique (P < 0.001). CONCLUSION: The Finn Chamber technique detects more contact allergy to FM I than the TRUE Test technique.

Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry.

BACKGROUND: The CARPE registry was set up in 2009 to prospectively investigate the management of patients with chronic hand eczema (CHE). OBJECTIVES: To report comprehensive follow-up data from the CARPE registry. PATIENTS AND METHODS: We investigated sociodemographic and clinical characteristics, provision of medical care, physician-assessed outcomes, and patient-reported outcomes (PROs). Data were collected between 2009 and 2016, with up to 5 years of follow-up, and are reported descriptively. RESULTS: Overall, 1281 patients were included in the registry (53.7% female). Mean age was 47.0 years. Of the patients, 793 and 231 completed the 2-year follow-up and 5-year follow-up, respectively. At baseline, 5.4% had changed or given up their job because of CHE, the average duration of CHE was 6.1 years, and, in 22.4%, the CHE was severe according to physician global assessment. Systemic treatment (alitretinoin, acitretin, and methotrexate) was prescribed at least once to 39.0% of the patients during the course of the follow-up. Disease severity, quality of life and treatment satisfaction improved over time, and the proportion of patients receiving systemic treatments decreased. CONCLUSIONS: Under continued dermatological care, substantial improvements in disease severity and PROs over time was achieved during the course of the CARPE registry, even in patients with long-standing and severe hand eczema.

Skin sensitization quantitative risk assessment for occupational exposure of hairdressers to hair dye ingredients.

Occupational exposure of hairdressers to hair dyes has been associated with the development of allergic contact dermatitis (ACD) involving the hands. p-Phenylenediamine (PPD) and toluene-2,5-diamine (PTD) have been implicated as important occupational contact allergens. To conduct a quantitative risk assessment for the induction of contact sensitization to hair dyes in hairdressers, available data from hand rinsing studies following typical occupational exposure conditions to PPD, PTD and resorcinol were assessed. By accounting for wet work, uneven exposure and inter-individual variability for professionals, daily hand exposure concentrations were derived. Secondly, daily hand exposure was compared with the sensitization induction potency of the individual hair dye defined as the No Expected Sensitization Induction Levels (NESIL). For PPD and PTD hairdresser hand exposure levels were 2.7 and 5.9 fold below the individual NESIL. In contrast, hand exposure to resorcinol was 50 fold below the NESIL. Correspondingly, the risk assessment for PPD and PTD indicates that contact sensitization may occur, when skin protection and skin care are not rigorously applied. We conclude that awareness of health risks associated with occupational exposure to hair dyes, and of the importance of adequate protective measures, should be emphasized more fully during hairdresser education and training.

Prevalence of contact allergy to metals in the European general population with a focus on nickel and piercings: The EDEN Fragrance Study.

BACKGROUND: Studies on sensitization to metals in the general population are scarce. OBJECTIVES: To determine the prevalence of sensitization to metals in the general population, and factors associated with nickel sensitization. METHODS: In 5 European countries (The Netherlands, Germany, Italy, Portugal and Sweden), a random sample (N = 3119) from the general population (aged 18-74 years) was patch tested and interviewed by use of a questionnaire on exposure to metals, piercing, and jewellery. RESULTS: Overall, the age-standardized prevalences of sensitization to nickel, cobalt and chromium were, respectively, 14.5%, 2.1%, and 0.8%. The highest prevalence of nickel sensitization was seen in Portugal (18.5%) and the lowest (8.3%) in Sweden. The prevalence of cobalt sensitization varied between 3.8% (The Netherlands) and 0.9% (Italy), and the prevalence of chromium sensitization varied between 1.3% (Portugal) and 0.2% (Sweden). Significant associations were observed between nickel allergy and female sex (odds ratio [OR] 5.19; 95% confidence interval [95%CI]: 3.99-6.74), past piercing use (OR 3.86; 95%CI: 2.85-5.24), and currently having ≥3 piercings (OR 5.58; 95%CI: 4.02-7.76). CONCLUSIONS: The prevalence of sensitization to metals in the European general population was high, mostly because of nickel. The lowest prevalence of contact allergy to nickel and chromium observed in Sweden supports the effectiveness of long-standing regulation.

Allergic contact dermatitis caused by nail acrylates in Europe. An EECDRG study.

BACKGROUND: Allergic contact dermatitis (ACD) caused by nail acrylates, also including methacrylates and cyanoacrylates here, is being increasingly reported. METHODS: A retrospective study in 11 European Environmental Contact Dermatitis Research Group (EECDRG) clinics collected information on cases of ACD caused by nail acrylates diagnosed by aimed testing between 2013 and 2015. RESULTS: Among 18 228 studied patients, 136 had ACD caused by nail acrylates (0.75%; 95%CI: 0.60-0.90), representing 67.3% (95%CI: 60.4-73.7) of ACD cases caused by acrylates. There were 135 females and 1 male, with a mean age ± standard deviation of 36.7 ± 12.2 years; 59 (43.4%) were exposed as consumers, and 77 (56.6%) were occupationally exposed. Occupational cases were more frequent in southern Europe (83.7%), and were younger (mean age of 33.4 ± 8.9 years); most developed ACD during the first year at work (65.0%), and at least 11.7% had to leave their jobs. Skin lesions involved the hands in 121 patients (88.9%) and the face in 50 (36.8%), with the face being the only affected site in 14 (10.3%). Most patients reacted to two or more acrylates on patch testing, mainly to 2-hydroxyethyl methacrylate (HEMA) (92.5%), 2-hydroxypropyl methacrylate (88.6%), ethylene glycol dimethacrylate (69.2%), and ethyl cyanoacrylate (9.9%). CONCLUSIONS: Nail cosmetics were responsible for the majority of ACD cases caused by acrylates, affecting nail beauticians and consumers, and therefore calling for stricter regulation and preventive measures. As HEMA detects most cases, and isolated facial lesions may be overlooked, inclusion of this allergen in the baseline series may be warranted.

Chronic hand eczema: A prospective analysis of the Swiss CARPE registry focusing on factors associated with clinical and quality of life improvement.

BACKGROUND: Hand eczema (HE) is common and may follow a chronic disease course. So far, prospective studies investigating the risk factors for disease progression as a prerequisite for targeted prevention are scarce. OBJECTIVE: To evaluate the overall association of HE-associated factors with clinical and quality of life (QoL) improvement during a follow-up of 2 years. METHODS: Data of the prospective patient cohort (N = 199) followed by the Swiss chronic HE (CHE) registry on long-term patient management (CARPE-CH) were analysed by means of both classic regression and semantic map analyses. RESULTS: Both severity of HE and QoL significantly improved over the period of 2 years (P < .001). However, 20% of patients had moderate to severe HE after 2 years of follow-up. As factors associated with an unfavourable CHE clinical course and QoL, environmental exposures, male sex, occupational skin disease, job loss or change at baseline, allergic contact dermatitis, a chronic disease course, palmar localization and widespread eczema were identified. CONCLUSIONS: Analysis of prospective data from CARPE-CH shows a complex pattern of associations among variables as shown by semantic map and classic statistical analyses. Factors related to occupational exposure had the highest impact on CHE.

Commentary on the "Evidence- and Consensus-Based (S3) Guidelines for the Treatment of Actinic Keratosis" Published by the International League of Dermatological Societies in Cooperation with the European Dermatology Forum.

In 2015, the International League of Dermatological Societies and the European Dermatology Forum published a guideline for the treatment of actinic keratosis, which is classified as an evidence- and consensus-based S3 guideline. From the point of view of the GD Task Force "Licht.Hautkrebs.Prävention," an interdisciplinary expert panel of the Society for Dermopharmacy for the prevention and treatment of skin cancer, this guideline reveals strengths and weaknesses but, in summary, does not meet the claim for an evidence- and consensus-based S3 guideline.

Position paper: Telemedicine in occupational dermatology - current status and perspectives.

Teledermatology is the use of telecommunication technologies to exchange medical information for diagnosis, consultation, treatment and teaching in dermatology. While its use has been evaluated in a wide range of dermatological diagnoses, only few studies exist on its validity, diagnostic precision, feasibility, and cost-effectiveness in occupational dermatology. However, these studies show a considerable potential for diagnosis, prevention, treatment support and follow-up of patients with occupational skin diseases. Asynchronous (store and forward; SAF) or synchronous dermatology teleconsults could assist occupational medicine specialists not only in occupational preventive care, but also in the context of skin cancer screening in outdoor workers. Thus, teledermatology might contribute to earlier prevention and notification of occupational skin diseases. Modern smartphone apps with artificial intelligence technologies may also facilitate self-monitoring in employees working in high-risk jobs.

Guideline for translation and national validation of the Quality of Life in Hand Eczema Questionnaire (QOLHEQ).

There is a need for well-developed and validated questionnaires to measure patient reported outcomes. The Quality of Life in Hand Eczema Questionnaire (QOLHEQ) is such a validated instrument measuring disease-specific health-related quality of life in hand eczema patients. A re-validation of measurement properties is required before an instrument is used in a new population. With the objective of arriving at a guideline for translation and national validation of the QOLHEQ, we have developed the design of a reference study on how to adequately assess measurement properties of the QOLHEQ based on interdisciplinary discussions and current standards. We present a step-by-step guideline to assess translation (including cross-cultural adaptation), scale structure, validity, reproducibility, responsiveness, and interpretability. We describe which outcomes should be reported for each measurement property, and give advice on how to calculate these. It is also specified which sample size is needed, how to deal with missing data, and which cutoff values should be applied for the measurement properties assessed during the validation process. In conclusion, this guideline, presenting a reference validation study for the QOLHEQ, creates the possibility to harmonize the national validation of the various language versions of the QOLHEQ.