Understanding the biopsychosocial knee osteoarthritis pain experience: an ecological momentary assessment.

Introduction: Psychological, social, and lifestyle factors contribute to the knee osteoarthritis (OA) pain experience. These factors could be measured more accurately using smartphone ecological momentary assessment (EMA). Objectives: The objective of this study was to characterise the pain experiences of those with knee OA by a smartphone EMA survey and explain how momentary psychological and social states influence knee OA pain experiences. Methods: A smartphone EMA survey was designed and piloted. Eligible participants completed smartphone EMA assessing the knee OA pain experience 3 times daily for 2 weeks. Descriptive statistics were used to characterise factors involved in knee OA pain followed by the development of mixed-effects location scale models to explore heterogeneity and relationships between symptoms involved in the knee OA pain experience. Results: Eighty-six community-dwelling volunteers with knee OA were recruited. Pain, psychosocial, and lifestyle factors involved in knee OA pain experience were heterogeneous and variable. Those with greater variability in pain, fatigue, negative affect, and stress had worse levels of these symptoms overall. In addition, fatigue, negative affect, stress, anxiety, loneliness, and joint stiffness demonstrated within-person relationships with knee OA pain outcomes. Conclusions: Knee OA pain is a heterogeneous biopsychosocial condition. Momentary experiences of psychological, social, fatigue, and joint stiffness explain individual and between-individual differences in momentary knee OA pain experiences. Addressing these momentary factors could improve pain and functional outcomes in those with knee OA. Validation studies, including individuals with more severe knee OA presentations, are required to support findings and guide clinical interventions to improve outcomes for those with knee OA.

Activity-related pain and sensitization predict within- and between-person pain experience in people with knee osteoarthritis: An ecological momentary assessment study.

Background and objectives: Knee Osteoarthritis (OA) is a prevalent musculoskeletal condition that often results in pain and disability. Determining factors predicting variability in pain experience is critical to improving clinical outcomes. Underlying pain sensitization and its clinical manifestations, such as activity-related pain, may better predict the knee OA pain experience. This study aimed to determine whether Quantitative Sensory Testing (QST) derived sensitization measures and activity-related pain predict knee OA pain experiences collected via smartphone ecological momentary assessment (EMA). Design: Individuals with knee OA were recruited from an urban community in New Zealand. Those eligible to participate underwent baseline QST with clinical measures of activity-related pain also being collected. The knee OA pain experience was collected via smartphone EMA three times daily for two weeks. Mixed effects location scale models were developed using a multilevel modelling approach. Results: Eighty-six participants with knee OA participated in the study. Mean age was 67.3 years, with most of the participants being female (64%) and New Zealand European (90.6%). Activity-related pain predicted worse and more variable pain intensity, pain interference, and bothersomeness outcomes within and between individuals with knee OA. Widespread cold hyperalgesia and local mechanical hyperalgesia were shown to predict higher within-person variability in pain intensity and pain interference respectively, while mechanical temporal summation predicted less within-person variability in pain intensity and interference. Discussion: Those demonstrating activity-related pain and sensitization could be at risk of experiencing worse and more variable knee OA pain in the subsequent weeks. Testing for sensitization in clinical practice could therefore identify those at greatest risk of higher and more variable knee OA pain experiences and in greatest need of treatment. Larger validation studies are required, which include individuals with more severe knee OA.

Experiences and Perceptions of Using Smartphone Ecological Momentary Assessment for Reporting Knee Osteoarthritis Pain and Symptoms.

BACKGROUND: Knee osteoarthritis (OA) is a prevalent, painful, and disabling musculoskeletal condition. One method that could more accurately monitor the pain associated with knee OA is ecological momentary assessment (EMA) using a smartphone. OBJECTIVES: The aim of this study was to explore participant experiences and perceptions of using smartphone EMA as a way of communicating knee OA pain and symptoms following participating in a 2-week smartphone EMA study. MATERIALS AND METHODS: Using a maximum variation sampling method, participants were invited to share their thoughts and opinions in semistructured focus group interviews. Interviews were recorded and transcribed verbatim before thematic analysis using the general inductive approach. RESULTS: A total of 20 participants participated in 6 focus groups. Three themes and 7 subthemes were identified from the data. Identified themes included: user experience of smartphone EMA, data quality of smartphone EMA, and practical aspects of smartphone EMA. DISCUSSION: Overall, smartphone EMA was deemed as being an acceptable method for monitoring pain and symptoms associated with knee OA. These findings will assist researchers in designing future EMA studies alongside clinicians implementing smartphone EMA into practice. PERSPECTIVE: This study highlights that smartphone EMA is an acceptable method for capturing pain-related symptoms and experiences of those expereiencing knee OA. Future EMA studies should ensure design features are considered that reduce missing data and limit the responder burden to improve data quality.

Are Ecological Momentary Assessments of Pain Valid and Reliable? A Systematic Review and Meta-analysis.

OBJECTIVES: This systematic review and meta-analysis aimed to determine the level of evidence for the psychometric properties of Ecological Momentary Assessment (EMA) in populations with persistent pain. MATERIALS AND METHODS: Five databases were searched from 1980 to December 2021. Two reviewers independently screened the titles, abstracts, and full text, extracted data, and assessed adherence to reporting standards and methodological rigor before evaluating the quality of evidence. A meta-analysis, including the pooling of correlations for the relevant EMA pain outcomes, was completed. RESULTS: Overall, 3270 studies were identified, with 14 studies meeting inclusion criteria. Meta-analyses confirmed good to excellent relationships demonstrated between EMA and recalled pain intensity and interference across different timeframes. Many of the included studies did not fully adhere to recommended reporting standards, and the quality of included studies was either doubtful or inadequate due to methodological flaws. The level of evidence for measurement properties of pain outcomes was low for the criterion validity of pain intensity and interference and very low for reliability and construct validity of pain intensity and interference. DISCUSSION: Ecological momentary assessment of pain experience appears both valid and reliable. Although the levels of evidence were low or very low, these findings provide preliminary support for the use of EMA in clinical practice and research settings. Potential strengths of EMA include providing measures with greater ecological validity while also reducing recall bias, both pertinent in pain outcome measurement. More research, including higher-quality studies, is needed to demonstrate further support for EMA, including the need for establishing other types of validity.

Activity-related pain predicts pain and functional outcomes in people with knee osteoarthritis: A longitudinal study.

Knee Osteoarthritis (OA) is a prevalent musculoskeletal condition, commonly resulting in pain and disability. However, pain and disability in this population are poorly related with the degree of structural joint damage. Underlying pain mechanisms, including activity-related pain and sensitization assessed via Quantitative Sensory Testing (QST), may better predict pain and functional outcomes of those with knee OA. Therefore, the aim of this study was to explore whether activity-related pain and sensitization assessed via QST predict future pain, function, fatigue, physical performance and quality of life outcomes in those living in the community with knee OA. Eighty-six participants with knee OA were recruited in Dunedin, New Zealand. Those eligible to participate underwent baseline testing including QST as well as measures of activity-related pain including Movement-evoked Pain (MEP) and Sensitivity to Physical Activity (SPA). Outcome measures exploring pain, function, fatigue and quality of life outcomes were collected at baseline, and two follow-up periods (two and nine weeks). Univariable linear regression models were developed followed by multivariable linear regression models for each prognostic marker adjusting for age, gender, BMI, OA duration, baseline pain intensity and socioeconomic status. Activity-related measures of pain, including MEP and SPA, demonstrated predictive associations with pain and functional outcomes prospectively in those with knee OA. Therefore, those demonstrating activity-related pain are at future risk of greater pain, disability and reduced quality of life. Larger, externally validated longitudinal studies are required which include individuals with more severe knee OA.

Electromyography of neck and shoulder muscles in instrumental musicians with musculoskeletal pain compared to asymptomatic controls: A systematic review and meta-analysis.

Musicians report a high prevalence of annual musculoskeletal pain (86-89%), attributed to prolonged playing times consisting of repetitive static and dynamic muscle activity. The aim of this study was to explore, compare and synthesise evidence on electromyographic (EMG) muscle activity in neck, shoulder and spinal musculature between painful and asymptomatic instrumental musicians. Ovid, Wiley, Web of Science and Scopus databases were searched in August 2016 for cross-sectional studies that compared EMG activity of neck, shoulder and spinal musculature between musicians with musculoskeletal pain and asymptomatic comparisons. An updated search was performed in May 2017, adding a further study. Two authors independently assessed papers for inclusion and then quality, determined using a modified Downs and Black Checklist. Means and standard deviations were extracted from each study to calculate effect sizes and compare results. Six studies were found to fulfil inclusion criteria. Five studies were deemed high-quality with one being low-quality. Conflicting evidence was found supporting increases in upper trapezius EMG muscle activity in musicians reporting of pain. Moderate-quality evidence indicates increased SCM activity in musicians reporting pain. There was limited evidence supporting increased activity of deltoids, lower trapezius and the upper cervical extensors in musicians reporting of musculoskeletal pain. Meta-analysis of results of three studies assessing upper trapezius activity were conflicting with these not being statistically significant. Further studies with prospective designs, larger population sizes and on broader instrumental groups are warranted.

The interface of child mental health and juvenile diabetes mellitus.

Diabetes mellitus is a common childhood illness, and its management is often complicated by mental health challenges. Psychiatric comorbidities are common, including anxiety, depression, and eating disorders. The illness can profoundly affect the developing brain and family functioning and have lifelong consequences. The child mental health provider can provide valuable assistance to support the child and family and assessment and treatment of comorbid mental health problems and to promote positive family functioning and normal developmental progress.

The interface of child mental health and juvenile diabetes mellitus.

Diabetes mellitus is a common childhood illness, and its management is often complicated by mental health challenges. Psychiatric comorbidities are common, including anxiety, depression, and eating disorders. The illness can profoundly affect the developing brain and family functioning and have lifelong consequences. The child mental health provider can provide valuable assistance to support the child and family and assessment and treatment of comorbid mental health problems and to promote positive family functioning and normal developmental progress.

The interface of child mental health and juvenile diabetes mellitus.

Diabetes mellitus is a common childhood illness, and its management is often complicated by mental health challenges. Psychiatric comorbidities are common, including anxiety, depression, and eating disorders. The illness can profoundly affect the developing brain and family functioning and have lifelong consequences. The child mental health provider can provide valuable assistance to support the child and family and assessment and treatment of comorbid mental health problems and to promote positive family functioning and normal developmental progress.

Subunits of a yeast oligomeric G protein-coupled receptor are activated independently by agonist but function in concert to activate G protein heterotrimers.

G protein-coupled receptors (GPCRs) form dimeric or oligomeric complexes in vivo. However, the function of oligomerization in receptor-mediated G protein activation is unclear. Previous studies of the yeast alpha-factor receptor (STE2 gene product) have indicated that oligomerization promotes signaling. Here we have addressed the mechanism by which oligomerization facilitates G protein signaling by examining the ability of ligand binding- and G protein coupling-defective alpha-factor receptors to form complexes in vivo and to correct their signaling defects when co-expressed (trans complementation). Newly and previously identified receptor mutants indicated that ligand binding involves the exofacial end of transmembrane domain (TM) 4, whereas G protein coupling involves ic1, ic3, the C-terminal tail, and the intracellular ends of TM2 and TM3. Mutant receptors bearing substitutions in these domains formed homo-oligomeric or hetero-oligomeric complexes in vivo, as indicated by results of fluorescence resonance energy transfer experiments. Co-expression of ligand binding- and G protein coupling-defective mutant receptors did not significantly improve signaling. In contrast, co-expression of ic1 and ic3 mutations in trans but not in cis significantly increased signaling efficiency. Therefore, we suggest that subunits of the alpha-factor receptor: 1) are activated independently rather than cooperatively by agonist, and 2) function in a concerted fashion to promote G protein activation, possibly by contacting different subunits or regions of the G protein heterotrimer.

Oligomerization, biogenesis, and signaling is promoted by a glycophorin A-like dimerization motif in transmembrane domain 1 of a yeast G protein-coupled receptor.

G protein-coupled receptors (GPCRs) can form dimeric or oligomeric complexes in vivo. However, the functions and mechanisms of oligomerization remain poorly understood for most GPCRs, including the alpha-factor receptor (STE2 gene product) of the yeast Saccharomyces cerevisiae. Here we provide evidence indicating that alpha-factor receptor oligomerization involves a GXXXG motif in the first transmembrane domain (TM1), similar to the transmembrane dimerization domain of glycophorin A. Results of fluorescence resonance energy transfer, fluorescence microscopy, endocytosis assays of receptor oligomerization in living cells, and agonist binding assays indicated that amino acid substitutions affecting the glycine residues of the GXXXG motif impaired alpha-factor receptor oligomerization and biogenesis in vivo but did not significantly impair agonist binding affinity. Mutant receptors exhibited signaling defects that were not due to impaired cell surface expression, indicating that oligomerization promotes alpha-factor receptor signal transduction. Structure-function studies suggested that the GXXXG motif in TM1 of the alpha-factor receptor promotes oligomerization by a mechanism similar to that used by the GXXXG dimerization motif of glycophorin A. In many mammalian GPCRs, motifs related to the GXXXG sequence are present in TM1 or other TM domains, suggesting that similar mechanisms are used by many GPCRs to form dimers or oligomeric arrays.

C5a receptor oligomerization. II. Fluorescence resonance energy transfer studies of a human G protein-coupled receptor expressed in yeast.

Recent studies demonstrate that members of the superfamily of G protein-coupled receptors (GPCRs) form oligomers both in vitro and in vivo. The mechanisms by which GPCRs oligomerize and the roles of accessory proteins in this process are not well understood. We used disulfide-trapping experiments to show that C5a receptors, expressed in mammalian cells, reside in membranes as oligomers (Klco, J. M., Lassere, T. B., and Baranski, T. J. (2003) J. Biol. Chem. 278, 35345-35353). To begin to address how C5a receptors form oligomers, we now use fluorescence resonance energy transfer experiments on human C5a receptors expressed in the lower eukaryote Saccharomyces cerevisiae. C5a receptors tagged with variants of the green fluorescent protein display energy transfer in intact yeast, demonstrating that mammalian accessory proteins are not required for C5a receptor oligomerization. In both intact yeast cells and membrane preparations, agonist does not affect FRET efficiency, and little energy transfer is observed between the C5a receptor and a co-expressed yeast pheromone receptor (encoded by STE2), indicating that C5a receptor oligomerization is both receptor-specific and constitutive. FRET studies performed on fractionated membranes demonstrate similar levels of energy transfer between tagged C5a receptors in endoplasmic reticulum compared with plasma membrane, and urea washing of membranes has little effect on the extent of energy transfer. The oligomerization of C5a receptors expressed in yeast displays characteristics similar to those observed for other GPCRs studied in mammalian cells. This model system should prove useful for further studies to define mechanisms of oligomerization of mammalian GPCRs.

Use of fluorescence resonance energy transfer to analyze oligomerization of G-protein-coupled receptors expressed in yeast.

Oligomerization or dimerization of G-protein-coupled receptors (GPCRs) has emerged as an important theme in signal transduction. This concept has recently gained widespread interest due to the application of direct and noninvasive biophysical techniques such as fluorescence resonance energy transfer (FRET), which have shown unequivocally that several types of GPCR can form dimers or oligomers in living cells. Current challenges are to determine which GPCRs can self-associate and/or interact with other GPCRs, to define the molecular principles that govern these specific interactions, and to establish which aspects of GPCR function require oligomerization. Although these questions ultimately must be addressed by using GPCRs expressed endogenously in their native cell types, analysis of GPCR oligomerization in heterologous expression systems will be useful to survey which GPCRs can interact, to conduct structure-function studies, and to identify peptides or small molecules that disrupt GPCR oligomerization and function. Here, we describe methods employing scanning fluorometry to detect FRET between GPCRs tagged with enhanced cyan and yellow fluorescent proteins (CFP and YFP) in living yeast cells. This approach provides a powerful means to analyze oligomerization of a variety of GPCRs that can be expressed in yeast, such as adrenergic, adenosine, C5a, muscarinic acetylcholine, vasopressin, opioid, and somatostatin receptors.

The extracellular N-terminal domain and transmembrane domains 1 and 2 mediate oligomerization of a yeast G protein-coupled receptor.

G protein-coupled receptors (GPCRs) can form homodimers/oligomers and/or heterodimers/oligomers. The mechanisms used to form specific GPCR oligomers are poorly understood because the domains that mediate such interactions and the step(s) in the secretory pathway where oligomerization occurs have not been well characterized. Here we have used subcellular fractionation and fluorescence resonance energy transfer (FRET) experiments to show that oligomerization of a GPCR (alpha-factor receptor; STE2 gene product) of the yeast Saccharomyces cerevisiae occurs in the endoplasmic reticulum. To identify domains of this receptor that mediate oligomerization, we used FRET and endocytosis assays of oligomerization in vivo to analyze receptor deletion mutants. A mutant lacking the N-terminal extracellular domain and transmembrane (TM) domain 1 was expressed at the cell surface but did not self-associate. In contrast, a receptor fragment containing only the N-terminal extracellular domain and TM1 could self-associate and heterodimerize with wild type receptors. Analysis of other mutants suggested that oligomerization is facilitated by the N-terminal extracellular domain and TM2. Therefore, the N-terminal extracellular domain, TM1, and TM2 appear to stabilize alpha-factor receptor oligomers. These domains may form an interface in contact or domain-swapped oligomers. Similar domains may mediate dimerization of certain mammalian GPCRs.