Non-Expert Markings of Active Chronic Graft-Versus-Host Disease Photographs: Optimal Metrics of Training Effects.

Lack of reliable measures of cutaneous chronic graft-versus-host disease (cGVHD) remains a significant challenge. Non-expert assistance in marking photographs of active disease could aid the development of automated segmentation algorithms, but validated metrics to evaluate training effects are lacking. We studied absolute and relative error of marked body surface area (BSA), redness, and the Dice index as potential metrics of non-expert improvement. Three non-experts underwent an extensive training program led by a board-certified dermatologist to mark cGVHD in photographs. At the end of the 4-month training, the dermatologist confirmed that each trainee had learned to accurately mark cGVHD. The trainees' inter- and intra-rater intraclass correlation coefficient estimates were "substantial" to "almost perfect" for both BSA and total redness. For fifteen 3D photos of patients with cGVHD, the trainees' median absolute (relative) BSA error compared to expert marking dropped from 20 cm2 (29%) pre-training to 14 cm2 (24%) post-training. Total redness error decreased from 122 a*·cm2 (26%) to 95 a*·cm2 (21%). By contrast, median Dice index did not reflect improvement (0.76 to 0.75). Both absolute and relative BSA and redness errors similarly and stably reflected improvements from this training program, which the Dice index failed to capture.

Guideline for in vivo assessment of adherent and rolling leukocytes in human skin microvasculature via reflectance confocal videomicroscopy.

OBJECTIVE: To develop a guideline that reliably identifies cutaneous adherent and rolling leukocytes from mimicking scenarios via in vivo reflectance confocal videomicroscopy. METHODS: We used a clinical reflectance confocal microscope, the VivaScope 1500, to acquire 1522 videos of the upper dermal microcirculation from 12 healthy subjects and 60 patients after allogeneic hematopoietic cell transplantation. Blinded to clinical information, two trained raters independently counted the number of adherent and rolling leukocytes in 88 videos. Based on discrepancies in the initial assessments, we developed a guideline to identify both types of leukocyte-endothelial interactions via a modified Delphi method (without anonymity). To test the guideline's ability to improve the inter-rater reliability, the two raters assessed the remaining 1434 videos by using the guideline. RESULTS: We demonstrate a guideline that consists of definitions, a step-by-step flowchart, and corresponding visuals of adherent and rolling leukocytes and mimicking scenarios. The guideline improved the inter-rater reliability of the manual assessment of both interactions. The intraclass correlation coefficient (ICC) of adherent leukocyte counts increased from 0.056 (95% confidence interval: 0-0.236, n = 88 videos, N = 10 subjects) to 0.791 (0.770-0.809, n = 1434, N = 67). The ICC of rolling leukocyte counts increased from 0.385 (0.191-0.550, n = 88, N = 10) to 0.626 (0.593-0.657, n = 1434, N = 67). Intra-rater ICC post-guideline was 0.953 (0.886-0.981, n = 20, N = 12) and 0.956 (0.894-0.983, n = 20, N = 12) for adherent and rolling, respectively. CONCLUSION: The guideline aids in the manual identification of adherent and rolling leukocytes via in vivo reflectance confocal videomicroscopy.

Individual cell motion in healthy human skin microvasculature by reflectance confocal video microscopy.

OBJECTIVE: To describe upper dermal microvasculature of healthy human skin in terms of density and size of cutaneous blood vessels, leukocyte velocity, and leukocyte interactions with the endothelium. METHODS: We used a reflectance confocal microscope, the VivaScope 1500, to acquire videos of individual cell motion. RESULTS: We found no rolling leukocytes in the upper microvasculature of ten healthy subjects. We observed "paused" leukocytes, that is, leukocytes that temporarily stop, coinciding with the simultaneous stopping of the rest of the blood flow. We imaged more paused (median: 1.0 per subject) and adherent (1.5) leukocytes in the forearm than in the chest (median 0 paused and 0 adherent per subject) per 5 minutes of videos per body site. Leukocytes were paused for a median of 7 seconds in the forearm and 3 seconds in the chest, and we found no correlation between this parameter and the blood vessel or leukocyte size. We visualized blood flow change direction. Flowing leukocyte velocities followed a lognormal distribution and were on average higher in the chest (117 µm/s) than in the forearm (66 µm/s). CONCLUSION: The proposed method and reported values in healthy skin provide new insights into intact human skin microcirculation.

The Anatomic Distribution of Skin Involvement in Patients with Incident Chronic Graft-versus-Host Disease.

Little is known about the anatomic distribution of cutaneous chronic graft-versus-host disease (cGVHD). Using data from the cGVHD Consortium Improving Outcomes Assessment Study, we describe the frequency and extent of erythema and superficial and deep sclerosis in 8 anatomic sites in patients with incident disease (ie, new cGVHD diagnosis within 3 months of study entry) receiving systemic therapy. Of 339 patients with incident disease, 182 (54%) had skin involvement. When an extremity was involved, the same type of disease was present contralaterally in 92% of cases, revealing a high level of symmetry. As anticipated, erythema was the most common incident feature; however, sclerotic skin involvement at the time of cGVHD diagnosis was more common than has been suggested by previous studies. Erythema occurred in 155 (85%) and sclerosis in 53 (29%) of the patients with skin involvement (46% and 16%, respectively, of the entire cohort of 339 incident cGVHD cases). Erythema was least common on the lower extremities (n = 71; 39% of patients with skin involvement). Moveable sclerosis was rare on the head, neck, and scalp (n = 4; 2%). Deep sclerosis did not occur in this region, and instead was most likely to occur on the upper extremities (n = 14; 8%) and lower extremities (n = 14; 8%). More than one-half of patients with erythema (n = 107; 58.7%) had diffuse involvement (4 or more of 8 sites involved), compared with less than one-third of those with sclerosis (n = 16; 30.2%).

miR-10a-5p is increased in atopic dermatitis and has capacity to inhibit keratinocyte proliferation.

BACKGROUND: miR-10a-5p has been shown to regulate cancer cell proliferation and invasiveness and endothelial cell inflammatory responses. The function of miR-10a-5p in the skin has not been previously studied. The aim of the current study was to examine miR-10a-5p expression, regulation, and function in keratinocytes (KCs) in association with atopic dermatitis (AD). METHODS: The expression of miR-10a-5p and its target genes was analyzed using RT-qPCR, mRNA array analysis, in situ hybridization, and immunofluorescence. The transfection of miRNA mimics, cell cycle distribution analysis, and luciferase assays was used to study miR-10a-5p functions in human primary KCs. RESULTS: miR-10a-5p was found to be upregulated in lesional skin from patients with AD and in proliferating KCs. Array and pathway analysis of IL-1ß-stimulated KCs revealed that miR-10a-5p inhibited many genes that affect cell cycle progression and only a few inflammation-related genes. Accordingly, fewer cells in S-phase and reduced proliferation were detected as characteristics of miR-10a-5p-transfected KCs. The influence of miR-10a-5p on cell proliferation was also evident in KCs induced by AD-related cytokines, including IL-4, IL-17, and IL-1ß, as measured by the capacity to strongly suppress the expression of the proliferation marker Ki-67. Among AD-related putative direct target genes, we verified hyaluronan synthase 3, a damage-associated positive regulator of KC migration and proliferation, as a direct target of miR-10a-5p. CONCLUSIONS: miR-10a-5p inhibits KC proliferation and directly targets hyaluronan synthase 3 and thereby may modulate AD-associated processes in the skin.

Reproducibility of the durometer and myoton devices for skin stiffness measurement in healthy subjects.

BACKGROUND: Clinical assessment of skin stiffness is unreliable in many applications. The durometer, an industrial device to measure hardness, has previously been applied in scleroderma. The Myoton is a noninvasive handheld device for assessing soft tissue biomechanical parameters. MATERIALS AND METHODS: We evaluated the reproducibility of both devices in six healthy subjects in the volar forearm, dorsal forearm, upper arm, shin, and calf bilaterally. The intraclass correlation coefficient (ICC) was used as a measure of reproducibility among three observers. RESULTS: The interobserver intraclass correlation coefficient (ICC) of overall stiffness for the Myoton was 0.74 [95% confidence interval (CI) 0.45-1.00] and 0.71 [0.39-1.00] for the durometer. Coefficient of variation (CV) for the Myoton was 6.4% [range 1.3-12.1] and 7.6% [range 4.4-13.8] for the durometer. Myoton and durometer values had a Pearson correlation of 0.69. The intraobserver Myoton ICC was 0.89 [0.74-1.00] and CV 3.1% [range 1.6-5.0]. The 95% confidence minimal detectable change by the Myoton for a single observer is 32.4 N/m, which is 7.6% of the average subject's overall stiffness. CONCLUSION: The Myoton demonstrated high reproducibility, particularly in the overall stiffness parameter, and merits further investigation to assess disease progression and treatment efficacy.

Crowdsourcing to delineate skin affected by chronic graft-vs-host disease.

BACKGROUND: Estimating the extent of affected skin is an important unmet clinical need both for research and practical management in many diseases. In particular, cutaneous burden of chronic graft-vs-host disease (cGVHD) is a primary outcome in many trials. Despite advances in artificial intelligence and 3D photography, progress toward reliable automated techniques is hindered by limited expert time to delineate cGVHD patient images. Crowdsourcing may have potential to provide the requisite expert-level data. MATERIALS AND METHODS: Forty-one three-dimensional photographs of three cutaneous cGVHD patients were delineated by a board-certified dermatologist. 410 two-dimensional projections of the raw photos were each annotated by seven crowd workers, whose consensus performance was compared to the expert. RESULTS: The consensus delineation by four of seven crowd workers achieved the highest agreement with the expert, measured by a median Dice index of 0.7551 across all 410 images, outperforming even the best worker from the crowd (Dice index 0.7216). For their internal agreement, crowd workers achieved a median Fleiss's kappa of 0.4140 across the images. The time a worker spent marking an image had only weak correlation with the surface area marked, and very low correlation with accuracy. Percent of pixels selected by the consensus exhibited good correlation (Pearson R = 0.81) with the patient's affected surface area. CONCLUSION: Crowdsourcing may be an efficient method for obtaining demarcations of affected skin, on par with expert performance. Crowdsourced data generally agreed with the current clinical standard of percent body surface area to assess cGVHD severity in the skin.

Optical differential temperature measurement with beat frequency phase fluorometry.

We present, to the best of our knowledge, a new method for differential temperature measurement based on thermal sensitivity of the fluorescence lifetime of thermographic phosphors. Pairs of thermographic phosphors are excited with intensity-modulated light at frequencies ω and ω+Δω. The phase shift Δθ of the summary fluorescence intensity beat signal envelope is measured. A prototype of a fluorometric differential temperature sensor is developed, and feasibility of the method is experimentally demonstrated with a Sm2+:SrFCl crystal and the D15->F70 transition for high thermal sensitivity. The observed linear dependence between envelope phase shift Δθ and temperature difference ΔT agrees with the theoretical prediction. Sensitivity of S=-0.97°/°C was achieved. This method could also be applied to differential measurements of any parameter affecting fluorescence lifetime.

Mpox-A Rapidly Evolving Disease.

The 2022 mpox outbreak has rapidly emerged onto the global medical scene while the world continues to grapple with the COVID-19 pandemic. Unlike COVID-19, however, most patients with mpox present with skin findings, the evolving clinical presentation of which may be mistaken for other common skin diseases, particularly sexually transmitted infections. This Special Communication provides an overview of the evolution of mpox skin findings from its initial description in humans in 1970 to the present-day multinational outbreak.

Effect of camera distance and angle on color of diverse skin tone-based standards in smartphone photos.

Accurate and reproducible color capture is vital in medical photography. Camera distance and angle are particularly important as they are highly variable in a clinical setting. To account for variability in illumination, camera technology, and geometric effects, color standards are often used for color correction. To explore how geometry affects color, we quantified the change in CIELAB color value of a color standard for diverse skin tones at varying smartphone camera distances and angles. Whereas both chromaticity (a* and b*) and lightness (L*) were affected by angle, distance only affected L* (standard error of measurement, SEM > 1 CIELAB unit). Flash usage did not generally reduce distance and angle associated variability. Compared to compressed (JPG) format, raw (DNG) images had decreased median variability across different distances and angles. These findings suggest that in medical photography, inconsistent camera distance and angle can increase variability in photographed skin appearance over time.

Hyperspectral imaging to accurately segment skin erythema and hyperpigmentation in cutaneous chronic graft-versus-host disease.

In 51 lesions from 15 patients with the inflammatory skin condition chronic graft-versus-host-disease, hyperspectral imaging accurately delineated active erythema and post-inflammatory hyperpigmentation. The method was validated by dermatologist-approved confident delineations of only definitely affected and definitely unaffected areas in photographs. A prototype hyperspectral imaging system acquired a 2.5 × 3.5 cm2 area of skin at 120 wavelengths in the 450-850 nm range. Unsupervised extraction of unknown absorbers by endmember analysis achieved a comparable accuracy to that of supervised extraction of known absorbers (melanin, hemoglobin) by chromophore mapping: 0.78 (IQR: 0.39-0.85) vs. 0.83 (0.53-0.91) to delineate erythema and 0.74 (0.57-0.87) vs. 0.73 (0.52-0.84) to delineate hyperpigmentation. Both algorithms achieved higher specificity than sensitivity. Whereas a trained human confidently marked a median of 7% of image pixels, unsupervised and supervised algorithms delineated a median of 14% and 27% pixels. Hyperspectral imaging could overcome a fundamental practice gap of distinguishing active from inactive manifestations of inflammatory skin disease.

Introduction to the Biophotonics Congress 2022 feature issue.

A feature issue is being presented by a team of guest editors containing papers based on studies presented at the Optica Biophotonics Congress: Biomedical Optics held on April 24-27, 2022 in Fort Lauderdale, Florida, USA.

Crowdsourcing Skin Demarcations of Chronic Graft-Versus-Host Disease in Patient Photographs: Training Versus Performance Study.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is a significant cause of long-term morbidity and mortality in patients after allogeneic hematopoietic cell transplantation. Skin is the most commonly affected organ, and visual assessment of cGVHD can have low reliability. Crowdsourcing data from nonexpert participants has been used for numerous medical applications, including image labeling and segmentation tasks. OBJECTIVE: This study aimed to assess the ability of crowds of nonexpert raters-individuals without any prior training for identifying or marking cGHVD-to demarcate photos of cGVHD-affected skin. We also studied the effect of training and feedback on crowd performance. METHODS: Using a Canfield Vectra H1 3D camera, 360 photographs of the skin of 36 patients with cGVHD were taken. Ground truth demarcations were provided in 3D by a trained expert and reviewed by a board-certified dermatologist. In total, 3000 2D images (projections from various angles) were created for crowd demarcation through the DiagnosUs mobile app. Raters were split into high and low feedback groups. The performances of 4 different crowds of nonexperts were analyzed, including 17 raters per image for the low and high feedback groups, 32-35 raters per image for the low feedback group, and the top 5 performers for each image from the low feedback group. RESULTS: Across 8 demarcation competitions, 130 raters were recruited to the high feedback group and 161 to the low feedback group. This resulted in a total of 54,887 individual demarcations from the high feedback group and 78,967 from the low feedback group. The nonexpert crowds achieved good overall performance for segmenting cGVHD-affected skin with minimal training, achieving a median surface area error of less than 12% of skin pixels for all crowds in both the high and low feedback groups. The low feedback crowds performed slightly poorer than the high feedback crowd, even when a larger crowd was used. Tracking the 5 most reliable raters from the low feedback group for each image recovered a performance similar to that of the high feedback crowd. Higher variability between raters for a given image was not found to correlate with lower performance of the crowd consensus demarcation and cannot therefore be used as a measure of reliability. No significant learning was observed during the task as more photos and feedback were seen. CONCLUSIONS: Crowds of nonexpert raters can demarcate cGVHD images with good overall performance. Tracking the top 5 most reliable raters provided optimal results, obtaining the best performance with the lowest number of expert demarcations required for adequate training. However, the agreement amongst individual nonexperts does not help predict whether the crowd has provided an accurate result. Future work should explore the performance of crowdsourcing in standard clinical photos and further methods to estimate the reliability of consensus demarcations.

Prognostic Value of Cutaneous Disease Severity Estimates on Survival Outcomes in Patients With Chronic Graft-vs-Host Disease.

Importance: Prior studies have demonstrated an association between cutaneous chronic graft-vs-host disease (cGVHD) and mortality. Assessment of the prognostic value of different measures of disease severity would assist in risk stratification. Objective: To compare the prognostic value of body surface area (BSA) and National Institutes of Health (NIH) Skin Score on survival outcomes stratified by erythema and sclerosis subtypes of cGVHD. Design, Setting, and Participants: Multicenter prospective cohort study from the Chronic Graft-vs-Host Disease Consortium including 9 medical centers in the US, enrolled from 2007 through 2012 and followed until 2018. Participants were adults and children with a diagnosis of cGVHD requiring systemic immunosuppression and with skin involvement during the study period, who had longitudinal follow-up. Data analysis was performed from April 2019 to April 2022. Exposures: Patients underwent continuous BSA estimation and categorical NIH Skin Score grading of cutaneous cGVHD at enrollment and every 3 to 6 months thereafter. Main Outcomes and Measures: Nonrelapse mortality (NRM) and overall survival (OS), compared between BSA and NIH Skin Score longitudinal prognostic models, adjusted for age, race, conditioning intensity, patient sex, and donor sex. Results: Of 469 patients with cGVHD, 267 (57%) (105 female [39%]; mean [SD] age, 51 [12] years) had cutaneous cGVHD at enrollment, and 89 (19%) developed skin involvement subsequently. Erythema-type disease had earlier onset and was more responsive to treatment compared with sclerosis-type disease. Most cases (77 of 112 [69%]) of sclerotic disease occurred without prior erythema. Erythema-type cGVHD at first follow-up visit was associated with NRM (hazard ratio, 1.33 per 10% BSA increase; 95% CI, 1.19-1.48; P < .001) and OS (hazard ratio, 1.28 per 10% BSA increase; 95% CI, 1.14-1.44; P < .001), while sclerosis-type cGVHD had no significant association with mortality. The model with erythema BSA collected at baseline and first follow-up visits retained 75% of the total prognostic information (from all covariates including BSA and NIH Skin Score) for NRM and 73% for OS, with no statistical difference between prognostic models (likelihood ratio test χ2, 5.9; P = .05). Conversely, NIH Skin Score collected at the same intervals lost significant prognostic information (likelihood ratio test χ2, 14.7; P < .001). The model incorporating NIH Skin Score instead of erythema BSA accounted for only 38% of the total information for NRM and 58% for OS. Conclusions and Relevance: In this prospective cohort study, erythema-type cutaneous cGVHD was associated with increased risk of mortality. Erythema BSA collected at baseline and follow-up predicted survival more accurately than the NIH Skin Score in patients requiring immunosuppression. Accurate assessment of erythema BSA may assist in identifying patients with cutaneous cGVHD at high risk for mortality.

Vectorial laws of refraction and reflection using the cross product and dot product.

We demonstrate that published vectorial laws of reflection and refraction of light based solely on the cross product do not, in general, uniquely determine the direction of the reflected and refracted waves without additional information. This is because the cross product does not have a unique inverse operation, which is explained in this Letter in linear algebra terms. However, a vector is in fact uniquely determined if both the cross product (vector product) and dot product (scalar product) with a known vector are specified, which can be written as a single equation with a left-invertible matrix. It is thus possible to amend the vectorial laws of reflection and refraction to incorporate both the cross and dot products for a complete specification with unique solution. This enables highly efficient, unambiguous computation of reflected and refracted wave vectors from the incident wave and surface normal.

Gaussian beam reflection and refraction by a spherical or parabolic surface: comparison of vectorial-law calculation with lens approximation.

A ray-tracing approach is used to demonstrate efficient application of the vectorial laws of reflection and refraction to computational optics problems. Both the full width at half-maximum (fwhm) and offset of Gaussian beams resulting from off-center reflection and refraction are calculated for spherical and paraboloidal surfaces of revolution. It is found that the magnification and displacement depend nonlinearly on the miscentering. For these geometries, the limits of accuracy of the lens approximation are examined quantitatively. In contrast to the ray-tracing solution, this paraxial approximation would predict a magnification of a beam's fwhm that is independent of miscentering, and an offset linearly proportional to the miscentering. The focusing property of paraboloidal surfaces of revolution is also derived in setting up the calculation.

Expanding Personalized, Data-Driven Dermatology: Leveraging Digital Health Technology and Machine Learning to Improve Patient Outcomes.

The current revolution of digital health technology and machine learning offers enormous potential to improve patient care. Nevertheless, it is essential to recognize that dermatology requires an approach different from those of other specialties. For many dermatological conditions, there is a lack of standardized methodology for quantitatively tracking disease progression and treatment response (clinimetrics). Furthermore, dermatological diseases impact patients in complex ways, some of which can be measured only through patient reports (psychometrics). New tools using digital health technology (e.g., smartphone applications, wearable devices) can aid in capturing both clinimetric and psychometric variables over time. With these data, machine learning can inform efforts to improve health care by, for example, the identification of high-risk patient groups, optimization of treatment strategies, and prediction of disease outcomes. We use the term personalized, data-driven dermatology to refer to the use of comprehensive data to inform individual patient care and improve patient outcomes. In this paper, we provide a framework that includes data from multiple sources, leverages digital health technology, and uses machine learning. Although this framework is applicable broadly to dermatological conditions, we use the example of a serious inflammatory skin condition, chronic cutaneous graft-versus-host disease, to illustrate personalized, data-driven dermatology.

Association of Leukocyte Adhesion and Rolling in Skin With Patient Outcomes After Hematopoietic Cell Transplantation Using Noninvasive Reflectance Confocal Videomicroscopy.

Importance: Hematopoietic cell transplantation (HCT) is a potential cure for hematologic cancer but is associated with a risk of relapse and death. Dynamic biomarkers to predict relapse and inform treatment decisions after HCT are a major unmet clinical need. Objective: To identify a quantitative characteristic of leukocyte-endothelial interactions after HCT and test its associations with patient outcomes. Design, Setting, and Participants: In this prospective single-center cohort study from June 2017 to January 2020, patients of any age, sex, race, and ethnicity who had HCT for hematologic cancer were referred by health care professionals as either suspected of having symptoms or not having symptoms of acute graft-vs-host disease between 25 and 161 days after HCT. Patients underwent noninvasive skin videomicroscopy. Videos of dermal microvascular flow were recorded with a reflectance confocal microscope. Two blinded observers (J.R.P. and Z.Z.) counted leukocytes adherent to and rolling along the vessel wall per hour (A&R). Of 57 enrolled patients, 1 relapsed before imaging and was excluded, resulting in 56 patients included in analyses. Main Outcomes and Measures: Relapse of cancer, relapse-free survival, and overall survival. Results: Among the 56 patients (median age, 59 years; 38 [68%] male) who underwent imaging a median of 40 days after HCT, 21 had high A&R and 35 had low A&R. After correcting for the revised Disease Risk Index, patients with high A&R had higher rates of relapse (hazard ratio [HR], 4.24; 95% CI, 1.32-13.58; P = .02), reduced relapse-free survival (HR, 3.29; 95% CI, 1.26-8.55; P = .02), and reduced overall survival (HR, 3.06, 95% CI, 1.02-9.19; P = .05). These associations were preserved after correcting for possible confounders, steroid treatment, and acute graft-vs-host disease status. In the prognostic adequacy calculation by using Cox models, the new imaging biomarker (A&R) accounted for 82% to 95% of the prognostic information to predict each outcome. By contrast, the best existing clinical predictor routinely available, the revised Disease Risk Index, accounted for 10% to 28% of the prognostic information in the same model. Conclusions and Relevance: In this cohort study, leukocyte-endothelial interactions, visualized directly in skin after HCT, were associated with the patient outcomes of relapse, relapse-free survival, and overall survival. Assessing this dynamic marker could help patients at high risk for relapse who may benefit from interventions, such as early withdrawal of immunosuppression.