Development and Validation of Short Forms of the Pain Catastrophizing Scale (F-PCS-5) and Tampa Scale for Kinesiophobia (F-TSK-6) in Musculoskeletal Chronic Pain Patients.

Purpose: Chronic pain is a complex phenomenon. Understanding its multiple dimensions requires the use of a combination of several patient-reported outcome measures (PROMs). However, completing multiple PROMs is time-consuming and can be a burden for patients. The objective of our study was to simultaneously reduce the French versions of the Pain Catastrophizing Scale (PCS) and Tampa Scale for Kinesiophobia (TSK) questionnaires to enable their use in an ambulatory and clinical settings. Patients and Methods: We conducted a clinical study between May 2014 and August 2020 in our rehabilitation center. 1428 chronic musculoskeletal pain patients (CMSP) were included. The originality of our approach is that the reduction method included qualitative as well as quantitative analyses. The study was divided into two parts: 1) reduction of the questionnaires (n=1363) based on internal consistency (item-to-total correlation), principal component analysis (item loadings), Rasch analysis (infit/outfit), floor and ceiling effect (quantitative analyses) and expert judgment of items (qualitative analysis), and 2) validation of the reduced questionnaires (n=65), including test-retest reliability (intraclass correlation coefficient [ICC]), homogeneity (Cronbach α), criterion validity (Pearson correlation [r] with the long-version score), determination of the pathological cutoff and Minimal Clinically Important Difference (MCID). The two full-length questionnaires include 30 items in total. Results: The reduction resulted in a 5-item PCS (score 0-20) and 6-item TSK (score 0-24). Psychometric properties of the reduced questionnaires were all acceptable as compared with other version (α=0.89 and 0.71, ICC=0.75 and 0.60, r=0.86 and 0.70, MCID=2 and 2 for PCS and TSK, respectively) while keeping the structure and coherence of the long versions. Conclusion: The two reduced versions of the PCS and TSK can be used in CMSP patient. As their administration only requires a few minutes, they can be implemented in outpatient consultation as well as in clinical settings.

The effect of the menstrual cycle on the circulating microRNA pool in human plasma: a pilot study.

STUDY QUESTION: Do ovarian hormone changes influence the levels of cell-free or circulating microRNA (cf-miRNA) across the menstrual cycle? SUMMARY ANSWER: This exploratory study suggests that fluctuations in hormonal levels throughout the menstrual cycle may alter cf-miRNAs levels. WHAT IS KNOWN ALREADY: cf-miRNA levels vary with numerous pathological and physiological conditions in both males and females and are regulated by exogenous and endogenous factors, including hormones. STUDY DESIGN, SIZE, DURATION: A prospective, monocentric study was conducted between March and November 2021. Since this was a pilot study, the sample size was based on feasibility as well as previous similar human studies conducted in different tissues. A total of 20 participants were recruited for the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: We conducted an exploratory study where blood samples were collected from 16 eumenorrheic females in the early follicular phase, the ovulation phase and the mid-luteal phase of the menstrual cycle. The levels of oestrogen, progesterone, LH and FSH were measured in serum by electrochemiluminescence. The levels of 174 plasma-enriched miRNAs were profiled using a PCR-based panel, including stringent internal and external controls to account for the potential differences in RNA extraction and reverse-transcription stemming from low-RNA input samples. MAIN RESULTS AND THE ROLE OF CHANCE: This exploratory study suggests that cf-miRNAs may play an active role in the regulation of the female cycle by mediating the expression of genes during fluctuating hormonal changes. Linear mixed-models, adjusted for the relevant variables, showed associations between phases of the menstrual cycle, ovarian hormones and plasma cf-miRNA levels. Validated gene targets of the cf-miRNAs varying with the menstrual cycle were enriched within female reproductive tissues and are primarily involved in cell proliferation and apoptosis. LARGE SCALE DATA: All relevant data are available from the Mendeley database: LEGER, Bertrand (2022), 'MiRNA and menstrual cycle', Mendeley Data, V1, doi: 10.17632/2br3zp79m3.1. LIMITATIONS, REASONS FOR CAUTION: Our study was conducted on a small participant cohort. However, it was tightly controlled for endogenous and exogenous confounders, which is critical to ensure robust and reproducible cf-miRNA research. Both adjusted and non-adjusted P-values are presented throughout the article. WIDER IMPLICATIONS OF THE FINDINGS: Measures of ovarian hormones should be rigorously included in future studies assessing cf-miRNA levels in females and used as time-varying confounders. Our results reinforce the importance of accounting for female-specific biological processes in physiology research by implementing practical or statistical mitigation strategies during data collection and analysis. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Clinique romande de réadaptation, Sion, Switzerland. S.L. was supported by an Australian Research Council (ARC) Future Fellowship (FT10100278). D.H. was supported by an Executive Dean's Postdoctoral Research Fellowship from Deakin University. The authors declare no competing interests.

Altered BDNF Methylation in Patients with Chronic Musculoskeletal Pain and High Biopsychosocial Complexity.

PURPOSE: The INTERMED instrument, which was developed to measure patient's biopsychosocial (BPS) complexity, represents a powerful diagnostic and therapeutic tool. Epigenetic changes are the interface between signals from the environment and genetic modifications, affecting gene expression, in particular, by DNA methylation of CpG dinucleotides in promotor regions of the corresponding genes. The brain-derived neurotrophic factor (BDNF) gene plays a crucial role in the central sensitization (CS) of pain. In this study, we hypothesized that chronic pain modifies the methylation levels of the BDNF gene in a manner that is interconnected with the BPS status. PATIENTS AND METHODS: Fifty-eight chronic musculoskeletal pain patients (CMSP) were enrolled in the study. DNA was extracted from blood samples, the methylation levels of 13 CpG sites in the BDNF promoter were measured by pyrosequencing, and association studies with various patient parameters and the INTERMED scores were performed. RESULTS: Interestingly, a negative correlation (-0.40) was found between the total INTERMED scores and the average CpG methylation values of the BDNF gene, but no correlation was observed with the severity of pain, degree of anxiety, depression, or kinesiophobia and catastrophism. Moreover, the association was independent of age, sex and level of comorbidities. CONCLUSION: This result shows that CMSP, in association with its biopsychosocial context, epigenetically decreases the degree of methylation of the BDNF promoter and should therefore increase the level of BDNF transcription. It also suggests a role of the INTERMED tool to detect a relationship between the BPS complexity and the epigenetic control of a target gene. The possible upregulation of BDNF expression might be, at least in part, the signal for chronic pain-induced central sensitization (CS). This could partly explain why patients with a higher level of complexity feel more pain than those with lower complexity.

Differences in the miRNA signatures of chronic musculoskeletal pain patients from neuropathic or nociceptive origins.

BACKGROUND: The quality of life for millions of people worldwide is affected by chronic pain. In addition to the effect of chronic pain on well-being, chronic pain has also been associated with poor health conditions and increased mortality. Due to its multifactorial origin, the classification of pain types remains challenging. MicroRNAs (miRNA) are small molecules that regulate gene expression. They are released into the bloodstream in a stable manner under normal and pathological conditions and have been described as potential biomarkers. In the present study, we aimed to investigate whether pain may induce an aberrant, specific dysregulation of miRNA expression, depending on the origin of the pain. METHODS AND FINDINGS: To do so, we measured the expression changes of 184 circulating miRNAs (c-miRNAs) in the plasma samples of patients with different origins of chronic musculoskeletal pain. After statistical analyses, we identified seven c-miRNA candidates that were differentially expressed depending on the nociceptive or neuropathic origin of the pain. We then developed a two c-miRNA signature (hsa-miR-320a and hsa-miR-98-5p) that was able to correctly classify the pain type of 70% of the patients from the validation set. CONCLUSIONS: In conclusion, circulating miRNAs are promising biomarkers to identify and characterize the chronic pain type and to further improve its clinical management.

Influencing walking behavior can increase the physical activity of patients with chronic pain hospitalized for multidisciplinary rehabilitation: an observational study.

BACKGROUND: Physical therapy and exercising are key components of biopsychosocial rehabilitation for chronic pain. Exercise helps reduce pain and improve physical functions. In addition, a high level of physical activity benefits quality of life and emotional well-being. However, the degree to which hospitalization for extensive rehabilitation effectively increases physical activity has not yet been studied. Therefore, we investigated the physical activity level and the walking behavior of inpatients with musculoskeletal pain. The objectives were 1) to compare physical activity level and walking with or without rehabilitation, 2) to evaluate whether pain site influences physical activity level, and 3) to measure the association between physical activity and pain-related interference with physical functioning. METHODS: During a rehabilitation stay, 272 inpatients with lower limb, spine, or upper limb pain wore an accelerometer over 1 week. We assessed the daily duration of the practice of moderate physical activity and walking. Weekend days, during which the participants went home (days off), were used as a reference for habitual activities. We also evaluated 93 patients before the hospitalization to validate the use of days off as a baseline. Pain interference was measured with the brief pain inventory questionnaire. Generalized linear mixed models analyzed the association between physical activity and walking levels, and 1) rehabilitation participation, 2) pain sites, and 3) pain interference. RESULTS: Weekend days during the stay have similar physical activity level as days measured before the stay (73 min / day at the clinic, versus 70 min / day at home). Rehabilitation days had significantly higher physical activity levels and walking durations than days off (+ 28 min [+ 37%] and + 32 min [+ 74%], respectively). Mixed models revealed 1) a negative association between physical activity and pain interference, and 2) no effect of pain sites. Overall, patients increased their physical activity level independently of reported pain interference. CONCLUSIONS: Despite their painful condition, the inpatients were able to engage themselves in a higher level of physical activity via increased participation in walking activities. We conclude that walking incentives can be a valid solution to help patients with chronic pain be more physically active.

Transcultural adaptation and validation of a French version of the Prosthetic Limb Users Survey of Mobility 12-item Short-Form (PLUS-M/FC-12) in active amputees.

BACKGROUND: The PLUS-M 12-item Short-Form is a self-questionnaire that assesses the perceived capacity of lower limb amputees (LLAs) to perform a number of daily-life activities. Its psychometric properties are excellent (intraclass correlation coefficient [ICC]>0.9, fast administration and scoring, normative data available), and it can be used in clinical practice or for research purposes. OBJECTIVE: We aimed to develop a French version of this questionnaire and to assess its psychometric properties. METHODS: We followed international recommendations for translation and cross-cultural validation of questionnaires. In total, 52 LLAs (age 53±16, 40 males, 28/12/12 transtibial/Gritti-Stokes/transfemoral, 20/28/4 ischemic/traumatic/other) participated. Criterion and construct validities were assessed with the Pearson correlation coefficient (PCC) between the PLUS-M 12-item Short-Form and other constructs (Prosthetic-Profile-of-the-Amputee-Locomotor Capabilities Index, Activities-specific Balance Confidence scale, 2-min walking test and Timed Up and Go test), internal consistency with the Cronbach α and reliability with the ICC in 46 individuals who completed the questionnaire twice in a 7-day interval. RESULTS: The mean (SD) PLUS-M 12-item Short-Form T-score was 56.1 (7.8; range 40.3 to 71.4). Construct and criterion validity, internal consistency and reliability ranged from low to excellent (r=0.43 to 0.84, P<10-2 to 0.002; Cronbach α=0.90, ICC=0.89 [0.81-0.94]). We found no floor or ceiling effect. CONCLUSIONS: The French version of the PLUS-M 12-item Short-Form has good to excellent psychometric properties, comparable to those of the original version. Its use could definitely be proposed for both clinical and research purposes, once its validation is completed by assessing other psychometric qualities, especially sensitivity to change.

Monitoring of Gait Quality in Patients With Chronic Pain of Lower Limbs.

Severe injuries of lower extremities often lead to chronic pain and reduced walking abilities. We postulated that measuring free-living gait can provide further information about walking ability in complement to clinical evaluations. We sought to validate a method that characterizes free gaits with a wearable sensor. Over one week, 81 healthy controls (HC) and 66 chronic lower limb pain patients (CLLPP) hospitalized for multidisciplinary rehabilitation wore a simple accelerometer (Actigraph). In the acceleration signals, steady 1-min walks detected numbered 7,835 (5,085 in CLLPP and 2,750 in HC). Five gait quality measures were assessed: movement intensity, cadence, stride regularity, and short-term and long-term local dynamic stability. Gait quality variables differed significantly between CLLPP and HC (4%-26%). Intraclass correlation coefficients revealed moderate to high repeatability (0.71-0.91), which suggests that seven days of measurement are sufficient to assess average gait patterns. Regression analyses showed significant association (R2 = 0.44) between the gait quality variables and a clinical evaluation of walking ability, i.e., the 6-min walk test. Overall, the results show that the method is easy to implement, valid (high concurrent validity), and reliable to assess walking abilities ecologically.

Validation of a multiplex reverse transcription and pre-amplification method using TaqMan(®) MicroRNA assays.

Since the discovery of microRNAs (miRNAs), different approaches have been developed to label, amplify and quantify miRNAs. The TaqMan(®) technology, provided by Applied Biosystems (ABIs), uses a stem-loop reverse transcription primer system to reverse transcribe the RNA and amplify the cDNA. This method is widely used to identify global differences between the expression of 100s of miRNAs across comparative samples. This technique also allows the quantification of the expression of targeted miRNAs to validate observations determined by whole-genome screening or to analyze few specific miRNAs on a large number of samples. Here, we describe the validation of a method published by ABIs on their web site allowing to reverse transcribe and pre-amplify multiple miRNAs and snoRNAs simultaneously. The validation of this protocol was performed on human muscle and plasma samples. Fast and cost efficient, this method achieves an easy and convenient way to screen a relatively large number of miRNAs in parallel.

Altered expression of ß-galactosidase-1-like protein 3 (Glb1l3) in the retinal pigment epithelium (RPE)-specific 65-kDa protein knock-out mouse model of Leber's congenital amaurosis.

PURPOSE: In this study, we investigated the expression of the gene encoding ß-galactosidase (Glb)-1-like protein 3 (Glb1l3), a member of the glycosyl hydrolase 35 family, during retinal degeneration in the retinal pigment epithelium (RPE)-specific 65-kDa protein knockout (Rpe65(-/-)) mouse model of Leber congenital amaurosis (LCA). Additionally, we assessed the expression of the other members of this protein family, including ß-galactosidase-1 (Glb1), ß-galactosidase-1-like (Glb1l), and ß-galactosidase-1-like protein 2 (Glb1l2). METHODS: The structural features of Glb1l3 were assessed using bioinformatic tools. mRNA expression of Glb-related genes was investigated by oligonucleotide microarray, real-time PCR, and reverse transcription (RT) -PCR. The localized expression of Glb1l3 was assessed by combined in situ hybridization and immunohistochemistry. RESULTS: Glb1l3 was the only Glb-related member strongly downregulated in Rpe65(-/-) retinas before the onset and during progression of the disease. Glb1l3 mRNA was only expressed in the retinal layers and the RPE/choroid. The other Glb-related genes were ubiquitously expressed in different ocular tissues, including the cornea and lens. In the healthy retina, expression of Glb1l3 was strongly induced during postnatal retinal development; age-related increased expression persisted during adulthood and aging. CONCLUSIONS: These data highlight early-onset downregulation of Glb1l3 in Rpe65-related disease. They further indicate that impaired expression of Glb1l3 is mostly due to the absence of the chromophore 11-cis retinal, suggesting that Rpe65 deficiency may have many metabolic consequences in the underlying neuroretina.