Sentinel lymph node biopsy is unreliable in predicting melanoma mortality for both younger and older patients.

BACKGROUND: Melanoma disease patterns vary with patient age. AIM: To evaluate sentinel lymph node biopsy (SLNB) in managing melanoma at differing patient ages. METHODS: Online prediction tools were applied to compare SLNB positivity (SLNB+) and survival risk at patient ages 20-80. Tübingen melanoma data were used to determine variations in the hazard ratio of SLNB+ for mortality at different patient ages. RESULTS: Regardless of tumour thickness, predicted SLNB+ rates were markedly higher than mortality rates for 20-year-old patients. For 80-year-old patients, it is the opposite. DISCUSSION: If 1000 20-year-olds with a 0.4 mm thickness non-ulcerated melanoma underwent SLNB, 100 would likely be positive. If all 100 were to be offered adjuvant drug therapy (ADT), fewer than three more melanoma deaths in those 1000 patients would be avoided. In total, 97 patients would have received medication they may never have needed. If 1000 80-year-olds with a 3 mm thickness non-ulcerated melanoma underwent SLNB, only 40 would likely be positive. In total, 274 patients would be predicted to die of melanoma, 245 being SLNB negative and 29 SLNB+. ADT linked to SLNB+ could deny treatment to 89% of these high-risk patients. LIMITATIONS: The authors relied on published risk data. CONCLUSION: SLNB has poor specificity at predicting mortality in young melanoma patients and poor sensitivity in older patients. SLNB is not indicated in managing cutaneous melanoma for patients under 40 or over 60 years of age. Many such patients could be managed with wide local excision alone in their clinician's office-based practice. For all cutaneous melanoma patients at all ages, linking ADT to BAUSSS biomarker, (an algorithm of Breslow thickness, age, ulceration, subtype, sex and Site) rather than SLNB+ is likely more appropriate. BAUSSS provides a more accurate melanoma-specific mortality risk assessment for patients without burdening them with added surgery, hospitalization, costs or morbidity risk.

Evaluation of Digitalisation in Healthcare and the Quantification of the "Unmeasurable".

Evaluating healthcare digitalisation, where technology implementation and adoption transforms existing socio-organisational processes, presents various challenges for outcome assessments. Populations are diverse, interventions are complex and evolving over time, meaningful comparisons are difficult as outcomes vary between settings, and outcomes take a long time to materialise and stabilise. Digitalisation may also have unanticipated impacts. We here discuss the limitations of evaluating the digitalisation of healthcare, and describe how qualitative and quantitative approaches can complement each other to facilitate investment and implementation decisions. In doing so, we argue how existing approaches have focused on measuring what is easily measurable and elevating poorly chosen values to inform investment decisions. Limited attention has been paid to understanding processes that are not easily measured even though these can have significant implications for contextual transferability, sustainability and scale-up of interventions. We use what is commonly known as the McNamara Fallacy to structure our discussions. We conclude with recommendations on how we envisage the development of mixed methods approaches going forward in order to address shortcomings.

Socio-Organizational Dimensions: The Key to Advancing the Shared Care Record Agenda in Health and Social Care.

Integrating health and social care delivery with the help of digital technologies is a grand challenge. We argue that previous attempts have largely failed to achieve their objectives because implementers and decision makers disregard the complex socio-organizational dimensions of change associated with initiatives. These include structural and organizational complexity inhibiting the development of shared care pathways; professional jurisdictions, interests, and expertise; and existing data and governance structures. We provide an overview of those dimensions that can inform strategic decisions going forward, thereby contributing to the chances of success of shared care initiatives.

Learning From Experience and Finding the Right Balance in the Governance of Artificial Intelligence and Digital Health Technologies.

Artificial intelligence (AI) and machine learning medical tools have the potential to be transformative in care delivery; however, this change will only be realized if accompanied by effective governance that ensures patient safety and public trust. Recent digital health initiatives have called for tighter governance of digital health. A correct balance must be found between ensuring product safety and performance while also enabling the innovation needed to deliver better approaches for patients and affordable efficient health care for society. This requires innovative, fit-for-purpose approaches to regulation. Digital health technologies, particularly AI-based tools, pose specific challenges to the development and implementation of functional regulation. The approaches of regulatory science and "better regulation" have a critical role in developing and evaluating solutions to these problems and ensuring effective implementation. We describe the divergent approaches of the European Union and the United States in the implementation of new regulatory approaches in digital health, and we consider the United Kingdom as a third example, which is in a unique position of developing a new post-Brexit regulatory framework.

SARS-CoV-2 structural coverage map reveals viral protein assembly, mimicry, and hijacking mechanisms.

We modeled 3D structures of all SARS-CoV-2 proteins, generating 2,060 models that span 69% of the viral proteome and provide details not available elsewhere. We found that ˜6% of the proteome mimicked human proteins, while ˜7% was implicated in hijacking mechanisms that reverse post-translational modifications, block host translation, and disable host defenses; a further ˜29% self-assembled into heteromeric states that provided insight into how the viral replication and translation complex forms. To make these 3D models more accessible, we devised a structural coverage map, a novel visualization method to show what is-and is not-known about the 3D structure of the viral proteome. We integrated the coverage map into an accompanying online resource (https://aquaria.ws/covid) that can be used to find and explore models corresponding to the 79 structural states identified in this work. The resulting Aquaria-COVID resource helps scientists use emerging structural data to understand the mechanisms underlying coronavirus infection and draws attention to the 31% of the viral proteome that remains structurally unknown or dark.

Late-onset Tay-Sachs disease.

We discuss the assessment and differential diagnoses of a young adult Hungarian man with a 1-year history of a progressive and symmetric amyotrophic lateral sclerosis-like syndrome, along with irregular action tremor and stimulus-sensitive myoclonus of the arms. MR scan of the brain showed isolated cerebellar atrophy and formal neuropsychometric testing identified significant subclinical deficits in attention, processing speed and memory. We suspected a form of GM2 gangliosidosis, and white cell enzyme analysis showed markedly reduced enzymatic activity of ß-hexosaminidase A. Genetic testing subsequently revealed two heterozygous pathogenic mutations in the HEXA gene (c.1499delT p.(Leu500fs) and c.805G>A p.(Gly269Ser)), confirming the very rare diagnosis of adult-onset Tay-Sachs disease.

From Pulling Teeth to Promoting Oral Health. Pharmacy and Dentistry 1815-2015.

Two hundred years ago the occupational boundaries between different medical practitioners were blurred and unspecified, with many practicing in several fields. However the 1815 Apothecaries Act had a major impact on both the emerging pharmaceutical and dental professions. The 1878 and 1921 Dentists Acts enabled pharmacists who did some dentistry to continue practicing dentistry. Changes proposed by the British Dental Association (BDA) resulted in the formation of a Chemists Dental Association in 1910 to defend the interests of this group, which continued in existence until 1951. This paper explores the changing relationship between chemists and dentists from the early nineteenth century through to the early twenty-first century. Sources used include the published work of both dental and pharmaceutical historians, documentary sources, and quotations from oral history interviews.

Novel photodynamic therapy does not prevent new skin cancers--randomized controlled trial.

OBJECTIVES: To determine whether field photodynamic therapy (PDT) of actinic keratoses using a novel preparation of 5-aminolevulonic acid (novel ALA) results in fewer subsequent invasive skin cancers developing on the face of individuals with previous facial cutaneous malignancy in a prospective randomized controlled trial. METHODS AND MATERIALS: Intervention patients received two treatments of novel ALA 2 weeks apart. Controls were observed. Patients were followed up with biopsy of any suspicious lesions for 3 years. RESULTS: The trial was suspended early because of problems with trial governance and the reporting of severe adverse events. Sixty-four patients who were recruited at that time at one center were monitored. Their average age was 71, and 57% were male. Patients were randomized to intervention (n = 34) or observation (n = 29). Over the subsequent 3 years, 13 intervention patients (38%) developed 30 new cutaneous malignancies in the field treated, and 11 control patients (38%) developed 22 new malignancies. Some intervention patients experienced prolonged adverse events, including permanent scarring. CONCLUSION: Novel ALA made no difference in the likelihood of new malignancies developing. The risks without benefit of this novel ALA are troubling. Lack of efficacy and safety of novel ALA cannot be extrapolated to other PDT products.

Prolonged adverse events following photodynamic therapy: regulatory implications.

OBJECTIVE: To determine whether field photodynamic therapy (PDT) of actinic keratoses (AKs) using a novel preparation of 5-aminolevulonic acid (ALA) would result in fewer subsequent invasive skin cancers developing on the face. DESIGN: A prospective multi-center randomized controlled trial. The protocol was approved by the Bond University Human Research Ethics Committee in accord with the TGA's Clinical Trial Notification Scheme. The trial was registered (12609000025235) on the Australian New Zealand Clinical Trials Registry. SETTING: Six centers in four states in Australia. PROTOCOL: Two treatments of ALA PDT, 2 weeks apart for each patient. Controls were observed. Patients were followed up with biopsies of any suspicious lesions every 6 months for 2 years. MAIN OUTCOME MEASURE(S): Development of new skin cancers. RESULTS: The trial was suspended after 3 months and closed after 6 months after ethics committee approval was withdrawn on the basis of a breakdown in trial governance. Over the following 2 years, some investigators noted and formally reported the continued occurrence of serious adverse events in excess of those described with other approved cutaneous PDT treatments. USA dermatologists with experience managing AKs with FDA approved ALA products subsequently confirmed prolonged and severe adverse events in 6 of the former trial intervention patients. DISCUSSION AND CONCLUSIONS: Adverse effects experienced by patients using the investigational ALA PDT appeared more severe than those experienced when an FDA-approved ALA product is used. We believe the former should be further evaluated for safety. It is of concern that this ALA product and lamp could be promoted and used widely in Australia following these reports of significant adverse events and continued lack of TGA approval.

How do experts reporting for the legal process validate symptoms? The results of a survey.

This article examines the views of experts from a range of disciplines and how they view symptoms given to them by claimants in matters of personal injury or medical negligence assessments. The survey was carried out in 2009 and looks at current practice and attitudes from a number of different disciplines. The survey included questions looking at what percentage of cases were thought to be genuine, symptoms most likely to be elaborated, methods for assessing symptom validity, and documentary evidence required for a report. This article highlights the importance of looking at symptom validation in the legal process.

Sentinel lymph node biopsy now has a limited role in melanoma management.

SLNB is confirmed as a prognostic test but does not influence melanoma-specific survival at 10 years. SLNB-negative patients still need regular review and can still die from their melanoma. SLNB-positive patients should be carefully counselled regarding the risks and very limited benefit (if any) of proceeding to CL. SLNB should not be regarded as essential or standard of care for patients with melanomas. SLNB should be discussed with patients with intermediate-thickness melanoma. Note that 'discuss' is not the same as 'offer' or 'recommend'. The discussion should include: • SLNB does not alter survival prospects • SLNB provides added accuracy to survival prognostic figures−−70% vs. 90% for melanoma Breslow thickness of 1.2­3.5 mm • SLNB has a 10% complication rate • If positive, no added treatment can be offered that has demonstrated survival benefits−− this includes no apparent survival benefit in proceeding to CL−− SLNB-positive patients can be offered enrolment into further melanoma studies.

Evolutionary variation in the mechanics of fiddler crab claws.

BACKGROUND: Fiddler crabs, genus Uca, are classic examples of how intense sexual selection can produce exaggerated male traits. Throughout the genus the enlarged "major" cheliped (claw) of the male fiddler crab is used both as a signal for attracting females and as a weapon for combat with other males. However, the morphology of the major claw is highly variable across the approximately 100 species within the genus. Here we address variation, scaling, and correlated evolution in the mechanics of the major claw by analyzing the morphology and mechanical properties of the claws of 21 species of fiddler crabs from the Pacific, Gulf and Atlantic coasts of the Americas. RESULTS: We find that the mechanics that produce claw closing forces, the sizes of claws and the mechanical strength of the cuticle of claws are all highly variable across the genus. Most variables scale isometrically with body size across species but claw force production scales allometrically with body size. Using phylogenetically independent contrasts, we find that the force that a claw can potentially produce is positively correlated with the strength of the cuticle on the claw where forces are delivered in a fight. There is also a negative correlation between the force that a claw can potentially produce and the size of the claw corrected for the mass of the claw. CONCLUSIONS: These relationships suggest that there has been correlated evolution between force production and armoring, and that there is a tradeoff between claw mechanics for signaling and claw mechanics for fighting.

Progressive rash - a case study.

CASE STUDY: A man, 69 years of age, who previously had worked in the petroleum industry, presented with a 20 year history of an episodic rash on his arms, legs and trunk.

Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.

PURPOSE OF REVIEW: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). RECENT FINDINGS: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. SUMMARY: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.