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OBJECTIVE: To investigate whether duration of knee symptoms influenced the magnitude of the effect of exercise therapy compared to non-exercise control interventions on pain and physical function in people with knee osteoarthritis (OA). METHOD: We undertook an individual participant data (IPD) meta-analysis utilising IPD stored within the OA Trial Bank from randomised controlled trials (RCTs) comparing exercise to non-exercise control interventions among people with knee OA. IPD from RCTs were analysed to determine the treatment effect by considering both study-level and individual-level covariates in the multilevel regression model. To estimate the interaction effect (i.e., treatment x duration of symptoms (dichotomised)), on self-reported pain or physical function (standardised to 0-100 scale), a one-stage multilevel regression model was applied. RESULTS: We included IPD from 1767 participants with knee OA from 10 RCTs. Significant interaction effects between the study arm and symptom duration (≤1 year vs >1 year, and ≤2 years vs>2 years) were found for short- (∼3 months) (Mean Difference (MD) -3.57, 95%CI -6.76 to -0.38 and -4.12, 95% CI-6.58 to -1.66, respectively) and long-term (∼12 months) pain outcomes (MD -8.33, 95%CI -12.51 to -4.15 and -8.00, 95%CI -11.21 to -4.80, respectively), and long-term function outcomes (MD -5.46, 95%CI -9.22 to -1.70 and -4.56 95%CI -7.33 to-1.80, respectively). CONCLUSIONS: This IPD meta-analysis demonstrated that people with a relatively short symptom duration benefit more from therapeutic exercise than those with a longer symptom duration. Therefore, there seems to be a window of opportunity to target therapeutic exercise in knee OA.

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BACKGROUND During the COVID-19 pandemic, the incidence of opportunistic infections, including fungal infections, has increased. Blastomycosis is caused by inhalation of an environmental fungus, Blastomyces dermatides, which is endemic in parts of the USA and Canada. This case report is of a 44-year-old man from the American Midwest who presented with disseminated blastomycosis infection 3 months following a diagnosis of COVID-19. CASE REPORT Our patient initially presented to an outpatient clinic with mild upper-respiratory symptoms. He tested positive for SARS-CoV-2 via polymerase chain reaction (PCR). Three months later, he presented to our emergency department due to some unresolved COVID-19 symptoms and the development of a widely disseminated, painful rash of 1-week duration. A positive Blastomyces urine enzyme immunoassay was the first indication of his diagnosis, which was followed by the identification of the pathogen via fungal culture from bronchoscopy samples and pathology from lung and skin biopsies. Given the evidence of dissemination, the patient was treated with an intravenous and oral antifungal regimen. He recovered well after completing treatment. CONCLUSIONS The immunocompetent status of patients should not exclude disseminated fungal infections as a differential diagnosis, despite the less frequent manifestations. This is especially important when there is a history of COVID-19, as this may predispose once-healthy individuals to more serious disease processes. This case supports the recent recommendations made by the U.S. Centers for Disease Control and Prevention (CDC) for increased vigilance regarding fungal infections in patients with a history of COVID-19.

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BACKGROUND: There is considerable variation in the literature regarding the dermatopathologic diagnostic features of and reporting guidelines for actinic keratosis (AK) and cutaneous squamous cell carcinoma (cSCC). OBJECTIVE: To develop consensus recommendations regarding diagnostic criteria, nomenclature, and reporting of AK and cSCC. METHODS: Literature review and cross-sectional multiround Delphi process including an international group of expert dermatopathologists followed by a consensus meeting. RESULTS: Consensus was achieved regarding the key dermatopathologic features necessary for diagnosing cSCC, AK, and associated variants; grading of degree of cellular differentiation in cSCC; utility of immunohistochemistry for diagnosis of cSCC; and pathologic features that should be reported for cSCC and AK. LIMITATIONS: Consensus was not achieved on all questions considered. CONCLUSION: Despite the lack of clarity in the literature, there is consensus among expert dermatopathologists regarding diagnostic criteria and appropriate reporting of AK and cSCC. Widespread implementation of these consensus recommendations may improve communication between dermatopathologists and clinicians, facilitating appropriate treatment of AK and cSCC.

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The intracellular calcium handling system of cardiomyocytes is responsible for controlling excitation-contraction coupling (ECC) and has been linked to pro-arrhythmogenic cellular phenomena in conditions such as heart failure (HF). SERCA2a, responsible for intracellular uptake, is a primary regulator of calcium homeostasis, and remodelling of its function has been proposed as a causal factor underlying cellular and tissue dysfunction in disease. Whereas adaptations to the global (i.e. whole-cell) expression of SERCA2a have been previously investigated in the context of multiple diseases, the role of its spatial profile in the sub-cellular volume has yet to be elucidated. We present an approach to characterize the sub-cellular heterogeneity of SERCA2a and apply this approach to quantify adaptations to the length-scale of heterogeneity (the distance over which expression is correlated) associated with right-ventricular (RV)-HF. These characterizations informed simulations to predict the functional implications of this heterogeneity, and its remodelling in disease, on ECC, the dynamics of calcium-transient alternans and the emergence of spontaneous triggered activity. Image analysis reveals that RV-HF is associated with an increase in length-scale and its inter-cellular variability; simulations predict that this increase in length-scale can reduce ECC and critically modulate the vulnerability to both alternans and triggered activity. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

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We read with great interest the article entitled "Utility of Red Cell Distribution Width (RDW) as a Noninvasive Biomarker for the Diagnosis of Acute Appendicitis: A Systematic Review and Meta-Analysis of 5222 Cases" by S. Anand et al. which has been recently published in Diagnostics [...].

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BACKGROUND AND PURPOSE: High call frequency can lead to inadequate sleep, fatigue, and burnout, resulting in detrimental effects on physicians and patients. We aimed to assess the correlation between the frequency and burden of neurointerventional surgery calls and sleep deprivation with physician burnout, physical and driving safety, and fatigue-related medical errors. MATERIALS AND METHODS: We sent an online questionnaire to the members of the 2 neurointerventional surgery societies comprising 50 questions and spanning 3 main topics: 1) overnight/weekend call burden, 2) sleeping patterns, and 3) Copenhagen Burnout Inventory. RESULTS: One hundred sixty-four surveys were completed. Most (54%) neurointerventional surgeons reported burnout. Call burden of ≥1 every 3 days and being in practice >10 years were independent predictors of burnout. Thirty-nine percent reported falling asleep at the wheel, 23% reported a motor vehicle crash/near-crash, and 34% reported medical errors they considered related to call/work fatigue. On multivariate logistic regression, high call burden (called-in >3 times/week) was an independent predictor of sleeping at the wheel and motor vehicle crashes. Reporting <4 hours of uninterrupted sleep was an independent predictor of motor vehicle crashes and medical errors. Most neurointerventional surgeons recommended a maximum call frequency of once every 3 days. CONCLUSIONS: Call frequency and burden, number of years in practice, and sleep deprivation are associated with burnout of neurointerventional surgeons, sleeping at the wheel, motor vehicle crashes, and fatigue-related medical errors. These findings contribute to the increasing literature on physician burnout and may guide future societal recommendations related to call burden in neurointerventional surgery.

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Atypical fibroxanthoma (AFX) with osteoclast-like giant cells is a rare entity. We present the case of an elderly woman who presented with a pink-purple dome-shaped nodule with central hyperkeratotic crust. Biopsy revealed a cellular, dermal-based tumor comprised of spindle, oval, and osteoclast-like giant cells with pleomorphism. The immunohistochemistry profile supported a diagnosis of AFX with osteoclast-like giant cells. We performed a literature review through PubMed and Google Scholar for AFX with osteoclast-like giant cell formation and found 16 previously reported cases. We aim to provide a review and discuss features of these cases. We also discuss the pathogenesis of these osteoclast-like cells as well as potential pitfalls in diagnosis.

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PURPOSE: To explore the life experiences of pain in people with severe haemophilia and understand how such experiences influence beliefs and sensation of pain in adulthood. METHODS: A qualitative inquiry approach using focus groups and semi-structured individual interviews was used. Participants included people with severe haemophilia living with chronic pain. Data were analysed using reflexive thematic analysis. RESULTS: Fourteen men with a median age of 47 (range 23-73) agreed to take part. Eleven participated in two focus groups and three were interviewed over telephone. Two themes were conceptualised from the data: (i) haemophilia and pain - an evolving life biography (the personal narrative, historical, social, and medical context, continuous adaptation of activity choices, surveillance of pain and its meaning); (ii) "My normal isn't normal" - identity and self-agency (pain as a feature of life and identify with severe haemophilia, loss of enjoyable activities balanced against staying active, barriers to participation). CONCLUSIONS: Pain is a constantly evolving, lifetime feature for many adults with haemophilia and it is viewed as part of their identity with their condition. Healthcare professionals working in haemophilia should try to better understand the influence of an individuals lived experience with their haemophilia on beliefs and behaviours of pain.Implications for rehabilitationSevere haemophilia is a rare bleeding disorder that results in musculoskeletal joint disease.Adults with severe haemophilia have experienced multiple episodes of bleeding related musculoskeletal pain since childhood.Pain beliefs and behaviours in adulthood appear to be influenced by a lifetime of painful experiences associated with haemophilia.In order to better support people with haemophilia and chronic pain, healthcare professionals in haemophilia need to better understand how an individuals lived experience of pain helps inform their beliefs about it.

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PURPOSE: To explore the experiences, views and beliefs of people with severe haemophilia and healthcare professionals (HCPs) on approaches for pain management, as well as their views on exercise being used as an aspect of management. METHODS: Taking a qualitative inquiry approach using focus groups and semi-structured interviews, participants included people with severe haemophilia living with chronic pain and haemophilia HCPs. Data were analysed using reflexive thematic analysis. RESULTS: Fourteen men with haemophilia with a median age of 47 (range 23-73) and six haemophilia HCPs agreed to participate. Of the people with haemophilia, 11 attended two focus groups and three were interviewed over telephone. Healthcare professionals were interviewed face-to-face. Two themes were conceptualised from the data: (i) haemophilia management and pain management is discordant (imbalance between good haemophilia care but poor pain management, historical medico-social influences on pain management, the need for trust); (ii) uncertain about exercise but clear on what matters (conflicting views on exercise, the need for proof of safety, personalised care). CONCLUSIONS: Options for effective pain management remain limited and what is used is heavily influenced by beliefs and experience. Exercise as a treatment option in pain management is conceptually acceptable for people with haemophilia. Effective pain management requires understanding of individual beliefs and fears, and a personalised approach supported by knowledgeable, trusted clinicians.Implications for rehabilitationMusculoskeletal joint pain and its relationship with bleeding in people with haemophilia continues to be a management challenge.Current pain management strategies are of limited effectiveness with little evidence of an approach that reflects the multi-modal pain experience.Whilst exercise and rehabilitation approaches are conceptually possible for people with severe haemophilia, barriers remain regarding perception of overall safety and effectiveness.People with severe haemophilia may consider exercise as part of a pain management strategy if it is individualised, and they are supported to do it by clinicians who understand them and their haemophilia.

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ABSTRACT: Amyloid elastosis is an exceedingly rare form of amyloidosis characterized by amyloid material deposited on dermal elastic fibers. Most reported cases have been associated with systemic amyloid light-chain amyloidosis. A single previously reported case of amyloid elastosis showed evidence that the amyloid material was derived from light-chain proteins and was associated with a monoclonal plasma cell infiltrate but failed to demonstrate systemic involvement. As a result, the case was felt to represent localized cutaneous amyloid elastosis. We present a case of localized cutaneous amyloid elastosis that is not associated with a definitive monotypic plasma cell population or with systemic amyloidosis. We also review the clinical and histopathologic features of reported cases of amyloid elastosis and discuss possible etiologic considerations. Because amyloid elastosis can be either localized to the skin or associated with systemic involvement, additional workup to exclude an underlying plasma cell dyscrasia or hematologic malignancy is warranted.

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BACKGROUND: Experience with endoluminal flow diversion for the treatment of posterior circulation aneurysms is limited. PURPOSE: We sought to investigate factors associated with the safety and efficacy of this treatment by collecting disaggregated patient-level data from the literature. DATA SOURCES: PubMed, EMBASE, and Ovid were searched up through 2019 for articles reporting flow diversion of posterior circulation aneurysms. STUDY SELECTION: Eighty-four studies reported disaggregated data for 301 separate posterior circulation aneurysms. DATA ANALYSIS: Patient, aneurysm, and treatment factors were collected for each patient. Outcomes included the occurrence of major complications, angiographic occlusion, and functional outcomes based on the mRS. DATA SYNTHESIS: Significant differences in aneurysm and treatment characteristics were seen among different locations. Major complications occurred in 22%, angiographic occlusion was reported in 65% (11.3 months of mean follow-up), and good functional outcomes (mRS 0-2) were achieved in 67% (13.3 months of mean follow-up). Multivariate analysis identified age, number of flow diverters used, size, and prior treatment to be associated with outcome measures. Meta-analysis combining the current study with prior large nondisaggregated series of posterior circulation aneurysms treated with flow diversion found a pooled incidence of 20% (n = 712 patients) major complications and 75% (n = 581 patients) angiographic occlusions. LIMITATIONS: This study design is susceptible to publication bias. Use of antiplatelet therapy was not uniformly reported. CONCLUSIONS: Endoluminal flow diversion is an important tool in the treatment of posterior circulation aneurysms. Patient age, aneurysm size, prior treatment, and the number of flow diverters used are important factors associated with complications and outcomes.

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