Investigations into the function of mesenchymal-TG2 in epidermal formation and keratinocytes migration were established with varying success using coculture systems. Results indicate TG2 overexpression increases the rate of keratinocytes migration via an as yet unidentified soluble factor. Conversely, the presence of fibroblasts overexpressing this TG have demonstrated an inhibitory effect on keratinocyte migration.

Examining surface shape appearance by touching and observing a lesion from different points of view is a part of the clinical process for skin lesion diagnosis. Motivated by this, we hypothesise that surface shape embodies important information that serves to represent lesion identity and status. A new sensor, Dense Stereo Imaging System (DSIS) allows us to capture 1:1 aligned 3D surface data and 2D colour images simultaneously. This thesis investigates whether the extra surface shape appearance information, represented by features derived from the captured 3D data benefits skin lesion analysis, particularly on the tasks of segmentation and classification. In order to validate the contribution of 3D data to lesion identification, we compare the segmentations resulting from various combinations of images cues (e.g., colour, depth and texture) embedded in a region-based level set segmentation method. The experiments indicate that depth is complementary to colour. Adding the 3D information reduces the error rate from 7:8% to 6:6%. For the purpose of evaluating the segmentation results, we propose a novel ground truth estimation approach that incorporates a prior pattern analysis of a set of manual segmentations. The experiments on both synthetic and real data show that this method performs favourably compared to the state of the art approach STAPLE [1] on ground truth estimation. Finally, we explore the usefulness of 3D information to non-melanoma lesion diagnosis by tests on both human and computer based classifications of five lesion types. The results provide evidence for the benefit of the additional 3D information, i.e., adding the 3D-based features gives a significantly improved classification rate of 80:7% compared to only using colour features (75:3%). The three main contributions of the thesis are improved methods for lesion segmentation, non-melanoma lesion classification and lesion boundary ground-truth estimation.

Canine atopic dermatitis (cAD) is a common and severe pruritic, inflammatory skin disease that can be considered a naturally-occurring, spontaneous model of human Atopic Dermatitis (hAD). The genetics of cAD are poorly understood and therefore the aim of this project was to investigate the genetic factors involved in the pathogenesis of cAD and to identify specific gene associations with cAD within and between dog breeds. It was hoped that this study would further strengthen the evidence that dogs are a suitable model hAD. Using dogs as a model to study the genetic basis of AD is advantageous because dog breeds form genetically isolated populations exhibiting strong linkage disequilibrium (LD). In contrast to humans where LD across the genome is weak (10-100 kb), domestic dog breeds have strong LD which extends over long distances (0.8 -5 Mb). This is highly advantageous in genetic studies because fewer genetic markers and smaller sample sizes are needed to find disease associations in dogs. To study the genetic basis of cAD a dual approach of candidate gene association study and genome wide association study (GWAS) was used. This gave not only a novel unbiased approach but also used information from previous studies on which gene selection was based. Therefore increasing the likelihood that the causative genes involved in cAD pathogenesis could be identified. This thesis demonstrated altered mRNA expression in 54 genes out of 22,000 transcripts by mRNA microarray in cAD. Further to this qPCR was used to confirm the microarray results and quantify gene expression in potential cAD candidate genes. This approach identified 11 genes with altered expression in cAD. The qPCR results were further correlated 2 with the clinical outcomes: Canine Atopic Dermatitis and Severity Index (CADESI-03) and number of responses on intra-dermal allergen tests. Eleven novel SNPs and 1 novel microsatellite were identified by transgenomic WAVE analysis. The microsatellite was further typed in 659 dogs and but no association with cAD was found. A GWAS with 22,362 SNPs was performed. The significant results were validated by Sequenom along with the SNPs from the candidate gene study (literature selected genes) in 659 dogs across 8 breeds. In total, 232 SNPs across 54 genes and 41 intergenic regions were genotyped on Sequenom. From this 45 putative associations were found in various breeds. A large number of these associations had relevant functions to AD and/or previous association with hAD.

Microdialysis is a method of monitoring biochemistry of tissues in-vivo, and is established as a clinical and research tool for monitoring of other tissue such as liver and brain. The aim of this thesis was to investigate the use of the microdialysis method in monitoring the human dermis in healthy and burned skin, with a view to its use as a tool to detect progression of the burn wound. Ten healthy volunteers were used to establish a normal range for glucose, lactate, pyruvate and glycerol levels, and to assess the effect of temperature on results. Ten patients with burns <15%TBSA were recruited and microdialysis was undertaken in zones of coagulation and stasis and in unburned skin in each patient from recruitment until36 hours post-bum. A further 2 patients with burns >30%TBSA were also studied. Biochemical findings and the result of amino acid assays are reported. An attempt at correlating biochemical findings with Laser Doppler Images was made, to establish the role of the technique in predicting wound progression. However no wounds showed any evidence of progression in the areas of probe placement over the time of the study.

Overexposure to the sun is associated with an increased risk of melanoma and nonmelanoma skin cancer, but indications of improvements in sun protection behavior are poor. Attempts to identify emerging themes in skin cancer control have largely been driven by groups of experts from a single field. In December 2016, 19 experts from various disciplines convened for Interdisciplinary Perspectives on Skin Cancer, a 2-day meeting hosted by the National Academy of Sciences. The group discussed knowledge gaps, perspectives on sun exposure, implications for skin cancer risk and other health outcomes, and new directions. Five themes emerged from the discussion: (1) The definition of risk must be expanded, and categories for skin physiology must be refined to incorporate population diversities. (2) Risky sun exposure often co-occurs with other health-related behaviors. (3) Messages must be nuanced to target at-risk populations. (4) Persons at risk for tanning disorder must be recognized and treated. (5) Sun safety interventions must be scalable. Efficient use of technologies will be required to sharpen messages to specific populations and to integrate them within multilevel interventions. Further interdisciplinary research should address these emerging themes to build effective and sustainable approaches to large-scale behavior change.

This randomized clinical study aimed to compare the efficacy of written handouts with that of audio-visual computerized presentations in educating adolescents about acne vulgaris. The study included 101 adolescent patients, aged 13 to 17 years, presenting to a private dermatology practice or one of three pediatric clinics in New Haven, CT. All participants completed a brief enrollment questionnaire to gauge baseline knowledge about acne vulgaris. Subjects were then randomized to receive either a written handout or an audio-visual computerized presentation. Immediately following the intervention, and again at one month, patients were asked to complete identical questionnaires to assess change in knowledge about acne. The main outcome measure was change in knowledge about acne vulgaris, as indicated by performance on pre-intervention, post-intervention, and one-month follow-up questionnaires. Baseline questionnaires were completed by 21 patients in the pilot study and 80 subjects in the revised study; 17 (80.95%) and 77 (96.25%) completed the respective studies. In both the pilot and revised studies, there was no significant difference between intervention groups in terms of baseline knowledge or gain-in-knowledge. Immediately post- intervention, both groups showed significant improvement from baseline (P<.0001 revised study, P<.01 pilot study). At the one-month follow-up, patients in the pilot study randomized to receive the computerized presentation still showed significant gain in knowledge from baseline (p<.05), while those in the handout group did not. Meanwhile, both intervention groups in the revised study continued to show significant gain in knowledge from baseline at one month (p<.0001). From the above results it appears that both written handouts and audio-visual computerized presentations about acne vulgaris confer significant and equivalent benefits in terms of short- and long-term knowledge gains among adolescent patients with acne.

Introduction Squamous cell carcinoma of the auricle has an unusually high rate of lymph node metastases when compared to similar tumours at other sites. The lymph nodes affected are close to the base of the skull and in the neck. Development of metastasis carries a poor prognosis and most patients will subsequently die of failure of loco-regional control. Despite the likelihood of a poor outcome nothing can be done for patients prior to development of metastasis, as the risk of spread is not sufficiently high to warrant intervention in all patients. They are therefore treated with a ‘wait and see policy’ and only offered treatment once clinical evidence of metastatic spread is detected. This thesis sets out to examine what can be done, at the time of initial presentation with an auricular squamous cell carcinoma to identify patients who would benefit from treatment to the regional lymph node basins. Materials and Methods The thesis is divided into four separate studies. A systematic review examines the evidence available to date, an anatomical study examines the lymphatic drainage of the auricle in cadavers, a sentinel lymph node biopsy study examines the use of this technique to identify early tumour spread and a retrospective analysis of cases of auricular squamous cell carcinoma in our unit examines histopathological prognostic indictors of metastatic spread. Results The systematic review found that these tumours have a metastatic rate of about 11%. Patients developing metastasis usually die from failure of loco-regional control. Depth of tumour invasion, tumour size and mode of invasion seem to be potential indicators of metastatic risk. There is a strong argument for prophylactic intervention to the regional lymph nodes but there is no consensus of opinion as to when this should be carried out The anatomical study comprised 5 cadaveric dissections. They showed that the first echelon nodes draining the auricle lie in the superficial parotid gland, post-auricular/ mastoid nodal group and level II of the neck. There are anastamotic pathways around the mastoid and post-auricular nodes that could permit embolic tumour cells to bypass them. Five lymphatic pathways draining the auricle are described and some of these lie on the lateral and anterior surfaces of the mastoid bone and traverse the insertion of sternocleidomastoid. 28 cases of auricular squamous cell carcinoma were enrolled for sentinel lymph node biopsy. None of them were found to have any metastatic spread. One case showed non-viable tumour cells in a lymph node. There was a high incidence of complications (14%) directly related to the sentinel node biopsy procedure. The retrospective analysis identified 229 cases of auricular squamous cell carcinoma treated in our unit from 1992 - 2004. 212 of these cases had the primary pathology available for analysis. 24 (of 212) patients developed metastasis. 17 patients died as a result of their disease usually due to failure of control at the regional lymph node basin. Primary tumours with a depth of invasion greater than 8mm have metastatic rate of 56%. Tumours with a depth of invasion between 2-8mm and evidence of cartilage destruction, lymphovascular invasion or a non-cohesive invasive front have 24% metastatic rate. Tumours outwith these high-risk groups did not metastasise. Conclusions Elective lymph node dissections of the superficial parotid gland, post-auricular/mastoid and level II nodes should be considered in patients with primary auricular squamous cell carcinomas with a depth of invasion >8mm or a depth of invasion between 2 - 8 mm and evidence of cartilage destruction, lymphatic invasion or a non-cohesive invasive front. This should ideally be done as part of an observational study to evaluate the cost / benefit ratio for these patients. The neck dissection must clear the mastoid bone to a sub-periosteal level on its anterior and lateral surfaces. This will require the removal of the upper portion of sternocleidomastoid. Sentinel lymph node biopsy requires further study to evaluate it as a method for early detection of metastatic spread in auricular squamous cell carcinoma. This could be done as part of an observational study of elective neck dissections.

Hypothesis: Trimethoprim promotes wound healing, decreases lesion counts and improves quality of life of recessive dystrophic epidermolysis bullosa (RDEB) patients. Objectives: Assess feasibility of conducting a large randomized clinical trial. Determine efficacy of trimethoprim in healing of chronic wounds, decreasing lesion counts and improving quality of life of RDEB patients. Methods: Prospective, randomized, double-blinded, placebo-controlled, cross-over pilot study. Results: Ten patients enrolled in the trial, 7 completed both study periods. Despite showing that all patients improved on trimethoprim and that there was a 41% difference in affected area percent change favoring trimethoprim, the cross-over analysis did not show a significant difference between the drug and placebo (p=0.08). Secondary outcome measures did not achieve statistical significance. Limitations: Small sample size, large variation in wound size and unaccounted confounders. Conclusions: Although patients experienced improvement while on trimethoprim, no statistical significant change was showed when compared to placebo.

Hypothesis: Trimethoprim promotes wound healing, decreases lesion counts and improves quality of life of recessive dystrophic epidermolysis bullosa (RDEB) patients. Objectives: Assess feasibility of conducting a large randomized clinical trial. Determine efficacy of trimethoprim in healing of chronic wounds, decreasing lesion counts and improving quality of life of RDEB patients. Methods: Prospective, randomized, double-blinded, placebo-controlled, cross-over pilot study. Results: Ten patients enrolled in the trial, 7 completed both study periods. Despite showing that all patients improved on trimethoprim and that there was a 41% difference in affected area percent change favoring trimethoprim, the cross-over analysis did not show a significant difference between the drug and placebo (p=0.08). Secondary outcome measures did not achieve statistical significance. Limitations: Small sample size, large variation in wound size and unaccounted confounders. Conclusions: Although patients experienced improvement while on trimethoprim, no statistical significant change was showed when compared to placebo.

The decision whether or not to discharge an outpatient is vital in determining outpatient clinic attendance numbers, directly affecting overall patient care efficiency. A review of the factors influencing discharge decisions revealed that there was limited evidence of these factors and a lack of understanding how clinicians take discharge decisions. This project’s objectives were to describe the influential factors on discharge decisions from the clinicians’ and patients’ perspectives, to demonstrate the development and clinical evaluation of a novel "Traffic-light” design dermatology outpatient discharge information checklist to improve appropriateness and consistency in discharge decision-making. Semi-structured interviews were carried out with 40 consultant dermatologists across England. 148 influences were generated and thematically analysed manually and using NVivo10 software. A wide array of nonclinical factors, clinician-based, patient-based, practice-based and policy-based, influence discharge decision-making. Observations of 64 consultations and 56 semi-structured interviews with dermatology outpatients were carried out to understand their experience concerning the decision for their discharge. Twelve of 31 patients (39%) who were discharged considered their discharge inappropriate. A three-round Delphi exercise with 17 dermatology consultants (100% response) was carried out to reach agreement on what a high quality discharge information checklist should contain. There was strong inter-rater reliability (ICC=0.958) and fair inter-rater agreement (Fleiss Kappa=0.269). Thirteen items were identified that formed the "Trafficlight" design checklist. Twelve (67%) dermatology clinicians who evaluated the checklist found it useful. This study has demonstrated the importance of approaching discharge decision taking in an informed, structured manner. The checklist provide the basis for making discharge decisions more systematic, auditable and transparent, improving patient safety and optimising healthcare costs. These methods are potentially useful in other clinical disciplines.