Staging achilles tendinopathy using ultrasound imaging: The development and investigation of a new ultrasound imaging criteria based on the continuum model of tendon pathology

AimTo develop a standardised ultrasound imaging (USI)-based criteria for the diagnosis of tendinopathy that aligns with the continuum model of tendon pathology. Secondary aims were to assess both the intra-rater and inter-rater reliability of the criteria.MethodsA criteria was developed following a face validity assessment and a total of 31 Achilles tendon ultrasound images were analysed. Intra-rater and inter-rater reliability were assessed for overall tendinopathy stage (normal, reactive/early dysrepair or late dysrepair/degenerative) as well as for individual parameters (thickness, echogenicity and vascularity). Quadratic weighted kappa (kw) was used to report on reliability.ResultsIntra-rater reliability was ‘substantial’ for overall tendinopathy staging (kw rater A; 0.77, 95% CI 0.59 to 0.94, rater B; 0.70, 95% CI 0.52 to 0.89) and ranged from ‘substantial’ to ‘almost perfect’ for thickness (kw rater A; 0.75, 95% CI 0.59 to 0.90, rater B; 0.84, 95% CI 0.71 to 0.98), echogenicity (kw rater A; 0.78, 95% CI 0.62 to 0.95, rater B; 0.73, 95% CI 0.58 to 0.89) and vascularity (kw rater A; 0.86, 95% CI 0.74 to 0.98, rater B; 0.89, 95% CI 0.79 to 0.99). Inter-rater reliability ranged from ‘substantial’ to ‘almost perfect’ for overall tendinopathy staging (kw round 1; 0.75, 95% CI 0.58 to 0.91, round 2; 0.81, 95% CI 0.63 to 0.99), thickness (kw round 1; 0.65, 95% CI 0.48 to 0.83, round 2; 0.77, 95% CI 0.60 to 0.93), echogenicity (kw round 1; 0.70, 95% CI 0.54 to 0.85, round 2; 0.76, 95% CI 0.58 to 0.94) and vascularity (kw round 1; 0.89, 95% CI 0.79 to 0.99, round 2; 0.86, 95% CI 0.74 to 0.98). Inter-rater reliability increased from ‘substantial’ in round 1 (kw 0.75, 95% CI 0.58 to 0.91) to ‘almost perfect’ in round 2 (0.81, 95% CI 0.63 to 0.99).ConclusionIntra-rater and inter-rater reliability were ‘substantial’ to ‘almost perfect’ when utilising an USI-based criteria to diagnose Achilles tendinopathy. This is the first study to use the continuum model of tendon pathology to develop an USI-based criteria to diagnose tendinopathy

Effectiveness and reporting standards of psychological interventions for improving short-term and long-term pain outcomes after total knee replacement:a systematic review

Objectives: To assess the effectiveness and reporting standards of psychological interventions for improving outcomes after total knee replacement (TKR).Design: The systematic review protocol was registered on the International Prospective Register of Systematic reviews (CRD42018095100). MEDLINE, EMBASE, and PsycINFO were searched from inception to up to 9th May 2019 with no language restrictions applied. Randomised controlled trials (RCTs) assessing the effectiveness of psychological interventions for short and long-term post-operative pain after TKR were included. Screening, data extraction and assessment of methodological quality was performed in duplicate by two reviewers. The primary effectiveness outcome was post-operative pain severity and the primary harm outcome was serious adverse events. Secondary outcomes included function, quality of life, and psychological wellbeing. Reporting standards were assessed using the TIDieR checklist for intervention reporting. Results: 12 RCTs were included, with a total of 1299 participants. Psychological interventions comprised music therapy (five studies), guided imagery and music (one study), hypnosis (one study) progressive muscle relaxation with biofeedback (one study), pain coping skills programme (one study), cognitive behavioural therapy (two studies), and a post-operative management programme (one study). Due to the high heterogeneity of interventions and poor reporting of harms data, it was not possible to make any definitive statements about the overall effectiveness or safety of psychology interventions for pain outcomes after TKR. Conclusion: Further evidence about the effectiveness of psychological interventions for improving pain outcomes after TKR is needed. The reporting of harm outcomes and intervention fidelity is currently poor and could be improved. Future work exploring the impact of intervention timing on effectiveness and whether different psychological approaches are needed to address acute post-operative pain and chronic post-operative pain would be of benefit

Effect of Amoxicillin in combination with Imipenem-Relebactam against Mycobacterium abscessus

Infections caused by Mycobacterium abscessus are increasing in prevalence in cystic fibrosis patients. This opportunistic pathogen′s intrinsic resistance to most antibiotics has perpetuated an urgent demand for new, more effective therapeutic interventions. Here we report a prospective advance in the treatment of M. abscessus infection; increasing the susceptibility of the organism to amoxicillin, by repurposing the β-lactamase inhibitor, relebactam, in combination with the front line M. abscessus drug imipenem. We establish by multiple in vitro methods that this combination works synergistically to inhibit M. abscessus. We also show the direct competitive inhibition of the M. abscessus β-lactamase, BlaMab, using a novel assay, which is validated kinetically using the nitrocefin reporter assay and in silico binding studies. Furthermore, we reverse the susceptibility by overexpressing BlaMab in M. abscessus, demonstrating relebactam-BlaMab target engagement. Finally, we highlight the in vitro efficacy of this combination against a panel of M. abscessus clinical isolates, revealing the therapeutic potential of the amoxicillin-imipenem-relebactam combination

Cerebrospinal fluid immunoglobulin light chain ratios predict disease progression in multiple sclerosis

Objective To determine whether the ratio of cerebrospinal fluid (CSF) immunoglobulin kappa to lambda light chains at time of multiple sclerosis (MS) diagnosis predicts disease progression and whether this was intrinsic to CSF plasmablasts. Methods CSF and peripheral blood were obtained from patients undergoing elective diagnostic lumbar puncture and included clinically isolated syndrome (CIS) (n=43), relapsing remitting MS (RRMS; n=50), primary progressive MS (PPMS; n=20) and other neurological disease controls, both inflammatory (ONID; n=23) and non-inflammatory (OND; n=114). CSF samples were assayed for free and immunoglobulin-associated light chains and on B cells and plasmablasts. Clinical follow-up data were collected during a 5-year follow-up period where available. Results There was an increased median CSF κ:λ free light chain (FLC) in all MS groups (CIS: 18.2, 95% CI 6.8 to 30.3; RRMS: 4.4, 95% CI 2.7 to 11.4; PPMS: 12.0, 95% CI 3.6 to 37.1) but not controls (OND: 1.61, 95% CI 1.4 to 1.9; ONID: 1.7, 95% CI 1.3 to 2.2; p10) CSF κ:λ FLC (0.0, 95% CI 0 to 2.5 vs 2.5, 95% CI 0 to 4, high vs low; p=0.049). CSF κ:λ FLC correlated with CSF IgG1 κ:λ (r=0.776; p<0.0001) and was intrinsic to CSF plasmablasts (r=0.65; p=0.026). Conclusions These data demonstrate that CSF immunoglobulin κ:λ ratios, determined at the time of diagnostic lumbar puncture, predict MS disease progression and may therefore be useful prognostic markers for early therapeutic stratification

Structure-activity relationships of the N-terminus of calcitonin gene-related peptide:key roles of alanine-5 and threonine-6 in receptor activation

Background and purpose - The N-terminus of calcitonin gene-related peptide (CGRP) is important for receptor activation, especially the disulphide-bonded ring (residues 1-7). However, the roles of individual amino acids within this region have not been examined and so the molecular determinants of agonism are unknown. This study has examined the role of residues 1, 3-6 and 8-9, excluding Cys-2 and Cys-7. Experimental approach - CGRP derivatives were substituted with either cysteine or alanine; further residues were introduced at position 6. Their affinity was measured by radioligand binding and their efficacy by measuring cAMP production in SK-N-MC cells and ß-arrestin 2 translocation in CHO-K1 cells at the CGRP receptor. Key results - Substitution of Ala-5 by cysteine reduced affinity 270-fold and reduced efficacy for production of cAMP in SK-N-MCs. Potency at ß-arrestin translocation was reduced by 9-fold. Substitution of Thr-6 by cysteine destroyed all measurable efficacy of both cAMP and ß-arrestin responses; substitution with either alanine or serine impaired potency. Substitutions at positions 1, 4, 8 and 9 resulted in approximately 10-fold reductions in potency at both responses. Similar observations were made at a second CGRP-activated receptor, the AMY1(a) receptor. Conclusions and implications - Ala-5 and Thr-6 are key determinants of agonist activity for CGRP. Ala-5 is also very important for receptor binding. Residues outside of the 1-7 ring also contribute to agonist activity

Distinct small non-coding RNA landscape in the axons and released extracellular vesicles of developing primary cortical neurons and the axoplasm of adult nerves

Neurons have highlighted the needs for decentralized gene expression and specific RNA function in somato-dendritic and axonal compartments, as well as in intercellular communication via extracellular vesicles (EVs). Despite advances in miRNA biology, the identity and regulatory capacity of other small non-coding RNAs (sncRNAs) in neuronal models and local subdomains has been largely unexplored. We identified a highly complex and differentially localized content of sncRNAs in axons and EVs during early neuronal development of cortical primary neurons and in adult axons in vivo. This content goes far beyond miRNAs and includes most known sncRNAs and precisely processed fragments from tRNAs, sno/snRNAs, Y RNAs and vtRNAs. Although miRNAs are the major sncRNA biotype in whole-cell samples, their relative abundance is significantly decreased in axons and neuronal EVs, where specific tRNA fragments (tRFs and tRHs/tiRNAs) mainly derived from tRNAs Gly-GCC, Val-CAC and Val-AAC predominate. Notably, although 5ʹ-tRHs compose the great majority of tRNA-derived fragments observed in vitro, a shift to 3ʹ-tRNAs is observed in mature axons in vivo. The existence of these complex sncRNA populations that are specific to distinct neuronal subdomains and selectively incorporated into EVs, equip neurons with key molecular tools for spatiotemporal functional control and cell-to-cell communication

Non-adenine based purines accelerate wound healing

Wound healing is a complex sequence of cellular and molecular processes that involves multiple cell types and biochemical mediators. Several growth factors have been identified that regulate tissue repair, including the neurotrophin nerve growth factor (NGF). As non-adenine based purines (NABPs) are known to promote cell proliferation and the release of growth factors, we investigated whether NABPs had an effect on wound healing. Full-thickness, excisional wound healing in healthy BALB/c mice was significantly accelerated by daily topical application of NABPs such as guanosine (50% closure by days 2.5′.8). Co-treatment of wounds with guanosine plus anti-NGF reversed the guanosine-promoted acceleration of wound healing, indicating that this effect of guanosine is mediated, at least in part, by NGF. Selective inhibitors of the NGF-inducible serine/threonine protein kinase (protein kinase N), such as 6-methylmercaptopurine riboside abolished the acceleration of wound healing caused by guanosine, confirming that activation of this enzyme is required for this effect of guanosine. Treatment of genetically diabetic BKS.Cg-m+/+lepr db mice, which display impaired wound healing, with guanosine led to accelerated healing of skin wounds (25% closure by days 2.8′.0). These results provide further confirmation that the NABP-mediated acceleration of cutaneous wound healing is mediated via an NGF-dependent mechanism. Thus, NABPs may offer an alternative and viable approach for the treatment of wounds in a clinical setting

How people with knee pain understand why their pain changes or remains the same over time: A qualitative study

ObjectivesGuidelines recommend knee osteoarthritis pain management based on biopsychosocial mechanisms. Treatment adherence and effectiveness may be affected if there is a mismatch between patient perspectives and treatment focus. We therefore examined patient perspectives on mechanisms of their knee pain, why it persisted or changed over the past year, whether their understanding had changed, and whether their understanding aligned with that of others with whom they interact.MethodsIndividuals with chronic knee pain (n ​= ​50) were purposively recruited from the Knee Pain and related health In the Community (KPIC) cohort to represent worsened, improved, or unchanged pain or anxiety between baseline and one year later. Framework analysis, a comparative form of thematic analysis, was used across transcripts of semi-structured telephone interviews.ResultsData were collapsed into themes of diagnosis, joint structure, ageing, physical activity, weight management, and treatment. Participants focused on biomechanical rather than psychological pain mechanisms. Some participants attributed pain improvement to increased and others to decreased physical activity. Participants reported no change in their understanding of their pain during the preceding year, but that their attitudes to pain, for example acceptance, had changed. Participants reported that they and others around them lacked understanding of their pain and why it did or did not change.ConclusionPeople report a predominantly biomechanical understanding of why their knee pain remains constant or changes over time. Clinicians should support patients to develop a biopsychosocial understanding of knee pain aligned to treatment across the range of biological, psychological, and social modalities

The multiplicity of self: neuropsychological evidence and its implications for the self as a construct in psychological research

This paper examines the issue ofwhat the self is by reviewing neuropsychological research,which converges on the idea that the selfmay be more complex and differentiated than previous treatments of the topic have suggested. Although some aspects of self-knowledge such as episodic recollection may be compromised in individuals, other aspects—for instance, semantic trait summaries—appear largely intact. Taken together, these findings support the idea that the self is not a single, unified entity. Rather, it is a set of interrelated, functionally independent systems. Implications for understanding the self in various areas of psychological research—e.g., neuroimaging, autism, amnesia, Alzheimer’s disease, and mirror self-recognition—are discussed in brief