Investigating causal relationships between obesity and skin barrier function in a multi-ethnic Asian general population cohort.

BACKGROUND: Skin diseases impact significantly on the quality of life and psychology of patients. Obesity has been observed as a risk factor for skin diseases. Skin epidermal barrier dysfunctions are typical manifestations across several dermatological disturbances. OBJECTIVES: We aim to establish the association between obesity and skin physiology measurements and investigate whether obesity may play a possible causal role on skin barrier dysfunction. METHODS: We investigated the relationship of obesity with skin physiology measurements, namely transepidermal water loss (TEWL), skin surface moisture and skin pH in an Asian population cohort (n = 9990). To assess for a possible causal association between body mass index (BMI) and skin physiology measurements, we performed Mendelian Randomization (MR), along with subsequent additional analyses to assess the potential causal impact of known socioeconomic and comorbidities of obesity on TEWL. RESULTS: Every 1 kg/m2 increase in BMI was associated with a 0.221% (95%CI: 0.144-0.298) increase in TEWL (P = 2.82E-08), a 0.336% (95%CI: 0.148-0.524) decrease in skin moisture (P = 4.66E-04) and a 0.184% (95%CI: 0.144-0.224) decrease in pH (P = 1.36E-19), adjusting for age, gender, and ethnicity. Relationships for both TEWL and pH with BMI remained strong (Beta 0.354; 95%CI: 0.189-0.520 and Beta -0.170; 95%CI: -0.253 to -0.087, respectively) even after adjusting for known confounders, with MR experiments further supporting BMI's possible causal relationship with TEWL. Based on additional MR performed, none of the socioeconomic and comorbidities of obesity investigated are likely to have possible causal relationships with TEWL. CONCLUSION: We establish strong association of BMI with TEWL and skin pH, with MR results suggestive of a possible causal relationship of obesity with TEWL. It emphasizes the potential impact of obesity on skin barrier function and therefore opportunity for primary prevention.

Belinostat resolves skin barrier defects in atopic dermatitis by targeting the dysregulated miR-335:SOX6 axis.

BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Skin barrier defects contribute to disease initiation and development; however, underlying mechanisms remain elusive. OBJECTIVE: To understand the underlying cause of barrier defect, we investigated aberrant expression of specific microRNAs (miRNAs) in AD. Delineating the molecular mechanism of dysregulated miRNA network, we focused on identification of specific drugs that can modulate miRNA expression and repair the defective barrier in AD. METHODS: A screen for differentially expressed miRNAs between healthy skin and AD lesional skin resulted in the identification of miR-335 as the most consistently downregulated miRNA in AD. Using in silico prediction combined with experimental validation, we characterized downstream miR-335 targets and elucidated the molecular pathways by which this microRNA maintains epidermal homeostasis in healthy skin. RESULTS: miR-335 was identified as a potent inducer of keratinocyte differentiation; it exerts this effect by directly repressing SOX6. By recruiting SMARCA complex components, SOX6 suppresses epidermal differentiation and epigenetically silences critical genes involved in keratinocyte differentiation. In AD lesional skin, miR-335 expression is aberrantly lost. SOX6 is abnormally expressed throughout the epidermis, where it impairs skin barrier development. We demonstrate that miR-335 is epigenetically regulated by histone deacetylases; a screen for suitable histone deacetylase inhibitors identified belinostat as a candidate drug that can restore epidermal miR-335 expression and rescue the defective skin barrier in AD. CONCLUSION: Belinostat is of clinical significance not only as a candidate drug for AD treatment, but also as a potential means of stopping the atopic march and further progression of this systemic allergic disease.

Automated grading of acne vulgaris by deep learning with convolutional neural networks.

BACKGROUND: The visual assessment and severity grading of acne vulgaris by physicians can be subjective, resulting in inter- and intra-observer variability. OBJECTIVE: To develop and validate an algorithm for the automated calculation of the Investigator's Global Assessment (IGA) scale, to standardize acne severity and outcome measurements. MATERIALS AND METHODS: A total of 472 photographs (retrieved 01/01/2004-04/08/2017) in the frontal view from 416 acne patients were used for training and testing. Photographs were labeled according to the IGA scale in three groups of IGA clear/almost clear (0-1), IGA mild (2), and IGA moderate to severe (3-4). The classification model used a convolutional neural network, and models were separately trained on three image sizes. The photographs were then subjected to analysis by the algorithm, and the generated automated IGA scores were compared to clinical scoring. The prediction accuracy of each IGA grade label and the agreement (Pearson correlation) of the two scores were computed. RESULTS: The best classification accuracy was 67%. Pearson correlation between machine-predicted score and human labels (clinical scoring and researcher scoring) for each model and various image input sizes was 0.77. Correlation of predictions with clinical scores was highest when using Inception v4 on the largest image size of 1200 × 1600. Two sets of human labels showed a high correlation of 0.77, verifying the repeatability of the ground truth labels. Confusion matrices show that the models performed sub-optimally on the IGA 2 label. CONCLUSION: Deep learning techniques harnessing high-resolution images and large datasets will continue to improve, demonstrating growing potential for automated clinical image analysis and grading.

A retrospective clinico-pathological study comparing lichen planus pigmentosus with ashy dermatosis.

BACKGROUND/OBJECTIVES: Controversy persists as to whether lichen planus pigmentosus and ashy dermatosis are separate clinical entities. This study was conducted to examine the clinicopathological features and treatment outcome of the two conditions. METHODS: A retrospective medical chart review of all patients who were diagnosed with lichen planus pigmentosus or ashy dermatosis was conducted. The information collected included the participants' age at onset, site of onset, duration of disease, presence of precipitating factors, distribution of disease, pigmentation and presence of symptoms. In patients from whom a biopsy was taken the histopathological reports were included. RESULTS: Altogether 26 patients with ashy dermatosis and 29 with lichen planus pigmentosus were included in the study. Compared with ashy dermatosis, lichen planus pigmentosus had a more localised distribution with a preponderance for facial involvement, compared with the truncal preponderance in ashy dermatosis. Ashy dermatosis tended to have a more stable clinical course than lichen planus pigmentosus, which was more likely to wax and wane. The utility of histopathology in differentiating between the two conditions is low. CONCLUSION: Ashy dermatosis and lichen planus pigmentosus, as defined in this study, appear to be two separate clinical entities with distinguishable clinical features and natural histories.

Bridging the Gap Between Vitiligo Segmentation and Clinical Scores.

Quantitative evaluation of vitiligo is crucial for assessing treatment response. Dermatologists evaluate vitiligo regularly to adjust their treatment plans, which requires extra work. Furthermore, the evaluations may not be objective due to inter- and intra-assessor variability. Though automatic vitiligo segmentation methods provide an objective evaluation, previous methods mainly focus on patch-wise images, and their results cannot be translated into clinical scores for treatment adjustment. Thus, full-body vitiligo segmentation needs to be developed for recording vitiligo changes in different body parts of a patient and for calculating the clinical scores. To bridge this gap, the first full-body vitiligo dataset with 1740 images, following the international vitiligo photo standard, was established. Compared with patch-wise images, full-body images have more complicated ambient light conditions and larger variances in lesion size and distribution. Additionally, in some hand and foot images, skin can be fully covered by either vitiligo or healthy skin. Previous patch-wise segmentation studies completely ignore these cases, as they assume that the contrast between vitiligo and healthy skin is available in each image for segmentation. To address the aforementioned challenges, the proposed algorithm in this study exploits a tailor-made contrast enhancement scheme and long-range comparison. Furthermore, a novel confidence score refinement module is proposed to manage images fully covered by vitiligo or healthy skin. Our results can be converted to clinical scores and used by clinicians. Compared to the state-of-the-art method, the proposed algorithm reduces the average per-image vitiligo involvement percentage error from 3.69% to 1.81%, and the top 10% per-image errors from 23.17% to 8.29%. Our algorithm achieves 1.17% and 3.11% for the mean and max error for the per-patient vitiligo involvement percentage, which is better than an experienced dermatologist's naked-eye evaluation.

Structural and functional imaging of psoriasis for severity assessment and quantitative monitoring of treatment response using high-resolution optoacoustic imaging.

Psoriasis is a chronic inflammatory skin disease, characterized by thick scaly plaques. It imposes a notable disease burden with varying levels of severity affecting the quality of life significantly. Current disease severity assessment relies on semi-objective visual inspection based on the Psoriasis Area and Severity index (PASI) score that might not be sensitive to sub-clinical changes. Histology of psoriasis skin lesions necessitate invasive skin biopsies. This indicates an unmet need for a non-invasive, objective and quantitative approach to assess disease severity serially. Herein, we employ multispectral Raster-Scanning Optoacoustic Mesoscopy (ms-RSOM) derived structural and microvascular functional imaging metrics to examine the lesional and non-lesional skin in psoriasis subjects across different severities and also evaluate the treatment outcome in a subject with topical steroids and biologics, such as adalimumab. ms-RSOM derived structural metrics like epidermal thickness and total blood volume (TBV) and microvascular functional information such as oxygen saturation (sO2) are evaluated by spectrally resolving the endogenous chromophores like melanin, oxy-, and deoxy-hemoglobin. Initial findings reveal an elevated sO2 and TBV with severity in lesional and non-lesional psoriasis skin, thus representing increasing inflammation. An increase in epidermal thickness is also noted with the degree of severity, corresponding to the inflammation and increased abnormal cell growth. As a marker to evaluate the treatment response, we observed a decrease in epidermal thickness, sO2, and TBV in a psoriasis patient post-treatment, which is consistent with the decrease in the PASI score from 4.1 to 1.9. We envision that ms-RSOM has a huge potential to be translated into routine clinical setting for the diagnosis of severity and assessment of treatment monitoring in psoriasis subjects.

Non-invasive biochemical analysis and comparison of atopic dermatitis and psoriasis skin using handheld confocal Raman spectroscopy.

A handheld non-invasive confocal Raman system (CRS) was used to evaluate the differences in skin biochemicals between atopic dermatitis (AD) and psoriasis, which are inflammatory skin conditions. Raman spectral measurements in the fingerprint and high wavenumber region were acquired using a portable in-house CRS system with excitation lasers operating at 671 and 785 nm. It was deduced that relative amount of water decreases in the following sequence of skin: healthy, psoriasis and AD. Moreover, differential trends were observed for the subclasses of ceramides such that ceramide 3 is lower in the lesional AD and psoriasis skin as compared to healthy, while ceramide 2 showed a contrasting trend of decrease in lesional AD and increase in lesional psoriasis as opposed to healthy skin. Amount of cholesterol was significantly higher in lesional psoriasis as compared to lesional AD and healthy skin. These differences can aid in an objective classification of the skin conditions and in the formulation of new disease-specific topical treatments.

Multispectral raster-scanning optoacoustic mesoscopy differentiate lesional from non-lesional atopic dermatitis skin using structural and functional imaging markers.

Atopic dermatitis (AD) is a chronic and pruritic skin inflammatory disease causing a significant burden to health care management and patient's quality of life. Seemingly healthy skin or non-lesional sites on AD patients still presents skin barrier defects and immune response, which can develop to AD at a later stage. To investigate further the balance between the epidermal barrier impairment and intrinsic immune dysregulation in AD, we exploited multispectral Raster-Scanning Optoacoustic Mesoscopy (ms-RSOM) to image lesional and non-lesional skin areas on AD patients of different severities non-invasively to elucidate their structural features and functional information. Herein, we demonstrate the objective assessment of AD severity using relative changes in oxygen saturation (δsO2) levels in microvasculature along with other structural parameters such as relative changes in epidermis thickness (δET) and total blood volume (δTBV) between the lesional and non-lesional areas of the skin. We could observe an increasing trend for δsO2 and δTBV, which correlated well with the subjective clinical Scoring Atopic Dermatitis (SCORAD) for evaluating the severity. Notably, δET showed a decreasing trend with AD severity, indicating that the difference in epidermal thickness between lesional and non-lesional area of the skin decreases with AD severity. Our results also correlated well with conventional metrics such as trans-epidermal water loss (TEWL) and erythrosine sedimentation rate (ESR). We quantified the δsO2 and δET changes to objectively evaluate the treatment response before and four months after treatment using topical steroids and cyclosporine in one severe AD patient. We observed reduced δsO2 and δET post treatment. We envision that in future, functional and structural imaging metrics derived from ms-RSOM can be translated as objective markers to assess and stratify the severity of AD and understand the function of skin barrier dysfunctions and immune dysregulation. It could also be employed to monitor the treatment response of AD in regular clinical settings.

Microvascular imaging and monitoring of hemodynamic changes in the skin during arterial-venous occlusion using multispectral raster-scanning optoacoustic mesoscopy.

The ability to monitor oxygen delivery in microvasculature plays a vital role in measuring the viability of skin tissue and the probability of recovery. Using currently available clinical imaging tools, it is difficult to observe non-invasive hemodynamic regulation in the peripheral vessels. Here we propose the use of a novel multispectral raster-scanning optoacoustic mesoscopy (RSOM) system for noninvasive clinical monitoring of hemodynamic changes in the skin microvasculature's oxy- (HbO2) and deoxy-hemoglobin (Hb), total hemoglobin (HbT) and oxygen saturation (rsO2). High resolution images of hemoglobin distribution in the skin microvasculature from six healthy volunteers during venous and arterial occlusion, simulating systemic vascular diseases are presented. During venous occlusion, Hb and HbO2 optoacoustic signals showed an increasing trend with time, followed by a drop in the values after cuff deflation. During arterial occlusion, an increase in Hb value and decrease in HbO2 values was observed, followed by a drop in Hb and jump in HbO2 values after the cuff deflation. A decrease in rsO2 values during both venous and arterial occlusion was observed with an increase in value after occlusion release. Using this proof of concept study, hereby we propose multispectral RSOM as a novel tool to measure high resolution hemodynamic changes in microvasculature for investigating systemic vascular diseases on peripheral tissues and also for monitoring inflammatory skin diseases, and its therapeutic interventions.

Investigating causal relationships between Body Mass Index and risk of atopic dermatitis: a Mendelian randomization analysis.

Population studies suggest that atopic dermatitis (AD) is associated with an increased risk of obesity, however a causal relationship between these two conditions remains to be established. We therefore use Mendelian randomization (MR) to evaluate whether obesity and AD are causally interlinked. We used summary statistics extracted from genome wide association studies of Body Mass Index (BMI) and AD. MR analysis was performed in both directions to establish the direction of causality between BMI and AD. We find that genetically determined increase in adiposity is associated with increased risk of AD (odds ratio of AD 1.08 [95% CI 1.01 to 1.14; p = 0.015] per unit increase in BMI). Conversely, genetically determined increased risk of AD is not associated with a higher BMI (change in BMI attributable to AD based on genetic information: 0.00; 95% CI - 0.02 to 0.02; p = 0.862). There was no evidence for confounding of these genetic analyses by horizontal pleiotropy. Our results indicate that the association of AD with obesity is likely to reflect a causal role for adiposity in the development of AD. Our findings enhance understanding of the etiology of AD, and the basis for experimental studies to evaluate the mechanistic pathways by which adiposity promotes AD.

Handheld confocal Raman spectroscopy (CRS) for objective assessment of skin barrier function and stratification of severity in atopic dermatitis (AD) patients.

BACKGROUND: We developed the first-of-its-kind handheld confocal Raman spectroscopy (CRS) system to quantify the concentration of natural moisturizing factors in the skin. OBJECTIVE: To evaluate the feasibility of our handheld CRS system and propose a novel quantitative index to measure skin barrier function. METHODS: This prospective study included 30 atopic dermatitis (AD) patients and 14 healthy volunteers. All AD participants were assessed using the Scoring Atopic Dermatitis (SCORAD) severity instrument, a vapometer for trans-epidermal water loss and a moisture meter for skin surface moisture. A handheld CRS operating at 785 nm laser was used to measure the biochemical constituents of the skin up to a depth of ∼100 µm. We trained a linear kernel-based support vector machine (SVM) model for eczema classification based on the water, ceramide and urocanic acid content. A novel Eczema Biochemical Index (EBI) was then formulated using the skin constituents measured from the AD participants to stage disease severity. RESULTS: The SVM model used to classify healthy participants and AD patients obtained high cross-validated area under the curve of 0.857 and accuracy of 0.841, with high sensitivity and specificity values of 0.857 and 0.833 respectively. EBI can be used to stratify AD patients of varying severity, based on the biochemical constituents in the skin. CONCLUSION: As compared to the standard CRS system, the handheld CRS offers higher portability and provides Raman measurements at various body regions with similar sensitivity. This suggests that a handheld CRS device could be a valuable point-of-care resource in both research and clinical use.

Optoacoustic mesoscopy analysis and quantitative estimation of specific imaging metrics in Fitzpatrick skin phototypes II to V.

Raster Scanning Optoacoustic Mesoscopy (RSOM) is a novel optoacoustic imaging modality that offers non-invasive, label-free, high resolution (~7 µm axial, ~30 µm lateral) imaging up to 1 to 2 mm below the skin, providing novel quantitative insights into skin pathophysiology. As the RSOM image contrast mechanism is based on light absorption, it is expected that the amount of melanin present in the skin will affect RSOM images. However, the effect of skin tone in the performance of RSOM has not been addressed so far. Herein, we present the efficiency of RSOM for in vivo skin imaging of human subjects with Fitzpatrick (FP) skin types between II to V. RSOM images acquired from the volar forearms of the subjects were used to derive metrics used in RSOM studies, such as total blood volume, vessel diameter and melanin signal intensity. Our study shows that the melanin signal intensity derived from the RSOM images exhibited an excellent correlation with that obtained from a clinical colorimeter for the subjects of varying FP skin types. We could successfully estimate the vessel diameter at different depths of the dermis. Furthermore, our study shows that there is a need to compensate for total blood volume calculated for subjects with higher FP skin types due to the lower signal-to-noise ratio in dermis, owing to strong absorption of light by melanin. This study sheds light into how RSOM can be used for studying various skin conditions in populations with different skin phenotypes.

Classification of non-tumorous skin pigmentation disorders using voting based probabilistic linear discriminant analysis.

Non-tumorous skin pigmentation disorders can have a huge negative emotional impact on patients. The correct diagnosis of these disorders is essential for proper treatments to be instituted. In this paper, we present a computerized method for classifying five non-tumorous skin pigmentation disorders (i.e., freckles, lentigines, Hori's nevus, melasma and nevus of Ota) based on probabilistic linear discriminant analysis (PLDA). To address the large within-class variance problem with pigmentation images, a voting based PLDA (V-PLDA) approach is proposed. The proposed V-PLDA method is tested on a dataset that contains 150 real-world images taken from patients. It is shown that the proposed V-PLDA method obtains significantly higher classification accuracy (4% or more with p< 0.001 in the analysis of variance (ANOVA) test) than the original PLDA method, as well as several state-of-the-art image classification methods. To the authors' best knowledge, this is the first study that focuses on the non-tumorous skin pigmentation image classification problem. Therefore, this paper could provide a benchmark for subsequent research on this topic. Additionally, the proposed V-PLDA method demonstrates promising performance in clinical applications related to skin pigmentation disorders.

Noninvasive real-time characterization of non-melanoma skin cancers with handheld optoacoustic probes.

Currently, imaging technologies that enable dermsurgeons to visualize non-melanoma skin cancers (NMSC) in vivo preoperatively are lacking, resulting in excessive or incomplete removal. Multispectral optoacoustic tomography (MSOT) is a volumetric imaging tool to differentiate tissue chromophores and exogenous contrast agents, based on differences in their spectral signatures and used for high-resolution imaging of functional and molecular contrast at centimeter scale depth. We performed MSOT imaging with two- and three-dimensional handheld scanners on 21 Asian patients with NMSC. The tumors and their oxygenation parameters could be distinguished from normal skin endogenously. The lesion dimensions and depths were extracted from the spectral melanin component with three-dimensional spatial resolution up to 80 µm. The intraclass correlation coefficient correlating tumor dimension measurements between MSOT and ex vivo histology of excised tumors, showed good correlation. Real-time 3D imaging was found to provide information on lesion morphology and its underlying neovasculature, indicators of the tumor's aggressiveness.

A case of linear morphoea mistaken for reflex sympathetic dystrophy.

Morphoea, or localised scleroderma, is a disease entity with poorly understood pathogenesis. Early diagnosis of the condition is crucial in order to prevent permanent morbidity. However, initial presentations of morphoea can be nonspecific and easily mistaken for other conditions, resulting in late treatment and permanent disability. We report a case of linear morphoea in a 22-year-old man who was initially diagnosed with reflex sympathetic dystrophy. By the time the diagnosis of morphoea was confirmed, the patient had already developed contractures.