Pathways driving tendinopathy and enthesitis: siblings or distant cousins in musculoskeletal medicine?

Tendinopathy and enthesitis share clinical, anatomical, and molecular parallels. However, their relationship is complex, presenting challenges in diagnosis and treatment. The biomechanics underlying these pathologies, together with relative immune and stromal contributions to pathology, are characterised by crucial comparative elements. However, methodologies used to study enthesitis and tendinopathy have been divergent, which could account for discrepancies in how these conditions are perceived and treated. In this Review, we summarise key clinical parallels between these two common presentations in musculoskeletal medicine and address factors that currently preclude development of more effective therapeutics. Furthermore, we describe molecular similarities and disparities that govern pathological mechanisms in tendinopathy and enthesitis, thus informing translational studies and treatment strategies.

Frozen shoulder.

Frozen shoulder is a common debilitating disorder characterized by shoulder pain and progressive loss of shoulder movement. Frozen shoulder is frequently associated with other systemic conditions or occurs following periods of immobilization, and has a protracted clinical course, which can be frustrating for patients as well as health-care professionals. Frozen shoulder is characterized by fibroproliferative tissue fibrosis, whereby fibroblasts, producing predominantly type I and type III collagen, transform into myofibroblasts (a smooth muscle phenotype), which is accompanied by inflammation, neoangiogenesis and neoinnervation, resulting in shoulder capsular fibrotic contractures and the associated clinical stiffness. Diagnosis is heavily based on physical examination and can be difficult depending on the stage of disease or if concomitant shoulder pathology is present. Management consists of physiotherapy, therapeutic modalities such as steroid injections, anti-inflammatory medications, hydrodilation and surgical interventions; however, their effectiveness remains unclear. Facilitating translational science should aid in development of novel therapies to improve outcomes among individuals with this debilitating condition.

Biopsychosocial approach to tendinopathy.

Tendinopathy describes a spectrum of changes that occur in damaged tendons, leading to pain and reduced function that remains extremely challenging for all clinicians. There is an increasing awareness of the influence that psychological and psychosocial components, such as self-efficacy and fear-avoidance, have on rehabilitation outcomes in musculoskeletal medicine. Although it is widely accepted that psychological/psychosocial factors exist in tendinopathy, there is currently a distinct lack of trials measuring how these factors affect clinical outcomes. Biopsychosocial treatments acknowledge and address the biological, psychological and social contributions to pain and disability are currently seen as the most efficacious approach to chronic pain. Addressing and modulating these factors are crucial in the pathway of personalised treatments in tendinopathy and offer a real opportunity to drive positive outcomes in patients. In this education review, we also provide the current evidence-based guidance on psychological and psychosocial developments in musculoskeletal medicine and how these may be translated to treating tendinopathy using a biopsychosocial model.

ICON 2020-International Scientific Tendinopathy Symposium Consensus: A Scoping Review of Psychological and Psychosocial Constructs and Outcome Measures Reported in Tendinopathy Clinical Trials.

OBJECTIVE: To identify and describe the psychological and psychosocial constructs and outcome measures used in tendinopathy research. DESIGN: Scoping review. LITERATURE SEARCH: We searched the PubMed, EMBASE, Scopus, Web of Science, PEDro, CINAHL, and APA PsychNet databases on July 10, 2021, for all published studies of tendinopathy populations measuring psychological and psychosocial factors. STUDY SELECTION: Studies using a clinical diagnosis of tendinopathy or synonyms (eg, jumper's knee or subacromial impingement) with or without imaging confirmation. DATA SYNTHESIS: We described the volume, nature, distribution, and characteristics of psychological and psychosocial outcomes reported in the tendinopathy field. RESULTS: Twenty-nine constructs were identified, including 16 psychological and 13 psychosocial constructs. The most frequently-reported constructs were work-related outcomes (32%), quality of life (31%), depression (30%), anxiety (18%), and fear (14%). Outcome measures consisted of validated and nonvalidated questionnaires and 1-item custom questions (including demographics). The number of different outcome measures used to assess an individual construct ranged between 1 (emotional distress) and 11 (quality of life) per construct. CONCLUSION: There was a large variability in constructs and outcome measures reported in tendinopathy research, which limits conclusions about the relationship between psychological and psychosocial constructs, outcome measures, and tendinopathies. Given the wide range of psychological and psychosocial constructs reported, there is an urgent need to develop a core outcome set in tendinopathy. J Orthop Sports Phys Ther 2022;52(6):375-388. doi:10.2519/jospt.2022.11005.

Rapidly progressive crescentic diabetic nephropathy: two case reports.

Crescents are not a well recognised feature of diabetic nephropathy. We present two cases of patients presenting with a rapid decline in renal function and subacute onset of nephrotic syndrome. Glomerulonephritis screening was negative, and renal biopsy revealed non-necrotising cellular crescents and typical features of late-stage diabetic nephropathy. We review the literature for diabetic nephropathy with crescents and explore possible underlying mechanisms.

The effect of exercise on cytokines: implications for musculoskeletal health: a narrative review.

The physiological effects of physical exercise are ubiquitously reported as beneficial to the cardiovascular and musculoskeletal systems. Exercise is widely promoted by medical professionals to aid both physical and emotional wellbeing; however, mechanisms through which this is achieved are less well understood. Despite numerous beneficial attributes, certain types of exercise can inflict significant significant physiological stress. Several studies document a key relationship between exercise and immune activation. Activation of the innate immune system occurs in response to exercise and it is proposed this is largely mediated by cytokine signalling. Cytokines are typically classified according to their inflammatory properties and evidence has shown that cytokines expressed in response to exercise are diverse and may act to propagate, modulate or mitigate inflammation in musculoskeletal health. The review summarizes the existing literature on the relationship between exercise and the immune system with emphasis on how exercise-induced cytokine expression modulates inflammation and the immune response.

ICON 2020-International Scientific Tendinopathy Symposium Consensus: A Systematic Review of Outcome Measures Reported in Clinical Trials of Achilles Tendinopathy.

BACKGROUND: Nine core domains for tendinopathy have been identified. For Achilles tendinopathy there is large variation in outcome measures used, and how these fit into the core domains has not been investigated. OBJECTIVE: To identify all available outcome measures outcome measures used to assess the clinical phenotype of Achilles tendinopathy in prospective studies and to map the outcomes measures into predefined health-related core domains. DESIGN: Systematic review. DATA SOURCES: Embase, MEDLINE (Ovid), Web of Science, CINAHL, The Cochrane Library, SPORTDiscus and Google Scholar. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Clinical diagnosis of Achilles tendinopathy, sample size ≥ ten participants, age ≥ 16 years, and the study design was a randomized or non-randomized clinical trial, observational cohort, single-arm intervention, or case series. RESULTS: 9376 studies were initially screened and 307 studies were finally included, totaling 13,248 participants. There were 233 (177 core domain) different outcome measures identified across all domains. For each core domain outcome measures were identified, with a range between 8 and 35 unique outcome measures utilized for each domain. The proportion of studies that included outcomes for predefined core domains ranged from 4% for the psychological factors domain to 72% for the disability domain. CONCLUSION: 233 unique outcome measures for Achilles tendinopathy were identified. Most frequently, outcome measures were used within the disability domain. Outcome measures assessing psychological factors were scarcely used. The next step in developing a core outcome set for Achilles tendinopathy is to engage patients, clinicians and researchers to reach consensus on key outcomes measures. PROSPERO REGISTRATION: CRD42020156763.

Management of patellar tendinopathy: a systematic review and network meta-analysis of randomised studies.

OBJECTIVES: We performed a systematic review and network meta-analysis (NMA) of randomised controlled trials (RCTs) to provide insights into the effectiveness of available treatment modalities in patellar tendinopathy(PT). METHODS: Several databases were searched in May 2021 for RCTs assessing the effectiveness of any intervention compared with any other intervention, placebo or no treatment for pain and/or function in PT. The risk of bias and strength of evidence were assessed with the Cochrane Collaboration and GRADE (Grading of Recommendations, Assessment, Development and Evaluations)/GRADE-NMA tools. RESULTS: A total of 37 RCTs were eligible that assessed 33 different interventions and their combinations, most represented by single studies. Based on pairwise meta-analyses of two RCTs, extracorporeal shockwave therapy (ESWT) does not appear to be superior to sham ESWT (eccentric exercise in both groups) for short-term pain (mean differences (MD) +0.1, 95% CI (-0.8 to 1), p=0.84) or function (MD -1.8, 95% CI (-8 to 4.4), p=0.57). Based on a pairwise meta-analysis of three RCTs, isometric exercise appears as effective as isotonic exercise for immediate postintervention pain relief (MD -1.03, 95% CI (-2.6 to 0.5), p=0.19). Our NMA showed that topical glyceryl trinitrate (GTN) and hyaluronic acid injection, both combined with eccentric exercise and moderate, slow resistance exercise had the highest probability of being the most effective interventions (low/very low strength of evidence). CONCLUSIONS: Promising interventions with inadequate evidence, such as topical GTN, hyaluronic acid injections and isometric and slow resistance exercise, should be further investigated through high-quality RCTs. Meanwhile, eccentric loading with or without adjuncts should remain the first-line treatment for all individuals with patellar tendinopathy.

Primary membranous glomerulonephritis with negative serum PLA2R in haemophilia A successfully managed with rituximab - case report and review of the literature.

BACKGROUND: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate. CASE PRESENTATION: We present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results. CONCLUSIONS: Pursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN.

Tendinopathy.

Tendinopathy describes a complex multifaceted pathology of the tendon, characterized by pain, decline in function and reduced exercise tolerance. The most common overuse tendinopathies involve the rotator cuff tendon, medial and lateral elbow epicondyles, patellar tendon, gluteal tendons and the Achilles tendon. The prominent histological and molecular features of tendinopathy include disorganization of collagen fibres, an increase in the microvasculature and sensory nerve innervation, dysregulated extracellular matrix homeostasis, increased immune cells and inflammatory mediators, and enhanced cellular apoptosis. Although diagnosis is mostly achieved based on clinical symptoms, in some cases, additional pain-provoking tests and imaging might be necessary. Management consists of different exercise and loading programmes, therapeutic modalities and surgical interventions; however, their effectiveness remains ambiguous. Future research should focus on elucidating the key functional pathways implicated in clinical disease and on improved rehabilitation protocols.

How does surgery compare to sham surgery or physiotherapy as a treatment for tendinopathy? A systematic review of randomised trials.

PURPOSE: To assess the effectiveness of surgery on all tendinopathies by comparing it to no treatment, sham surgery and exercise-based therapies for both mid-term (12 months) and long-term (> 12 months) outcomes. METHODS: Our literature search included EMBASE, Medline, CINAHL and Scopus. A combined assessment of internal validity, external validity and precision of each eligible study yielded its overall study quality. Results were considered significant if they were based on strong (Level 1) or moderate (Level 2) evidence. RESULTS: 12 studies were eligible. Participants had the following types of tendinopathy: shoulder in seven studies, lateral elbow in three, patellar in one and Achilles in one. Two studies were of good, four of moderate and six of poor overall quality. Surgery was superior to no treatment or placebo, for the outcomes of pain, function, range of movement (ROM) and treatment success in the short and midterm. Surgery had similar effects to sham surgery on pain, function and range of motion in the midterm. Physiotherapy was as effective as surgery both in the midterm and long term for pain, function, ROM and tendon force, and pain, treatment success and quality of life, respectively. CONCLUSION: We recommend that healthcare professionals who treat tendinopathy encourage patients to comply with loading exercise treatment for at least 12 months before the option of surgery is seriously entertained.

Topical glyceryl trinitrate for the treatment of tendinopathies: a systematic review.

OBJECTIVE: To produce a best evidence synthesis of the clinical effects of topical glyceryl trinitrate (GTN) in the treatment of tendinopathies. DESIGN: A systematic review of published randomised controlled trials (RCTs) of the use of GTN in patients with tendinopathy. DATA SOURCES: MEDLINE, Embase, Scopus and CINAHL from database inception to January 2018. METHODS: We examined RCTs comparing the effects of topical GTN with either placebo or other treatments on tendinopathy. Overall quality of each eligible study was determined based on a combined assessment of internal validity, external validity and precision. The level of evidence for each assessed parameter was rated based on the system by van Tulder et al. RESULTS: A total of 10 eligible RCTs were identified including patients with tendinopathy of the rotator cuff (n=4), wrist extensors (n=3), Achilles (n=2) and patellar (n=1) tendons. For all tendinopathies, improvements in pain were significant when comparing GTN versus placebo in the short term (<8 weeks; poor evidence). Significant improvements in midterm outcomes for treatment with GTN versus placebo included the following: patient satisfaction (strong evidence); chances of being asymptomatic with activities of daily living (strong evidence); range of movement (moderate evidence); strength (moderate evidence); pain (at night and with activity; poor evidence) and local tenderness (poor evidence). Patients treated with topical GTN reported a higher incidence of headaches than those who received placebo (moderate evidence). CONCLUSIONS AND RELEVANCE: Treatment of tendinopathies with topical GTN for up to 6 months appears to be superior to placebo and may therefore be a useful adjunct to the treating healthcare professions.

Fibrosis of the Choroid Plexus Filtration Membrane.

We report a previously undescribed inflammatory lesion consisting of deposition of activated complement (C3d and C9neo) in association with major histocompatibility complex type II (MHC2)-positive activated microglia in choroid plexus villi exhibiting classical fibrous thickening of the pericapillary filtration membrane. The proportion of villi affected ranged from 5% to 90% in 56 adult subjects with diseases of the CNS and 11 subjects with no preexisting disease of the CNS. In 3 of the 4 children studied, 2% or less of examined villi showed stromal thickening, complement deposition, and the presence of MHC2-positive microglia; in adults, the proportion of villi affected increased with age. Other features of the lesion included loss of capillaries and failure by macrophages to clear extracellular particulate electron-dense material by clathrin-mediated phagocytosis. This choroid plexus lesion may relate pathogenetically to age-related macular degeneration and to Alzheimer disease, 2 other conditions with no known risk factors other than increasing age. All 3 conditions are characterized by the presence of damaged capillaries, inflammatory extracellular aggregates of mixed molecular composition and defective clearance of the deposits by macrophages.

Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia.

Functional defects of the mitochondrial translation machinery, as a result of mutations in nuclear-encoded genes, have been associated with combined oxidative phosphorylation (OXPHOS) deficiencies. We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver. One of the siblings had a more severe phenotype showing progressive hepatic and renal failure. Whole-exome sequencing revealed a homozygous mutation in the gene encoding mitochondrial ribosomal protein S7 (MRPS7), a c.550A>G transition that encodes a substitution of valine for a highly conserved methionine (p.Met184Val) in both affected siblings. MRPS7 is a 12S ribosomal RNA-binding subunit of the small mitochondrial ribosomal subunit, and is required for the assembly of the small ribosomal subunit. Pulse labeling of mitochondrial protein synthesis products revealed impaired mitochondrial protein synthesis in patient fibroblasts. Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function. Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7. Our data demonstrate the pathogenicity of the identified MRPS7 mutation as a novel cause of mitochondrial RC dysfunction, congenital sensorineural deafness and progressive hepatic and renal failure.

"I have the right to a private life": medical students' views about professionalism in a digital world.

BACKGROUND: Social media site use is ubiquitous, particularly Facebook. Postings on social media can have an impact on the perceived professionalism of students and practitioners. AIMS: In this study, we explored the attitudes and understanding of undergraduate medical students towards professionalism, with a specific focus on online behaviour. METHODS: A volunteer sample of students (n = 236) responded to an online survey about understanding of professionalism and perceptions of professionalism in online environments. Respondents were encouraged to provide free text examples and to elaborate on their responses through free text comments. Descriptive analyzes and emergent themes analysis were carried out. RESULTS: Respondents were nearly unanimous on most questions of professionalism in the workplace, while 43% felt that students should act professionally at all times (including free time). Sixty-four free text comments revealed three themes: "free time is private time";" professionalism is unrealistic as a way of life"; and "professionalism should be a way of life". CONCLUSIONS: Our findings indicate a disconnect between what students report of what they understand of professionalism, and what students feel is appropriate and inappropriate in both online and real life behaviour. Curriculum needs to target understanding of professionalism in online and real environments and communicate realistic expectations for students.

'Have you seen what is on Facebook?' The use of social networking software by healthcare professions students.

OBJECTIVE: The use of social networking software has become ubiquitous in our society. The aim of this study was to explore the attitudes and experiences of healthcare professional students using Facebook at our school, to determine if there is a need for development of policy to assist students in this area. DESIGN: A mixed-methods approach was employed, using semistructured interviews to identify themes which were explored using an online survey. A combination of descriptive statistics and thematic analysis was used for analysis. SETTING: Healthcare professions education programmes at a large Canadian university. PARTICIPANTS: Students of medicine, nursing, pharmacy, speech and language pathology, occupational therapy, physical therapy, dentistry, dental hygiene and medical laboratory Science were invited to participate. 14 participants were interviewed, and 682 participants responded to an online survey; the female:male balance was 3 : 1. RESULTS: 14 interviews were analysed in-depth, and 682 students responded to the survey (17% response rate). 93% reported current Facebook use. Themes identified included patterns of use and attitudes to friendship, attitudes to online privacy, breaches of professional behaviour on Facebook and attitudes to guidelines relating to Facebook use. A majority considered posting of the following material unprofessional: use of alcohol/drugs, crime, obscenity/nudity/sexual content, patient/client information, criticism of others. 44% reported seeing such material posted by a colleague, and 27% reported posting such material themselves. A majority of participants agreed that guidelines for Facebook use would be beneficial. CONCLUSIONS: Social networking software use, specifically Facebook use, was widespread among healthcare students at our school who responded to our survey. Our results highlight some of the challenges which can accompany the use of this new technology and offer potential insights to help understand the pedagogy and practices of Facebook use in this population, and to help students navigate the dilemmas associated with becoming 21st century healthcare professionals.