Increased Risk of Dementia in Patients with Atopic Dermatitis: A Nationwide Population-Based Cohort Study.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with bimodal incidence peaks in early childhood and middle-aged and older adults. Few studies have focused on the risk of dementia in AD. The aims of this study were to analyse the incidence, and risk factors for dementia in patients with AD. This nationwide population-based retrospective cohort study enrolled 38,391 adults ≥ 40 years of age with AD and 2,643,602 controls without AD from the Korean National Health Insurance System (NHIS) database from 2009 to 2016. The cumulative incidence probability of all-cause dementia, Alzheimer's disease, or vascular dementia at 8 years was 50, 39, and 7 per 1,000 person-years in patients with AD, respectively. The adjusted risks of all-cause dementia (hazard ratio (HR), 1.072; 95% confidence interval (95% CI) 1.026-1.120), and Alzheimer's disease (HR 1.051; 95% CI 1.000-1.104) were increased in patients with AD. The effect of AD on the development of all-cause dementia and Alzheimer's dementia varied according to age and diabetes mellitus (all p for interaction, < 0.05). The risks of all-cause dementia and Alzheimer's disease were increased in patients with AD. Management of modifiable risk factors is important for preventing dementia in patients with AD.

Metformin: A Potential Treatment for Acne, Hidradenitis Suppurativa and Rosacea.

Metformin is a widely used drug for treatment of diabetes mellitus, due to its safety and efficacy. In addition to its role as an antidiabetic drug, numerous beneficial effects of metformin have enabled its use in various diseases. Considering the anti-androgenic, anti-angiogenic, anti-fibrotic and antioxidant properties of metformin, it may have the potential to improve chronic inflammatory skin diseases. However, further evidence is needed to confirm the efficacy of metformin in dermatological conditions, This review focuses on exploring the therapeutic targets of metformin in acne vulgaris, hidradenitis suppurativa and rosacea, by studying their pathogeneses.

Itch and Janus Kinase Inhibitors.

Itch is a common skin symptom, with complex aetiology and pathogenesis. It is mediated by 2 pathways, the histaminergic and non-histaminergic pathways. Chronic itch is understood to be processed by the latter and is difficult to treat with traditional pruritus therapies. The Janus kinase and signal transducer and activator of transcription pathway is a signalling mechanism that regulates gene expression through various cytokines. Janus kinase inhibitors, which have been tested and used for several autoimmune diseases, have also been shown to be effective for itch through clinical trials and case reports. Janus kinase inhibitors could be a good choice for pruritus in atopic dermatitis, psoriasis, and other diseases, such as prurigo nodularis and lichen planus, with rapid itch relief compared with conventional treatments. The most common adverse effects reported include nasopharyngitis, acne, and elevated blood creatine phosphokinase levels. Janus kinase inhibitors are currently prescribed with warnings about a potential increase in malignancies and cardiovascular diseases and usage in people of older ages. This review aims to provide knowledge about itch and the Janus kinase and signal transducer and activator of transcription pathway and to analyse the current evidence for itch relief by Janus kinase inhibitors.

Deep Learning-Based TEM Image Analysis for Fully Automated Detection of Gold Nanoparticles Internalized Within Tumor Cell.

Transmission electron microscopy (TEM) imaging can be used for detection/localization of gold nanoparticles (GNPs) within tumor cells. However, quantitative analysis of GNP-containing cellular TEM images typically relies on conventional/thresholding-based methods, which are manual, time-consuming, and prone to human errors. In this study, therefore, deep learning (DL)-based methods were developed for fully automated detection of GNPs from cellular TEM images. Several models of "you only look once (YOLO)" v5 were implemented, with a few adjustments to enhance the model's performance by applying the transfer learning approach, adjusting the size of the input image, and choosing the best optimization algorithm. Seventy-eight original (12,040 augmented) TEM images of GNP-laden tumor cells were used for model implementation and validation. A maximum F1 score (harmonic mean of the precision and recall) of 0.982 was achieved by the best-trained models, while mean average precision was 0.989 and 0.843 at 0.50 and 0.50-0.95 intersection over union threshold, respectively. These results suggested the developed DL-based approach was capable of precisely estimating the number/position of internalized GNPs from cellular TEM images. A novel DL-based TEM image analysis tool from this study will benefit research/development efforts on GNP-based cancer therapeutics, for example, by enabling the modeling of GNP-laden tumor cells using nanometer-resolution TEM images.

Psychological Burden and Willingness to Pay Among Korean Rosacea Patients and Their Association With Rosacea Phenotype and Severity: A Multi-Center Cross-Sectional Study.

BACKGROUND: Rosacea is a chronic inflammatory disorder that can adversely affect the patient's quality of life (QOL). However, few studies have examined the association between the psychological burden and willingness to pay (WTP) with rosacea features and severity. OBJECTIVES: The study aimed to determine the overall psychological burden and WTP among Korean rosacea patients and identify factors that may contribute, such as patient demographics, clinical features, and rosacea severity. METHODS: This prospective cross-sectional study recruited Koreans with rosacea. All were asked to complete a questionnaire on their demographics, rosacea-related symptoms, self-rated severity, dermatology life quality index (DLQI), and WTP. The clinical features were assessed by a board-certified dermatologist. The investigator's global assessment and global flushing severity score (GFSS) were used to determine the clinical severity of rosacea. Multiple regression analysis was conducted to identify factors contributing to the psychological burden and WTP. RESULTS: Out of 201 rosacea patients, 147 (73.1%) were female, and 54 (26.9%) males, with a median age of 50.1 years. Their median DLQI score was 8 (interquartile range [IQR]): 4.0-13.0). The median WTP per month for the control of rosacea was $100, with relative WTP (WTP/household income per month x 100) being 3.3%. According to the multiple regression model, phymatous change (ß = .153, p = .030), DLQI score (ß = .152, P = .045), and GFSS (ß = .154, P = .041) contributed most to the WTP. CONCLUSION: Rosacea patients experience substantial psychological and economic burdens. More vigorous treatment should be performed for those with phyma and severe flushing whose QOL is most severely affected.

Oral health and risk of cognitive disorders in older adults: A biannual longitudinal follow-up cohort.

BACKGROUND: Oral health may be associated with cognitive disorders such as mild cognitive impairment or dementia. OBJECTIVE: This study elucidates the effects of oral health conditions on the progression of cognitive disorders. METHODS: Data were collected from 153 participants of the Korean Longitudinal Study on Cognitive Aging and Dementia cohort who completed the longitudinal dental examinations and cognitive function assessments using the three-wave biannual survey. We analysed the relationship between dental factors and the conversion of cognitive function. RESULTS: The ratio of maxillary removable partial denture use (p = .03) was high in the converter and mild cognitive impairment/dementia groups. The low-grade ratio of posterior masticatory performance increased in the converter and mild cognitive impairment/dementia groups (modified Eichner index 2, p = .04). The mild cognitive impairment/dementia group had a higher rate of complete mandibular denture use (p < .001). The converter and mild cognitive impairment/dementia groups had fewer remaining teeth (p < .05) or removable prostheses (p < .01) than the normal group. CONCLUSIONS: Masticatory performance is associated with the conversion of cognitive disorders. Our findings suggest that oral health management can help delay the progression of cognitive disorders.

Clinical implications of neoadjuvant chemotherapy in advanced endometrial cancer: a multi-center retrospective cohort study.

BACKGROUND: The mainstay of endometrial cancer treatment is surgical resection of tumors and postoperative adjuvant treatment is recommended if necessary. However, there is no consensus on the management of unresectable metastatic endometrial cancer. This study aimed to assess the feasibility and effectiveness of neoadjuvant chemotherapy followed by interval debulking surgery (NAC-IDS) in unresectable, metastatic endometrial cancer. METHODS: From the endometrial cancer cohorts of four institutions in Korea, we identified patients with International Federation of Gynecology and Obstetrics stages IIIC-IVB endometrial cancer who received NAC-IDS between January 2008 and December 2020. Through a medical record review, we collected patients' clinicopathological data. Progression-free survival (PFS), overall survival (OS), and the factors affecting survival outcomes were analyzed. RESULTS: Overall, 32 patients were included with endometrioid (n = 18), serous (n = 5), carcinosarcoma (n = 6), and other histological types (n = 3). Among them, 28 (87.5%) patients had stage IVB disease. The most common neoadjuvant chemotherapy (NAC) regimen was paclitaxel-carboplatin (n = 25, 78.1%), which was administered for a median of six cycles. While 26 (81.3%) patients showed an objective response, two (6.3%) progressed despite NAC. At the time of interval debulking surgery (IDS), 23 (71.9%) patients achieved complete cytoreduction. During 31.0 months of the median follow-up, there were 23 recurrences and 11 deaths, corresponding to a median PFS of 19.7 months and a 3-year OS rate of 69.7%. In multivariate analyses, non-endometrioid histology and residual tumor after IDS were identified as independent poor prognostic factors for PFS (adjusted hazard ratio [HR], 7.322; P < 0.001 and 5.934; P = 0.001, respectively). Multivariate analysis for OS could not be conducted because of the small number of events, although non-endometrioid histology was the only factor associated with worse OS in univariate analysis (adjusted HR, 4.523; P = 0.032). CONCLUSIONS: NAC-IDS may be a treatment option for unresectable metastatic endometrial cancer. Tumor histology and the possibility of complete cytoreduction are the primary considerations for NAC-IDS.

The Human Microbiota and Skin Cancer.

Skin cancer is the most common type of cancer in the US with an increasing prevalence worldwide. While ultraviolet (UV) radiation is a well-known risk factor, there is emerging evidence that the microbiota may also contribute. In recent years, the human microbiota has become a topic of great interest, and its association with inflammatory skin diseases (i.e., atopic dermatitis, acne, rosacea) has been explored. Little is known of the role of microbiota in skin cancer, but with the recognized link between microbial dysbiosis and inflammation, and knowledge that microbiota modulates the effect of UV-induced immunosuppression, theories connecting the two have surfaced. In this paper, we provide a comprehensive review of the key literature on human microbiota, especially the skin microbiota, and skin cancer (i.e., non-melanoma skin cancer, melanoma, cutaneous T cell lymphoma). Also, mechanistic perspectives as to how our microbiota influence skin cancer development and treatment are offered.

Incidence and treatment outcomes of ovarian sarcoma compared to epithelial ovarian cancer from the national cancer registry.

PURPOSE: To investigate the incidence and survival outcomes of primary ovarian sarcoma compared to those of epithelial ovarian cancer. METHODS: Data on primary ovarian sarcoma patients (n = 1361) and epithelial ovarian cancer patients (n = 30,366) between 1999 and 2017 were obtained from the Korea Central Cancer Registry, and their respective age-standardized incidence rate (ASR) and relative survival rate were calculated and compared. RESULTS: Based on the ASR, the incidence of epithelial ovarian cancer was 4.75 per 100,000 women, while that of primary ovarian sarcoma was 0.22 per 100,000 women. The ASR ratio was 21.94 without significant change of ASR during the study period. Primary ovarian sarcoma had a better survival curve compared with epithelial ovarian cancer, though the difference was not statistically significant (5 yr overall survival 64.0% vs. 61.5%; p = 0.6030). In addition, among the pure sarcomas, the fibrosarcoma histologic subtype showed the best overall survival, and that of liposarcomas and stromal cell sarcoma were behind that (5 yr overall survival 85.0%, 76.7%, and 72.7%; p < 0.0001). CONCLUSIONS: The incidence of primary ovarian sarcoma is quite low, with an ASR of 0.22/100,000 during the last 20 years. There were no significant differences between survival rates of primary ovarian sarcoma and epithelial ovarian cancer.

Antimycobacterial Rufomycin Analogues from Streptomyces atratus Strain MJM3502.

This study represents a systematic chemical and biological study of the rufomycin (RUF) class of cyclic heptapeptides, which our anti-TB drug discovery efforts have identified as potentially promising anti-TB agents that newly target the caseinolytic protein C1, ClpC1. Eight new RUF analogues, rufomycins NBZ1-NBZ8 (1-8), as well as five known peptides (9-13) were isolated and characterized from the Streptomyces atratus strain MJM3502. Advanced Marfey's and X-ray crystallographic analysis led to the assignment of the absolute configuration of the RUFs. Several isolates exhibited potent activity against both pathogens M. tuberculosis H37Rv and M. abscessus, paired with favorable selectivity (selectivity index >60), which collectively underscores the promise of the rufomycins as potential anti-TB drug leads.

Updates on the Risk of Neuropsychiatric and Gastrointestinal Comorbidities in Rosacea and Its Possible Relationship with the Gut-Brain-Skin Axis.

Rosacea is a common chronic cutaneous inflammatory disorder. Recently, patients with rosacea were identified as having a higher risk of developing various comorbidities such as cardiovascular disease, psychiatric disorders, neurologic disorders, and gastrointestinal disorders. However, the risks of some comorbidities in patients with rosacea are somewhat contradictory, depending upon the study design. Moreover, pathomechanisms associated with the comorbidities of patients with rosacea remain poorly elucidated. The purpose of this review was to provide the most up-to-date evidence on the risks of neuropsychiatric and gastrointestinal comorbidities in patients with rosacea. Moreover, the molecular pathomechanisms associated with neuropsychiatric and gastrointestinal comorbidities in patients with rosacea were evaluated based on recent studies. This review was also intended to focus more on the role of the gut-brain-skin axis in the association of neuropsychiatric and gastrointestinal comorbidities in rosacea.

High-sensitivity imaging and quantification of intratumoral distributions of gold nanoparticles using a benchtop x-ray fluorescence imaging system.

A high-sensitivity benchtop x-ray fluorescence (XRF) imaging system, based on a high-power x-ray source and silicon drift detector, has been developed. This system allows gold L-shell XRF-based quantitative imaging of gold nanoparticles (GNPs) at concentrations as low as 0.007 mg/cm3 (7 ppm) in biological tissues/water. Its capability for biomedical applications was demonstrated by imaging the GNP distribution within a small (∼12×11×2 mm3) ex vivo sample (extracted from a murine tumor after intravenous GNP administration). The results suggest direct translatability for routine preclinical ex vivo imaging tasks involving GNPs, as well as the possibility for in vivo imaging of small/superficial animal tumors.

Investigation of transmission computed tomography (CT) image quality and x-ray dose achievable from an experimental dual-mode benchtop x-ray fluorescence CT and transmission CT system.

OBJECTIVE: To investigate the image quality and x-ray dose associated with a transmission computed tomography (CT) component implemented within the same platform of an experimental benchtop x-ray fluorescence CT (XFCT) system for multimodal preclinical imaging applications. METHODS: Cone-beam CT scans were performed using an experimental benchtop CT + XFCT system and a cylindrically-shaped 3D-printed polymethyl methacrylate phantom (3 cm in diameter, 7 cm in height) loaded with various concentrations (0.05-1 wt. %) of gold nanoparticles (GNPs). Two commercial CT quality assurance phantoms containing 3D line-pair (LP) targets and contrast targets were also scanned. The x-ray beams of 40 and 62 kVp, both filtered by 0.08 mm Cu and 0.4 mm Al, were used with 17 ms of exposure time per projection at three current settings (2.5, 5, and 10 mA). The ordered-subset simultaneous algebraic reconstruction and total variation-minimization methods were used to reconstruct images. Sparse projection and short scan were considered to reduce the x-ray dose. The contrast-to-noise ratio (CNR) and modulation transfer function (MTF) were calculated. RESULTS: The lowest detectable concentration of GNPs (CNR > 5) and the highest spatial resolution (per MTF50%) were 0.10 wt. % and 9.5 LP/CM, respectively, based on the images reconstructed from 360 projections of the 40 kVp beam (or x-ray dose of 3.44 cGy). The background noise for the image resulting in the lowest GNP detection limit was 25 Hounsfield units. CONCLUSION: The transmission CT component within the current experimental benchtop CT + XFCT system produced images deemed acceptable for multimodal (CT + XFCT) imaging purposes, with less than 4 cGy of x-ray dose.

Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin.

Residual complexity (RC) involves the impact of subtle but critical structural and biological features on drug lead validation, including unexplained effects related to unidentified impurities. RC commonly plagues drug discovery efforts due to the inherent imperfections of chromatographic separation methods. The new diketopiperazine, rufomyazine (6), and the previously known antibiotic, rufomycin (7), represent a prototypical case of RC that (almost) resulted in the misassignment of biological activity. The case exemplifies that impurities well below the natural abundance of 13C (1.1%) can be highly relevant and calls for advanced analytical characterization of drug leads with extended molar dynamic ranges of >1:1,000 using qNMR and LC-MS. Isolated from an actinomycete strain, 6 was originally found to be active against Mycobacterium tuberculosis with a minimum inhibitory concentration (MIC) of 2 µg/mL and high selectivity. As a part of lead validation, the dipeptide was synthesized and surprisingly found to be inactive. The initially observed activity was eventually attributed to a very minor contamination (0.24% [m/m]) with a highly active cyclic peptide (MIC ∼ 0.02 µM), subsequently identified as an analogue of 7. This study illustrates the serious implications RC can exert on organic chemistry and drug discovery, and what efforts are vital to improve lead validation and efficiency, especially in NP-related drug discovery programs.

Fractional Carbon Dioxide Laser as an "Add-on" Treatment for Vitiligo: A Meta-analysis with Systematic Review.

Treatment of vitiligo is challenging and requires a multidisciplinary approach. Fractional carbon dioxide (CO2) laser as an add-on to conventional treatment has been reported to be effective, but there is no consensus on its use. A systematic review was performed by searching major databases for relevant publications to February 2017. Six studies with 85 participants were included. For those with refractory vitiligo, the addition of fractional CO2 laser to routine treatment modalities was superior to conventional treatment alone in terms of > 50% re-pigmentation (risk ratio (RR) 4.90, 95% confidence interval (95% CI), 1.15-20.93; p = 0.03), physician improvement score (mean difference (MD) 0.81, 95% CI 0.33-1.29; p < 0.001), < 25% re-pigmentation (RR 0.64, 95% CI, 0.49-0.85; p=0.002) and patient satisfaction (MD 1.61, 95% CI 0.73-2.49; p< 0.001). Side-effects were minor. These results provide evidence supporting that fractional CO2 laser is a valuable treatment modality for patients with vitiligo, especially for those with refractory vitiligo.

Development and validation of a simple solid-phase extraction method coupled with liquid chromatography-triple quadrupole tandem mass spectrometry for simultaneous determination of lincomycin, tylosin A and tylosin B in royal jelly.

We have developed an analytical method for the determination of lincomycin, tylosin A and tylosin B residues in royal jelly using liquid chromatography-triple quadrupole tandem mass spectrometry analysis. For extraction and purification, we employed 1% trifluoroacetic acid and 0.1 m Na2 EDTA solutions along with an Oasis HLB cartridge. The target antibiotics were well separated in a Kinetex EVO C18 reversed-phase analytical column using a combination of 0.1% formate acid in ultrapure water (A) and acetonitrile (B) as the mobile phase. Good linearity was achieved over the tested concentration range (5-50 µg/kg) in matrix-matched standard calibration. The coefficients of determination (R2 ) were 0.9933, 0.9933 and 0.996, for tylosin A, tylosin B and lincomycin, respectively. Fortified royal jelly spiked with three different concentrations of the tested antibiotics (5, 10 and 20 µg/kg) yielded recoveries in the range 80.94-109.26% with relative standard deviations ≤4%. The proposed method was applied to monitor 11 brand of royal jelly collected from domestic markets and an imported brand from New Zealand; all the samples tested negative for lincomycin, tylosin A and tylosin B residues. In conclusion, 1% trifluoroacetic acid and 0.1 m Na2 EDTA aqueous solvents combined with solid-phase extraction could effectively complete the sample preparation process for royal jelly before analysis. The developed approach can be applied for a routine analysis of lincomycin, tylosin A and tylosin B residues in royal jelly.

Delayed onset filler complication: Two case reports and literature review.

Soft tissue augmentation by fillers has become a popular cosmetic tool to offer rejuvenation and aesthetic improvement. Its results are comparable to those previously achieved only by plastic surgery. However, marked increase of filler procedures is associated with a great number of complications. Complications associated with filler injection might have early onset (within days) or late onset (after weeks to years). Delayed complications include infections, foreign body granulomatous reaction, migration of filler material, persistent discoloration, and scarring. Here we report two cases of delayed complications: one case of foreign body granuloma with migration and one case of acute inflammation involving a quiescent granuloma.

Different associations of albuminuria with total and cardiovascular mortality by concentrations of persistent organic pollutants in the elderly.

Epidemiologic studies have indicated that albuminuria is associated with mortality from all causes and cardiovascular disease (CVD), with substantial heterogeneity. We evaluated if the associations of urine albumin creatinine ratio (ACR) with all-cause and CVD mortality differed depending on serum concentrations of persistent organic pollutants (POPs), strong lipophilic chemical mixtures with very long half-lives, which are recently linked to many degenerative diseases. Study subjects were participants of the National Health and Nutrition Examination Survey 1999-2004 who were 60 years or older at baseline (n=1215 and 1067 for organochlorine pesticides (OCPs) and other POPs, respectively). They were followed-up through 2011 (mean follow-up periods: 8.1 and 8.0 years for OCPs and other POPs, respectively). The associations between the ACR and all-cause mortality significantly differed by the serum levels of POPs, especially organochlorine pesticides (OCPs; Pinteraction<0.01). Stratified analyses indicated that the associations between ACR and all-cause mortality became stronger as the serum levels of OCPs increased. Among the elderly with the highest tertile of OCPs, the adjusted hazard ratios were 1.0, 1.1, and 2.9 (Ptrend<0.01) across the categories of ACR (<10, 10-<30, and ≥30mg/g); however, ACR was not clearly related to mortality among the elderly with the lowest tertile of OCPs. CVD mortality showed similar interactions, as noted for all-cause mortality (Pinteraction<0.01). The different associations between albuminuria and mortality by the serum OCP levels and the little association among the elderly with low serum OCPs levels suggest that OCPs play an important role in albuminuria-related death risk. However, these findings need to be replicated in other cohort studies.

Efficacy and Safety of Tranexamic Acid in Melasma: A Meta-analysis and Systematic Review.

Tranexamic acid is a novel treatment option for melasma; however, there is no consensus on its use. This systematic review searched major databases for relevant publications to March 2016. Eleven studies with 667 participants were included. Pooled data from tranexamic acid-only observational studies with pre- and post-treatment Melasma Area and Severity Index (MASI) showed a decrease of 1.60 in MASI (95% confidence interval (CI), 1.20-2.00; p<0.001) after treat-ment with tranexamic acid. The addition of tranexamic acid to routine treatment modalities resulted in a further decrease in MASI of 0.94 (95% CI 0.10-1.79; p = 0.03). Side-effects were minor, with a few cases reporting hypo-menorrhoea, mild abdominal discomfort, and transient skin irritation. These results support the efficacy and safety of tranexamic acid, either alone or as an adjuvant to routine treatment modalities for melasma.

Protective Effect of Botulinum Toxin Type A Against Atopic Dermatitis-Like Skin Lesions in NC/Nga Mice.

BACKGROUND: Botulinum neurotoxin (BTX) A possesses various biological activities, including anti-inflammatory and antipruritic actions. Human and animal studies have shown that BTX is effective in treating histamine-induced itch, lichen simplex chronicus, psoriasis, rosacea, allergic rhinitis, and scar prevention. However, its effect on atopic dermatitis (AD) has not been studied yet. OBJECTIVE: To examine the effect of BTX on AD using a mouse model. The primary outcome was skin thickness and transepidermal water loss (TEWL), and the secondary outcome was the alteration in skin severity scores, histological, and laboratory test results. METHODS: Forty-two NC/Nga mice (a mouse model for AD) were allocated into 6 groups (the untreated, 2-Chloro-1,3,5-trinitrobenzene [TNCB] alone, TNCB + BTX 30 U/kg, TNCB + BTX 60 U/kg, TNCB + vehicle [0.9% saline], TNCB + 0.03% tacrolimus). Those of the BTX group received intradermal injections of BTX on the rostral back once on the day of TNCB sensitization. The effect of BTX in TNCB-treated NC/Nga mice was assessed by measuring skin thickness, TEWL (primary outcome), the skin severity scores, histological changes of test skin including mast cell count, interleukin (IL)-4 mRNA and protein expression, and total serum IgE (secondary outcome). RESULTS: A single intradermal injection of BTX significantly suppressed skin thickness and TEWL in the TNCB-applied skin. The clinical severity scores, acanthosis and mast cell infiltration, were less in the BTX groups. BTX injection also inhibited TNCB-induced increase in IL-4 mRNA and protein expression in mice, but its effect on serum IgE level was not significant. CONCLUSION: The preliminary results suggest that BTX may be a novel approach to the prevention and supplemental treatment of acute AD lesions.