Skin cancer, and some limitations on how we innovate and practice medicine.

Successfully delivering medical care and acquiring and disseminating the new knowledge that underpins clinical advance requires dealing with a number of both theoretical and organizational issues that may impede progress. Firstly, we have to move beyond the idea that biology and medicine are synonymous, and realize that tropes such as 'bench to bedside' or 'translational' frequently do not capture the way medical advance occurs. Medicine is more engineering than science, and the constraints imposed by society and economics, as well as historical models of working, may all delay improvements in healthcare delivery. Secondly, the generation of new ideas is influenced by the social organization and financial underpinning of science. Comparisons with other areas of science and technology suggest that medical science is dysfunctional and lacking in genuine innovation, particularly when cost is factored in as a key denominator. There are reasons to believe that matters are getting worse, and that the climate for revolutionary discovery is less supportive in both academia and industry than it was in the mid-to-late twentieth century. Thirdly, healthcare delivery is subject to a number of factors that limit cheap and effective care. These include payment systems that encourage unnecessary care, self-interest by medical guilds and insurers, and regulators that seek to limit new ways of working. Finally, there is also a striking failure to study and understand medical competence, how we educate doctors and other clinicians, and how technology might help to reduce costs.

Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans.

Melanin pigmentation protects the skin from the damaging effects of ultraviolet radiation (UVR). There are two types of melanin, the red phaeomelanin and the black eumelanin, both of which are present in human skin. Eumelanin is photoprotective whereas phaeomelanin, because of its potential to generate free radicals in response to UVR, may contribute to UV-induced skin damage. Individuals with red hair have a predominance of phaeomelain in hair and skin and/or a reduced ability to produce eumelanin, which may explain why they fail to tan and are at risk from UVR. In mammals the relative proportions of phaeomelanin and eumelanin are regulated by melanocyte stimulating hormone (MSH), which acts via its receptor (MC1R), on melanocytes, to increase the synthesis of eumelanin and the product of the agouti locus which antagonises this action. In mice, mutations at either the MC1R gene or agouti affect the pattern of melanogenesis resulting in changes in coat colour. We now report the presence of MC1R gene sequence variants in humans. These were found in over 80% of individuals with red hair and/or fair skin that tans poorly but in fewer than 20% of individuals with brown or black hair and in less than 4% of those who showed a good tanning response. Our findings suggest that in humans, as in other mammals, the MC1R is a control point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response.

Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease.

Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.

Predicting pain and function outcomes in people consulting with shoulder pain: the PANDA-S clinical cohort and qualitative study protocol.

INTRODUCTION: People presenting with shoulder pain considered to be of musculoskeletal origin is common in primary care but diagnosing the cause of the pain is contentious, leading to uncertainty in management. To inform optimal primary care for patients with shoulder pain, the study aims to (1) to investigate the short-term and long-term outcomes (overall prognosis) of shoulder pain, (2) estimate costs of care, (3) develop a prognostic model for predicting individuals' level and risk of pain and disability at 6 months and (4) investigate experiences and opinions of patients and healthcare professionals regarding diagnosis, prognosis and management of shoulder pain. METHODS AND ANALYSIS: The Prognostic And Diagnostic Assessment of the Shoulder (PANDA-S) study is a longitudinal clinical cohort with linked qualitative study. At least 400 people presenting to general practice and physiotherapy services in the UK will be recruited. Participants will complete questionnaires at baseline, 3, 6, 12, 24 and 36 months. Short-term data will be collected weekly between baseline and 12 weeks via Short Message Serevice (SMS) text or software application. Participants will be offered clinical (physiotherapist) and ultrasound (sonographer) assessments at baseline. Qualitative interviews with ≈15 dyads of patients and their healthcare professional (general practitioner or physiotherapist).Short-term and long-term trajectories of Shoulder Pain and Disability Index (using SPADI) will be described, using latent class growth analysis. Health economic analysis will estimate direct costs of care and indirect costs related to work absence and productivity losses. Multivariable regression analysis will be used to develop a prognostic model predicting future levels of pain and disability at 6 months using penalisation methods to adjust for overfitting. The added predictive value of prespecified physical examination tests and ultrasound findings will be examined. For the qualitative interviews an inductive, exploratory framework will be adopted using thematic analysis to investigate decision making, perspectives of patients and clinicians on the importance of diagnostic and prognostic information when negotiating treatment and referral options. ETHICS AND DISSEMINATION: The PANDA-S study has ethical approval from Yorkshire and The Humber-Sheffield Research Ethics Committee, UK (18/YH/0346, IRAS Number: 242750). Results will be disseminated through peer-reviewed publications, social and mainstream media, professional conferences, and the patient and public involvement and engagement group supporting this study, and through newsletters, leaflets and posters in participating sites. TRIAL REGISTRATION NUMBER: ISRCTN46948079.

Use of implantable meshes for augmented rotator cuff repair: a systematic review and meta-analysis.

OBJECTIVE: To appraise studies reporting on clinical effectiveness and safety of surgical meshes used to augment rotator cuff repairs (RCRs). DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase and Cochrane databases were searched between April 2006 and April 2020. ELIGIBILITY CRITERIA: All studies evaluating adults (≥18 years) undergoing RCR were considered. There were no language restrictions. DATA EXTRACTION AND SYNTHESIS: Screening, data extraction and quality appraisal were conducted by two independent reviewers. Meta-analysis was conducted using a random-effects models if ≥2 comparative studies reported the same outcome measure. Risk of bias assessment was undertaken for randomised (RoB2, Cochrane) and comparative studies (ROBINS-I, Cochrane). RESULTS: We included 60 studies, consisting of 7 randomised controlled trials, 13 observational comparative studies and 40 observational case series. All comparative studies reported on shoulder-specific functional outcome scores, 18 on the radiographic occurrence of re-tear and 14 on pain score metrics. All studies contained some risk of bias.Compared with non-augmented repair, a small improvement in shoulder-specific function or pain scores was observed for synthetic patches with a mean improvement of 6.7 points on the University of California Los Angles (UCLA) shoulder score (95% CI 0.1 to 13.4) and 0.46 point reduction on the Visual Analogue Scale (95% CI -0.74 to -0.17), respectively. A reduced likelihood of radiologically observed re-tear was observed for synthetic (risk ratio (RR) 0.41, 95% CI 0.27 to 0.61) and allograft (RR 0.34, 95% CI 0.18 to 0.65) patches. A total of 49 studies reported on the occurrence of complications. Slightly higher crude complication rates were observed following patch-augmented repair (2.1%) than standard repair (1.6%). CONCLUSIONS: While several studies suggest a decreased failure rate and small improvements in shoulder function and pain following augmented RCR, a paucity of rigorous clinical evaluation, for both effectiveness and safety, prevents firm recommendations. PROSPERO REGISTRATION NUMBER: CRD42017057908.

The use of a patch to augment rotator cuff surgery - A survey of UK shoulder and elbow surgeons.

BACKGROUND: Rotator cuff tears are a common cause of shoulder pain and can result in prolonged periods of pain, disability and absence from work. Rotator cuff repair surgery is increasingly used in an attempt to resolve symptoms but has failure rates of around 40%. There is a pressing need to improve the outcome of rotator cuff repairs. Patch augmentation increasingly being used within the NHS in an attempt to reduce repair failures. The aim of this survey was to determine current UK practice and opinion relating to the factors that influence choice of patch, current patient selection and willingness to assist with generation of improved evidence. METHODS: An online survey was sent to the surgeon members of the British Elbow and Shoulder Society (BESS). Questions covered respondent demographics, experience with patches, indications for patch augmentation and willingness to be involved in a randomised trial of patch augmented rotator cuff surgery. RESULTS: The response rate was 105/550 (19%). 58% of respondents had used a patch to augment rotator cuff surgery. 70% of patch users had undertaken an augmented repair within the last 6 months. A wide surgical experience in augmentation was reported (ranging 1 to 200 implants used). However, most surgeons reported low volume usage, with a median of 5 rotator cuff augmentation procedures performed. At least 10 different products had been used. Most of the patches used were constructed from human decellularised dermis tissue, although porcine derived and synthetic based patches had also been used. Only 3-5% stated they would undertake an augmented repair for small tears across ages, whereas 28-40% and 19-59% would do so for large or massive tears respectively. When assessing patient suitability, patient age seemed relevant only for those with large and massive tears. Half of the surgeons reported an interest in taking part in a randomised controlled trial (RCT) evaluating the role of patch augmentation for rotator cuff surgery, with a further 22% of respondent's undecided. CONCLUSIONS: A variety of patches have been used by surgeons to augment rotator cuff repair with a wide range of operator experience. There was substantial uncertainty about which patch to use and differing views on which patients were most suitable. There is a clear need for robust clinical evaluation and further research in this area.

Cost-effectiveness analysis of a placebo-controlled randomized trial evaluating the effectiveness of arthroscopic subacromial decompression in patients with subacromial shoulder pain.

AIMS: The aims of this study were to compare the use of resources, costs, and quality of life outcomes associated with subacromial decompression, arthroscopy only (placebo surgery), and no treatment for subacromial pain in the United Kingdom National Health Service (NHS), and to estimate their cost-effectiveness. PATIENTS AND METHODS: The use of resources, costs, and quality-adjusted life-years (QALYs) were assessed in the trial at six months and one year. Results were extrapolated to two years after randomization. Differences between treatment arms, based on the intention-to-treat principle, were adjusted for covariates and missing data were handled using multiple imputation. Incremental cost-effectiveness ratios were calculated, with uncertainty around the values estimated using bootstrapping. RESULTS: Cumulative mean QALYs/mean costs of health care service use and surgery per patient from baseline to 12 months were estimated as 0.640 (standard error (se) 0.024)/£3147 (se 166) in the decompression arm, 0.656 (se 0.020)/£2830 (se 183) in the arthroscopy only arm and 0.522 (se 0.029)/£1451 (se 151) in the no treatment arm. Statistically significant differences in cumulative QALYs and costs were found at six and 12 months for the decompression versus no treatment comparison only. The probabilities of decompression being cost-effective compared with no treatment at a willingness-to-pay threshold of £20 000 per QALY were close to 0% at six months and approximately 50% at one year, with this probability potentially increasing for the extrapolation to two years. DISCUSSION: The evidence for cost-effectiveness at 12 months was inconclusive. Decompression could be cost-effective in the longer-term, but results of this analysis are sensitive to the assumptions made about how costs and QALYs are extrapolated beyond the follow-up of the trial.

Evidence and the industrialization of medicine.

Medicine is changing rapidly. In part, this is due to the accumulation of discoveries in biomedical science. However, this is not sufficient to explain the changes clinicians see. Whereas once medical advance concerned discoveries external to clinical practice (such as the identification of a causative microorganism or gene), medical practice itself is now a subject of study. What clinicians know, how they acquire knowledge, and how knowledge is distributed are all subjects of scrutiny. In short, medicine is being industrialized: we can see the twin changes of specialization, and the desire to codify practice such that those with different educational backgrounds can undertake a clinical role. Key to such change is the role played by evidence. Whereas once natural science was seen to determine clinical practice, this view is now known to be mistaken. How we can formally combine evidence from different traditions is, despite the claims of the evidence-based medicine movement, as yet unresolved.

In vivo measurement of tissue metabolism in tendons of the rotator cuff: implications for surgical management.

We have undertaken an in vivo assessment of the tissue metabolism and cellular activity in torn tendons of the rotator cuff. Cellular oxygen consumption was measured in 13 patients undergoing mini-open repair of small, medium, large and massive full-thickness tears. Measurements were also taken from three control patients who were undergoing open stabilisation of the shoulder with grossly normal tendons. The level of oxygen and nitrous oxide was measured amperometrically using silver needle microelectrodes at the apex of the tear and 1.5 cm from its edge. With nitrous oxide indicating the degree of perfusion, oxygen consumption was calculated at each location to reflect cellular activity. All of the torn tendons had lower levels of cellular activity than the control group. This activity was lower still in the tissue nearest to the edge of the tear with the larger tears showing the lowest activity. This indicated reduced levels of tissue metabolism and infers a reduction in tendon viability. Our findings suggest that surgical repair of torn tendons of the rotator-cuff should include the more proximal, viable tissue, and may help to explain the high rate of re-rupture seen in larger tears.

Pathology of the torn rotator cuff tendon. Reduction in potential for repair as tear size increases.

We have studied cellular and vascular changes in different stages of full thickness tears of the rotator cuff. We examined biopsies from the supraspinatus tendon in 40 patients with chronic rotator cuff tears who were undergoing surgery and compared them with biopsies from four uninjured subscapularis tendons. Morphological and immunocytochemical methods using monoclonal antibodies directed against leucocytes, macrophages, mast cells, proliferative and vascular markers were used. Histological changes indicative of repair and inflammation were most evident in small sized rotator cuff tears with increased fibroblast cellularity and intimal hyperplasia, together with increased expression of leucocyte and vascular markers. These reparative and inflammatory changes diminished as the size of the rotator cuff tear increased. Marked oedema and degeneration was seen in large and massive tears, which more often showed chondroid metaplasia and amyloid deposition. There was no association between the age of the patient and the duration of symptoms. In contrast, large and massive tears showed no increase in the number of inflammatory cells and blood vessels. Small sized rotator cuff tears retained the greatest potential to heal, showing increased fibroblast cellularity, blood vessel proliferation and the presence of a significant inflammatory component. Tissue from large and massive tears is of such a degenerative nature that it may be a significant cause of re-rupture after surgical repair and could make healing improbable in this group.

Basal cell carcinomas and squamous cell carcinomas of human skin show distinct patterns of chromosome loss.

Although basal cell carcinomas and squamous cell carcinomas are clinically and pathologically distinct, the molecular basis for these differences is not clear. We have used polymorphic microsatellite markers to determine the pattern and extent of chromosome losses in a series of 44 basal cell carcinomas and 47 squamous cell neoplasms of the skin. Basal cell carcinomas showed a distinctive allelotype with chromosome loss largely confined to a single chromosome arm, 9q (26 of 44 informative tumors). In contrast to the predominance of loss on a single chromosome arm in basal cell carcinomas, squamous cell neoplasms showed more widespread loss with loss of heterozygosity of markers from 35 of 39 chromosome arms in one or more of the tumors studied. The pattern of loss was also different from basal cell carcinomas with frequent loss of heterozygosity of markers from 9p (41%), 13q (46%), 17p (33%), 17q (33%), and 3p (23%) in squamous cell neoplasms. The frequent loss of markers from these chromosome arms relative to other chromosome losses suggests that these arms may contain genes important in the development of cutaneous squamous cell carcinomas.

Wavelength specific patterns of p53 induction in human skin following exposure to UV radiation.

We report that, in human skin, exposure to equally erythemogenic doses of UVA, UVB, and UVC increases immunocytochemically detected p53 in a wavelength-specific pattern. UVC produced immunostaining confined to the upper epidermis. With UVB, staining was seen throughout the epidermis, whereas with UVA staining predominated in the basal layer. The results with UVB and UVC are understandable on the basis of their known differences in penetration, whereas those with UVA are not. This suggests that within one cell type the pattern of p53 response to UV radiation is wavelength dependent.

Allelotypes of primary cutaneous melanoma and benign melanocytic nevi.

A multistep genetic model of tumorigenesis, based on genetic alterations in benign and primary malignant lesions, has been proposed for neoplasms such as colonic carcinoma. However, evidence for a similar genetic progression in melanoma has relied heavily on findings in cultured lesions or metastases. We have investigated every autosomal arm for loss of heterozygosity in 41 primary cutaneous melanomas and 32 benign melanocytic nevi, and have investigated several chromosome arms that show loss in melanoma in 27 Spitz nevi (a nevus with histological similarities to melanoma). Loss of heterozygosity in primary melanoma was identified most frequently on chromosomes 9p (46%) at loci near the p16INK4 gene, 10q (31%), 6q (31%), and 18q (22%); loss of these chromosome arms were related to the progression of the melanoma. Only two benign melanocytic nevi (both of which showed atypical features on histology) demonstrated genetic alterations, including p9 loss in one case. In addition, two Spitz nevi contained interstitial deletions on chromosome 9p. Our findings show that loss of heterozygosity of 9p is not confined to melanoma, but that other uncultured melanocytic lesions can also display loss of this chromosome arm, and that other genetic changes (e.g., loss of 10q, 6q, and 18q) may be important in conveying the malignant phenotype to melanoma.

Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues.

The p53-regulated gene product p21WAF1/CIP1 is the prototype of a family of small proteins that negatively regulate the cell cycle. To learn more about p21WAF1/CIP1 regulation in vivo, monoclonal antibodies were developed for immunohistochemistry. These revealed that p21WAF1/CIP1 expression followed radiation-induced DNA damage in human skin in a pattern consistent with its regulation by p53. A detailed comparison of the human, rat, and mouse p21WAF1/CIP1 promoter sequences revealed that this induction was probably mediated by conserved p53-binding sites upstream of the transcription start site. In unirradiated tissues, p21WAF1/CIP1 expression was apparently independent of p53 and was observed in a variety of cell types. Moreover, there was a striking compartmentalization of p21WAF1/CIP1 expression throughout the gastrointestinal tract that correlated with proliferation rather than differentiation. As epithelial cells migrated up the crypts, the Ki67-expressing proliferating compartment near the crypt base ended abruptly, with the coincident appearance of a nonproliferating compartment expressing p21WAF1/CIP1. In colonic neoplasms, this distinct compartmentalization was largely abrogated. Cell cycle inhibitors are thus subject to precise topological control, and escape from this regulation may be a critical feature of neoplastic transformation.

Surgical management of the elderly elbow.

The elbow has a major role in helping with the positioning of the hand in space. Any pathology of the joint can result in pain, loss of function and difficulties with activities of daily living. With an increasingly elderly population the degenerative conditions affecting the elbow are becoming more prevalent. Besides traumatic injury, the more commonly encountered problems are osteoarthritis, inflammatory arthritis, nerve compression and stiffness. An awareness of these conditions is important for those who provide care to this patient group. Whilst many of these conditions can be managed conservatively in primary care, some patients are referred to secondary care and elect for surgical treatments. This review considers the surgical treatments for the common elbow pathologies in the elderly population, including the potential complications associated with such treatments.

Genetic change in actinic keratoses.

Actinic keratoses (AKs) are small scaly red areas of skin characterised histologically by dysplasia, a minority of which are thought to be precursors of squamous cell carcinoma (SCC), and which show a high frequency of regression. Surprisingly, in view of their benign clinical course, they show a high frequency of loss of heterozygosity (LOH) with a median loss of four loci with almost 20% of lesions showing loss of eight or more alleles, as well as frequent p53 mutation. Loss was common on 3p (31%), 9p (39%), 9q (22%), 13q (52%), 17p (64%) and 17q (46%), and allele loss correlated with dysplasia. Topological disturbance of p21WAF1/CIP1 expression correlated with allele loss but was also seen together with increased wild-type p53 expression and an increase in the fraction of cycling cells in the absence of allele loss or p53 mutation, and is likely to represent an early change. P21WAF1/CIP1 expression appeared independent of p53 status. The frequency of LOH in AKs exceeded that of (invasive) SCCs suggesting that the relation between the accumulation of genetic change and behaviour for non-melanoma skin cancer is not straightforward.

Prognostic significance of allelic losses in primary melanoma.

Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine whether allelic loss is of prognostic importance in melanoma, disease-free survival was related to loss of heterozygosity on 6q, 9p and 10q in 83 individuals with sporadic primary cutaneous melanoma. Loss of chromosome arms 6q and 10q were each significantly associated with a poorer clinical outcome (P=0.013 and P=0.001 respectively). In a subgroup of 41 subjects whose primary tumours were allelotyped, the fractional allelic loss (FAL) at 39 autosomal arms also significantly correlated with disease-free survival (P=0.013), with an increase in FAL associated with a poorer outcome; this association remained significant when controlled for tumour thickness (P=0.035). In addition, a greater proportion of cells were immunopositive for Ki67 antigen, p53 and p21WAF1 protein in the primary melanomas than in the benign melanocytic nevi, however, only p53 over-expression was significantly associated with improved survival (P=0.041).

A repetitive movement detector used for automatic monitoring and quantification of scratching in mice.

We have designed an economical non-invasive movement detector for small animal studies and used it for monitoring and quantifying itch in mice. The system is based on a sensitive force transducer positioned below a recording platform holding a lightweight polystyrene recording box in which an animal is placed. A programmed micro-controller is used to discriminate between non-specific movement, grooming behaviour, and scratching movements made by the animal's hind limb. Following sub-dermal injection of histamine receptor agonists into the neck of a mouse, dose-related scratching occurred which was detected and quantified. There was 91% correlation between bouts of scratching as counted manually from playback of the video recording and recorded by the detector. The detector was also able rapidly to count the individual scratch movements of the hind limb that comprise a bout, with 95% accuracy in comparison with manual counting during slow motion playback of video tape, something that is impossible for an unaided observer to achieve because individual scratch movements are too fast to discriminate by eye. Separate detectors were used for the efficient non-invasive study of four animals simultaneously, and this number could easily be increased by adding more platforms. The system could also be modified to record the animal's position within the box, which would be of value in studies involving exploratory behaviour. In summary, the non-invasive multichannel repetitive movement detector will be very useful for accurate measurement of scratching during pruritus studies in small animals, with considerable savings in staff time and effort. It should therefore be a valuable tool for helping to investigate pruritus and in the evaluation of anti-pruritic drugs.

Evidence-based surgical training in orthopaedics: how many arthroscopies of the knee are needed to achieve consultant level performance?

Despite being one of the most common orthopaedic operations, it is still not known how many arthroscopies of the knee must be performed during training in order to develop the skills required to become a Consultant. A total of 54 subjects were divided into five groups according to clinical experience: Novices (n = 10), Junior trainees (n = 10), Registrars (n = 18), Fellows (n = 10) and Consultants (n = 6). After viewing an instructional presentation, each subject performed a simple diagnostic arthroscopy of the knee on a simulator with visualisation and probing of ten anatomical landmarks. Performance was assessed using a validated global rating scale (GRS). Comparisons were made against clinical experience measured by the number of arthroscopies which had been undertaken, and ROC curve analysis was used to determine the number of procedures needed to perform at the level of the Consultants. There were marked differences between the groups. There was significant improvement in performance with increasing experience (p < 0.05). ROC curve analysis identified that approximately 170 procedures were required to achieve the level of skills of a Consultant. We suggest that this approach to identify what represents the level of surgical skills of a Consultant should be used more widely so that standards of training are maintained through the development of an evidenced-based curriculum.