Effect of an interdisciplinary inpatient program for patients with complex regional pain syndrome in reducing disease activity-a single-center prospective cohort study.

OBJECTIVE: The aim of this study was to evaluate the benefit of inpatient treatment in reducing disease activity in patients with complex regional pain syndrome (CRPS) who have exhausted outpatient options. Furthermore, the study sought to identify patient-related outcome variables that predict a reduction in disease activity. METHODS: The primary outcome was disease severity (CRPS Severity Score, range 0-16 points). Secondary outcomes included depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and the ability to participate in social roles and activities, all of which were assessed using the PROMIS-29. Furthermore, pain catastrophizing, neuropathic pain, quality of life, pain self-efficacy, medication intake, and the patient's global impression of change were examined in accordance with current international agreed recommendations, assessed at discharge, 3-month, and 6-month post-discharge. Mixed-effects models were conducted to identify baseline variables associated with CRPS severity. RESULTS: Twenty-five patients completed the program (mean age 49.28 [SD 11.23] years, 92% females, mean symptom duration 8.5 [SD 6.5] months). Results showed a significant reduction between baseline and discharge of disease activity (CSS -2.36, P < .0001), pain (PROMIS-29 pain -0.88, P = .005), and emotional function (PROMIS-29 depression -5.05, P < .001; fatigue -4.63, P = .002). Moderate evidence for a reduction between baseline and discharge could be observed for pain interference (+2.27, P = .05), social participation (PROMIS-29 + 1.93, P = .05), anxiety (PROMIS-29 -3.32, P = .02) and physical function (PROMIS-29 + 1.3, P = .03). On discharge, 92% of patients (23 of 25) reported improvement in their overall condition. In the follow-up period, medication intake could be reduced after 3 (MQS -8.22, P = .002) and 6 months (MQS -8.69, P = .001), and there was further improvement in social participation after 3 months (PROMIS-29 + 1.72, 0.03) and sleep after 6 months (PROMIS-29 + 2.38, 0.008). In the mixed models, it was demonstrated that patients experiencing less pain at baseline also exhibited lower disease activity. CONCLUSION: The results of this study confirm that inpatient interdisciplinary treatment of CRPS patients improves disease activity, pain, physical function, emotional function, and social participation. Most improvements were maintained for up to 6 months after discharge. The majority of patients reported that their overall condition had improved during the study period.

Central sensitization in CRPS patients with widespread pain: a cross-sectional study.

OBJECTIVE: Widespread pain hypersensitivity and enhanced temporal summation of pain (TSP) are commonly reported in patients with complex regional pain syndrome (CRPS) and discussed as proxies for central sensitization. This study aimed to directly relate such signs of neuronal hyperexcitability to the pain phenotype of CRPS patients. METHODS: Twenty-one CRPS patients and 20 healthy controls (HC) were recruited. The pain phenotype including spatial pain extent (assessed in % body surface) and intensity were assessed and related to widespread pain hypersensitivity, TSP, and psychological factors. Quantitative sensory testing (QST) was performed in the affected, the contralateral and a remote (control) area. RESULTS: CRPS patients showed decreased pressure pain thresholds in all tested areas (affected: t(34) = 4.98, P < .001, contralateral: t(35) = 3.19, P = .005, control: t(31) = 2.65, P = .012). Additionally, patients showed increased TSP in the affected area (F(3,111) = 4.57, P = .009) compared to HC. TSP was even more enhanced in patients with a high compared to a low spatial pain extent (F(3,51) = 5.67, P = .008), suggesting pronounced spinal sensitization in patients with extended pain patterns. Furthermore, the spatial pain extent positively correlated with the Bath Body Perception Disturbance Scale (ρ = 0.491; P = .048). CONCLUSIONS: Overall, we provide evidence that the pain phenotype in CRPS, that is, spatial pain extent, might be related to sensitization mechanism within the central nociceptive system. This study points towards central neuronal excitability as a potential therapeutic target in patients with more widespread CRPS.

Resilience in patients with complex regional pain syndrome 1-a cross-sectional analysis of patients participating in a cross-sectional cohort study.

OBJECTIVE: To assess the degree of resilience in patients with complex regional pain syndrome (CRPS) 1, to explore the relationship between resilience and patient-related outcome measurements and to describe a pattern of clinical manifestations associated with low resilience. METHODS: This study presents a cross-sectional analysis of baseline information collected from patients enrolled in a single center study between February 2019 and June 2021. Participants were recruited from the outpatient clinic of the Department of Physical Medicine & Rheumatology of the Balgrist University Hospital, Zurich, Switzerland. We used linear regression analysis to explore association of resilience with patient reported outcomes at baseline. Furthermore, we explored the impact of significant variables on the low degree resilience using logistic regression analysis. RESULTS: Seventy-one patients (females 90.1%, mean age 51.2 ± 12.9 years) were enrolled. There was no association between CRPS severity and the level of resilience. Quality of Life was positively correlated with resilience, as was pain self-efficacy. Pain catastrophizing was inversely correlated with the level of resilience. We observed a significant inverse association between anxiety, depression and fatigue and the level of resilience. The proportion of patients with a low resilience increased with higher level of anxiety, depression and fatigue on the PROMIS-29, without reaching statistical significance. CONCLUSION: Resilience seems to be an independent factor in CRPS 1 and is associated with relevant parameters of the condition. Therefore, caretakers may screen the current resilience status of CRPS 1 patients to offer a supplementary treatment approach. Whether specific resilience training modifies CRPS 1 course, requires further investigations.

Skin biomarkers associated with complex regional pain syndrome (CRPS) Type I: a systematic review.

Despite increasing research, the pathophysiology of Complex Regional Pain Syndrome (CRPS) remains poorly understood. Due to its easy accessibility, the skin represents an ideal approach to gain a better understanding of the underlying processes. We conducted a systematic review of original studies investigating potential biomarkers cutaneous biomarkers in CRPS. Original articles with a minimum level IV of evidence were screened using the following databases: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Web of Science Core Collection. Quality assessment was performed using the Methodological Index for Non-Randomized Studies criteria. A total of 11 studies exploring cutaneous biomarkers in 299 CRPS Type I patients were included. The biomarkers identified revealed implications of the following pathophysiological processes: inflammation via interleukins and TNF-a, vascular dysregulation (ET-1/NOx disturbances and hypoxia-high lactate), small fiber neuropathy and hypersensitivity. In terms of skin morphology, evidence suggests: neurite loss, increased expression and disturbed migration of mast cells, as well as an increased expression of α1-adrenoceptors on keratinocytes. The data supporting hypersensitivity had a high risk of bias on quality assessment. The current review has emphasized the current state of knowledge regarding the cutaneous biomarkers in patients suffering from CRPS Type I. Our results serve as a basis for future developments of techniques that would either facilitate diagnosis or may represent therapeutic targets. Trial registration PROSPERO: CRD42020203405. Level of evidence: IV (Systematic Review).

Influence of pregnancy/childbirth on long-term bone marrow edema and subchondral sclerosis of sacroiliac joints.

OBJECTIVE: To investigate long-term effects of pregnancy/childbirth on bone marrow edema (BME) and subchondral sclerosis of sacroiliac joints (SIJ) in comparison to MRI changes caused by spondyloarthritis (SpA) and assess the influence of birth method and number of children on SIJ-MRI changes. MATERIALS AND METHODS: This is a retrospective cohort study with 349 women (mean age 47 ± 14 years) suffering low back pain. Four subgroups were formed based on SpA diagnosis and childbirth (CB) history. Two musculoskeletal radiologists scored the presence of BME and sclerosis on SIJ-MRI using the Berlin method. Further, an 11-point "global assessment score" representing the overall confidence of SpA diagnosis based on MRI was evaluated in addition to the ASAS (Assessment of Spondyloarthritis International Society) criterion of "positive MRI" for sacroiliitis. RESULTS: CB did not correlate with BME score (p = 0.38), whereas SpA diagnosis was associated with a higher BME score (r = 0.31, p < 0.001). Both CB (r = 0.21, p < 0.001) and SpA diagnosis (r = 0.33, p < 0.001) were correlated with a higher sclerosis score. CB was not associated with a higher confidence level in diagnosing SpA based on MRI (p = 0.07), whereas SpA diagnosis was associated with a higher score (r = 0.61, p < 0.001). Both CB (phi = 0.13, p = 0.02) and SpA diagnosis (phi = 0.23, p < 0.001) were significantly associated with a positive ASAS criterion for sacroiliitis. In non-SpA patients with CB, number of children (p = 0.001) was an independent predictor of sclerosis score, while birth method yielded no significant effect (p = 0.75). CONCLUSION: Pregnancy/CB has no impact on long-term BME on SIJ, however, may cause long-term subchondral sclerosis-similar to SpA-associated sclerosis. Number of children is positively correlated with SIJ sclerosis. Birth method yields no effect on SIJ sclerosis.

Serum Biomarkers for Connective Tissue and Basement Membrane Remodeling are Associated with Vertebral Endplate Bone Marrow Lesions as Seen on MRI (Modic Changes).

Vertebral endplate bone marrow lesions, visualized on magnetic resonance imaging (MRI) as Modic changes (MC), are associated with chronic low back pain (cLBP). Since guidelines recommend against routine spinal MRI for cLBP in primary care, MC may be underdiagnosed. Serum biomarkers for MC would allow early diagnosis, inform clinical care decisions, and supplement treatment monitoring. We aimed to discover biomarkers in the blood serum that correlate with MC pathophysiological processes. For this single-site cross-sectional study, we recruited 54 subjects with 38 cLBP patients and 16 volunteers without a history of LBP. All subjects completed an Oswestry Disability Index (ODI) questionnaire and 10-cm Visual Analog Score (VAS) for LBP (VASback) and leg pain. Lumbar T1-weighted and fat-saturated T2-weighted MRI were acquired at 3T and used for MC classification in each endplate. Blood serum was collected on the day of MRI. Biomarkers related to disc resorption and bone marrow fibrosis were analyzed with enzyme-linked immune-absorbent assays. The concentration of biomarkers between no MC and any type of MC (AnyMC), MC1, and MC2 were compared. The Area Under the Curve (AUC) of the Receiver Operating Characteristics were calculated for each biomarker and for bivariable biomarker models. We found that biomarkers related to type III and type IV collagen degradation and formation tended to correlate with the presence of MC (p = 0.060-0.088). The bivariable model with the highest AUC was PRO-C3 + C4M and had a moderate diagnostic value for AnyMC in cLBP patients (AUC = 0.73, specificity = 78.9%, sensitivity = 73.7%). In conclusion, serum biomarkers related to the formation and degradation of type III and type IV collagen, which are key molecules in bone marrow fibrosis, correlated with MC presence. Bone marrow fibrosis may be an important pathophysiological process in MC that should be targeted in larger biomarker and treatment studies.

[Pathophysiology and Diagnosis of Chronic Regional Pain Syndrome: What is important for the General Practitioner and the Surgeon?] / Pathophysiologie und Diagnostik des Komplexen Regionalen Schmerzsyndroms.

Pathophysiology and Diagnosis of Chronic Regional Pain Syndrome: What is important for the General Practitioner and the Surgeon? Abstract. Complex regional pain syndrome (CRPS) describes a variety of painful conditions following an initiating event and appears distally on the affected limb. Characteristically CRPS exceeds the expected clinical course in both magnitude and duration. CRPS affects mainly women between 61 and 70 years and the upper extremity is mainly involved. Clinical manifestations include sensory, vasomotor, sudomotor, motor and trophic changes. The clinical spectrum develops individually and changes over time. The diagnosis is based on the modified Budapest Criteria. Essential differential diagnosis includes infections, neurological compression and inflammatory conditions. Early signs encompass a disproportional painful swelling of the affected limb. Although benign courses are reported, many patients develop a chronic condition with persistent complaints after one year. Because there is no underlying or causal cure the therapy remains a challenge. The therapy is based on the presenting clinical signs or symptoms and includes a variety of pharmacological, interventional, physiotherapeutic, occupational and psychiatric measures.

Direct Health Care Cost and Work Incapacity Related to Complex Regional Pain Syndrome in Switzerland: A Retrospective Analysis from 2008 to 2015.

OBJECTIVE: First, to determine the number of accident-related complex regional pain syndrome (CRPS) cases from 2008 to 2015 and to identify factors associated with an increased risk for developing CRPS. Second, to analyze the duration of work incapacity and direct health care costs over follow-up periods of two and five years, respectively. DESIGN: Retrospective data analysis. SETTING: Database from the Statistical Service for the Swiss National Accident Insurances covering all accidents insured under the compulsory Swiss Accident Insurance Law. SUBJECTS: Subjects were registered after an accident between 2008 and 2015. METHODS: Cases were retrospectively retrieved from the Statistical Service for the Swiss National Accident Insurances. Cases were identified using the appropriate International Classification of Diseases, 10th Revision, codes. RESULTS: CRPS accounted for 0.15% of all accident cases. Age, female gender (odds ratio [OR] = 1.53, 95% confidence interval [CI] = 1.47-1.60), and fracture of the forearm (OR = 38, 95% CI = 35-42) were related to an increased risk of developing CRPS. Over five years, one CRPS case accumulated average insurance costs of $86,900 USD and treatment costs of $23,300 USD. Insurance costs were 19 times and treatment costs 13 times the average costs of accidents without CPRS. Within the first two years after the accident, the number of days lost at work was 20 times higher in patients with CRPS (330 ± 7 days) than in patients without CRPS (16.1 ± 0.1 days). Two-thirds of all CRPS cases developed long-term work incapacity of more than 90 days. CONCLUSION: CRPS is a relatively rare condition but is associated with high direct health care costs and work incapacity.

Frequency of inflammatory-like MR imaging findings in asymptomatic fingers of healthy volunteers.

OBJECTIVE: To describe the frequency of inflammatory-like findings on MR imaging in asymptomatic volunteers and compare them with patients with known rheumatoid arthritis and psoriatic arthritis. MATERIALS AND METHODS: MR images of fingers in 42 asymptomatic volunteers and 33 patients with rheumatoid/psoriatic arthritis were analyzed. The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatoid/Psoriatic Arthritis MRI Scoring System (RAMRIS/PsAMRIS) and tenosynovitis scoring system were used to assess: bone marrow edema (BME), erosions, tendon sheath fluid/tenosynovitis, joint effusion, and soft-tissue edema. Findings and scores were compared between volunteers and patients. Inter-reader agreement was calculated (intraclass correlation coefficients, ICC). RESULTS: In volunteers, tendon sheath fluid was very common in at least one location (42/42 volunteers for reader 1, 34/42 volunteers for reader 2). BME, erosions, joint effusion, and soft-tissue edema were absent (except one BME in the 3rd proximal phalanx for reader 1). Tendon sheath fluid scores in volunteers and tenosynovitis scores in patients were high (reader 1, 7.17 and 5.39; reader 2, 2.31 and 5.45). Overall, inter-reader agreement was substantial (ICC = 0.696-0.844), except for tendon sheath fluid (ICC = 0.258). CONCLUSION: Fluid in the finger flexor tendon sheaths may be a normal finding and without gadolinium administration should not be interpreted as tenosynovitis. Bone marrow edema, erosions, joint effusion, and soft-tissue edema in the fingers most likely reflect pathology if present.

Measurement properties of painDETECT: Rasch analysis of responses from community-dwelling adults with neuropathic pain.

BACKGROUND: painDETECT (PD-Q) is a self-reported assessment of pain qualities developed as a screening tool for pain of neuropathic origin. Rasch analysis is a strategy for examining the measurement characteristics of a scale using a form of item response theory. We conducted a Rasch analysis to consider if the scoring and measurement properties of PD-Q would support its use as an outcome measure. METHODS: Rasch analysis was conducted on PD-Q scores drawn from a cross-sectional study of the burden and costs of NeP. The analysis followed an iterative process based on recommendations in the literature, including examination of sequential scoring categories, unidimensionality, reliability and differential item function. Data from 624 persons with a diagnosis of painful diabetic polyneuropathy, small fibre neuropathy, and neuropathic pain associated with chronic low back pain, spinal cord injury, HIV-related pain, or chronic post-surgical pain was used for this analysis. RESULTS: PD-Q demonstrated fit to the Rasch model after adjustments of scoring categories for four items, and omission of the time course and radiating questions. The resulting seven-item scale of pain qualities demonstrated good reliability with a person-separation index of 0.79. No scoring bias (differential item functioning) was found for this version. CONCLUSIONS: Rasch modelling suggests the seven pain-qualities items from PD-Q may be used as an outcome measure. Further research is required to confirm validity and responsiveness in a clinical setting.

The impact of incidental durotomy on the outcome of decompression surgery in degenerative lumbar spinal canal stenosis: analysis of the Lumbar Spinal Outcome Study (LSOS) data--a Swiss prospective multi-center cohort study.

BACKGROUND: Incidental durotomy is a well-known complication during surgery for degenerative lumbar spinal stenosis (DLSS). In this prospective multicenter cohort study including eight medical centers our aim was to assess whether incidental durotomy during first-time lumbar spinal stenosis decompression surgery without fusion has an impact on long-term outcome. METHODS: Patients of the multi-center Lumbar Stenosis Outcome Study (LSOS) with confirmed DLSS undergoing first-time decompression without fusion were enrolled in this study. Baseline patient characteristics and outcomes were analyzed at 6, 12, and 24 months follow-up respectively with the Spinal Stenosis Measure (SSM), the Numeric Rating Scale (NRS), Feeling Thermometer (FT), the EQ-5D-EL, and the Roland and Morris Disability Questionnaire (RMDQ). RESULTS: A total of 167 patients met the inclusion criteria. Fifteen (9%) of those patients had an incidental durotomy. Baseline characteristics were similar between the durotomy and no-durotomy group. All patients improved over time. In the group of durotomy patients, the median improvement in SSM symptoms scale was 1.1 points at 6 months, 1.1 points at 12 months, and 1.6 points at 24 months after baseline. For the no-durotomy group, these improvements were 0.8, 0.9, and 0.9. For SSM function the improvements were 1.0, 0.8, and 0.9 in the durotomy group, and 0.6, 0.8, and 0.8 in the no-durotomy group. None of the between-group differences were statistically significant. CONCLUSIONS: Incidental durotomy in patients with DLSS undergoing first-time decompression surgery without fusion did not have negative effect on long-term outcome and quality of life. However, only 15 patients were included in the durotomy group but these findings remained even after adjusting for observed differences in baseline characteristics.

Cervical Facet Joint Imaging-Guided Injections: A Comparison of Outcomes in Patients Referred Based on Imaging Findings Vs Palpation for Pain.

OBJECTIVES: The purpose of this study was to compare outcomes of patients referred for cervical facet joint injections by either a medical doctor (MD) primarily basing the selection of facet levels on structural changes found on imaging vs a doctor of chiropractic (DC) selecting the levels for injection based on palpation for pain. METHODS: This was a prospective cohort outcome study including 121 consecutive patients receiving cervical facet injections with completed outcomes questionnaires. Medical doctors referred 91 patients and DCs referred 30 patients. Baseline pain numerical rating scale (NRS) data were collected. Outcomes collected at 1 day, 1 week, and 1 month after injection included NRS pain levels and overall "improvement" using the Patient Global Impression of Change scale (primary outcome). The responses "much better" and "better" were considered "improved." The proportion improved was compared between the 2 groups using the χ(2) test. NRS change scores for the 2 groups were compared using the unpaired t test. RESULTS: At 1 day, "improvement" was reported in 44.8% of DC-and 29.7% of MD-referred patients (P = .17). At 1 week, 37.9% of DC-and 21.3% of MD-referred patients reported improvement (P = .03). At 1 month, 50.0% of DC-and 31.0% of MD-referred patients reported improvement (P = .1). CONCLUSIONS: A greater proportion of DC-referred patients (injection level based on palpation for pain) reported "improvement" at all follow-up time points. This finding reached statistical significance at 1 week. These findings may be because DCs use palpation for pain to determine injection level whereas MDs rely more on imaging findings. The results suggest that the reported moderate results of facet injections partially may be due to the inaccurate selection of the spinal level treated.

Bayesian meta-analysis of test accuracy in the absence of a perfect reference test applied to bone scintigraphy for the diagnosis of complex regional pain syndrome.

There is conflicting evidence about the accuracy of bone scintigraphy (BS) for the diagnosis of complex regional pain syndrome 1 (CRPS 1). In a meta-analysis of diagnostic studies, the evaluation of test accuracy is impeded by the use of different imperfect reference tests. The aim of our study is to summarize sensitivity and specificity of BS for CRPS 1 and to identify factors to explain heterogeneity. We use a hierarchical Bayesian approach to model test accuracy and threshold, and we present different models accounting for the imperfect nature of the reference tests, and assuming conditional dependence between BS and the reference test results. Further, we include disease duration as explanatory variable in the model. The models are compared using summary ROC curves and the deviance information criterion (DIC). Our results show that those models which account for different imperfect reference tests with conditional dependence and inclusion of the covariate are the ones with the smallest DIC. The sensitivity of BS was 0.87 (95% credible interval 0.73-0.97) and the overall specificity was 0.87 (0.73-0.95) in the model with the smallest DIC, in which missing values of the covariate are imputed within the Bayesian framework. The estimated effect of duration of symptoms on the threshold parameter was 0.17 (-0.25 to 0.57). We demonstrate that the Bayesian models presented in this paper are useful to address typical problems occurring in meta-analysis of diagnostic studies, including conditional dependence between index test and reference test, as well as missing values in the study-specific covariates.

Rational pain management in complex regional pain syndrome 1 (CRPS 1)--a network meta-analysis.

OBJECTIVE: Guidelines for complex regional pain syndrome (CRPS) 1 advocate several substance classes to reduce pain and support physical rehabilitation, but guidance about which agent should be prioritized when designing a therapeutic regimen is not provided. Using a network meta-analytic approach, we examined the efficacy of all agent classes investigated in randomized clinical trials of CRPS 1 and provide a rank order of various substances stratified by length of illness duration. DESIGN: In this study a network meta-analysis was conducted. PATIENTS: The participants of this study were patients with CRPS 1. METHOD: Searches in electronic, previous systematic reviews, conference abstracts, book chapters, and the reference lists of relevant articles were performed. Eligible studies were randomized controlled trials comparing at least one analgesic agent with placebo or with another analgesic and reporting efficacy in reducing pain. Summary efficacy stratified by symptom duration and length of follow-up was computed across all substance classes. Two authors independently extracted data. RESULTS: In total, 16 studies were included in the analysis. Bisphosphonates appear to be the treatment of choice in early stages of CRPS 1. The effects of calcitonin surpass that of bisphosphonates and other substances as a short-term medication in more chronic stages of the illness. While most medications showed some efficacy on short-term follow-up, only bisphosphonates, NMDA analogs, and vasodilators showed better long-term pain reduction than placebo. LIMITATION: For some drug classes, only a few studies were available and many studies included a small group of patients. Insufficient data were available to analyze efficacy on disability. CONCLUSION: This network meta-analysis indicates that a rational pharmacological treatment strategy of pain management should consider bisphosphonates in early CRPS 1 and a short-term course of calcitonin in later stages. While most medications showed some efficacy on short-term follow-up, only bisphosphonates, NMDA analogs and vasodilators showed better long-term pain reduction than placebo.

Impacts of priming on distinct immunosuppressive mechanisms of mesenchymal stromal cells under translationally relevant conditions.

BACKGROUND: The multimodal properties of mesenchymal stromal cells (MSCs), particularly their ability to modulate immune responses is of high interest in translational research. Pro-inflammatory, hypoxic, and 3D culture priming are promising and often used strategies to improve the immunosuppressive potency of MSCs, but the underlying mechanisms are not well understood. Therefore, the aims of this study were (i) to compare the effects of pro-inflammatory, hypoxic, and 3D culture priming on the in vitro immunosuppressive potential of MSCs, (ii) to assess if immunosuppressive priming effects are temporally preserved under standard and translationally relevant culture conditions, and (iii) to investigate if the three priming strategies engage the same immunosuppressive mechanisms. METHODS: Functional in vitro T cell suppressive potency measurements were conducted to assess the impact of pro-inflammatory, hypoxic, and 3D culture priming on the immunosuppressive potential of human bone marrow-derived MSCs. Primed MSCs were either cultured under standard cell culture conditions or translationally relevant culture conditions, and their transcriptomic adaptations were monitored over time. Next-generation sequencing was performed to assess if different priming strategies activate distinct immunosuppressive mechanisms. RESULTS: (i) Pro-inflammatory, hypoxic, and 3D culture priming induced profound transcriptomic changes in MSCs resulting in a significantly enhanced T cell suppressive potential of pro-inflammatory and 3D culture primed MSCs. (ii) Priming effects rapidly faded under standard cell culture conditions but were partially preserved under translationally relevant conditions. Interestingly, continuous 3D culture priming of MSCs maintained the immunosuppressive potency of MSCs. (iii) Next-generation sequencing revealed that priming strategy-specific differentially expressed genes are involved in the T cell suppressive capacity of MSCs, indicating that different priming strategies engage distinct immunosuppressive mechanisms. CONCLUSION: Priming can be a useful approach to improve the immunosuppressive potency of MSCs. However, future studies involving primed MSCs should carefully consider the significant impact of translationally relevant conditions on the preservation of priming effects. Continuous 3D culture could act as a functionalized formulation, supporting the administration of MSC spheroids for a sustainably improved immunosuppressive potency.

Contact-Heat Evoked Potentials: Insights into Pain Processing in CRPS Type I.

Purpose: The pathophysiological mechanisms underlying the development of chronic pain in complex regional pain syndrome (CRPS) are diverse and involve both peripheral and central changes in pain processing, such as sensitization of the nociceptive system. The aim of this study was to objectively distinguish the specific changes occurring at both peripheral and central levels in nociceptive processing in individuals with chronic CRPS type I. Patients and Methods: Nineteen individuals with chronic CRPS type I and 16 age- and sex-matched healthy controls (HC) were recruited. All individuals underwent a clinical examination and pain assessment in the most painful limb, the contralateral limb, and a pain-free control area to distinguish between peripheral and central mechanisms. Contact-heat evoked potentials (CHEPs) were recorded after heat stimulation of the three different areas and amplitudes and latencies were analyzed. Additionally, quantitative sensory testing (QST) was performed in all three areas. Results: Compared to HC, CHEP amplitudes in CRPS were only increased after stimulation of the painful area (p=0.025), while no increases were observed for the pain-free control area (p=0.14). None of the CHEP latencies were different between the two cohorts (all p>0.23). Furthermore, individuals with CRPS showed higher pain ratings after stimulation of the painful limb compared to their contralateral limb (p=0.013). Lastly, compared to HC, mechanical (p=0.012) and thermal (p=0.046) sensitivity was higher in the painful area of the CRPS cohort. Conclusion: This study provides neurophysiological evidence supporting an intact thermo-nociceptive pathway with signs of peripheral sensitization, such as hyperexcitable primary afferent nociceptors, in individuals with CRPS type I. This is further supported by the observation of mechanical and thermal gain of sensation only in the painful limb. Additionally, the increased CHEP amplitudes might be related to fear-induced alterations of nociceptive processing.

Intervertebral disc microbiome in Modic changes: Lack of result replication underscores the need for a consensus in low-biomass microbiome analysis.

Introduction: The emerging field of the disc microbiome challenges traditional views of disc sterility, which opens new avenues for novel clinical insights. However, the lack of methodological consensus in disc microbiome studies introduces discrepancies. The aims of this study were to (1) compare the disc microbiome of non-Modic (nonMC), Modic type 1 change (MC1), and MC2 discs to findings from prior disc microbiome studies, and (2) investigate if discrepancies to prior studies can be explained with bioinformatic variations. Methods: Sequencing of 16S rRNA in 70 discs (24 nonMC, 25 MC1, and 21 MC2) for microbiome profiling. The experimental setup included buffer contamination controls and was performed under aseptic conditions. Methodology and results were contrasted with previous disc microbiome studies. Critical bioinformatic steps that were different in our best-practice approach and previous disc microbiome studies (taxonomic lineage assignment, prevalence cut-off) were varied and their effect on results were compared. Results: There was limited overlap of results with a previous study on MC disc microbiome. No bacterial genera were shared using the same bioinformatic parameters. Taxonomic lineage assignment using "amplicon sequencing variants" was more sensitive and detected 48 genera compared to 22 with "operational taxonomic units" (previous study). Increasing filter cut-off from 4% to 50% (previous study) reduced genera from 48 to 4 genera. Despite these differences, both studies observed dysbiosis with an increased abundance of gram-negative bacteria in MC discs as well as a lower beta-diversity. Cutibacterium was persistently detected in all groups independent of the bioinformatic approach, emphasizing its prevalence. Conclusion: There is dysbiosis in MC discs. Bioinformatic parameters impact results yet cannot explain the different findings from this and a previous study. Therefore, discrepancies are likely caused by different sample preparations or true biologic differences. Harmonized protocols are required to advance understanding of the disc microbiome and its clinical implications.

Morphological and Quantitative Parametric MRI Follow-up of Cartilage Changes Before and After Intra-articular Injection Therapy in Patients With Mild to Moderate Knee Osteoarthritis: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Intra-articular injections are routinely used for conservative treatment of knee osteoarthritis (OA). The detailed comparative therapeutic effects of these injections on cartilage tissue are still unclear. OBJECTIVE: The aim of this study was to detect and compare knee cartilage changes after intra-articular injection of glucocorticoid, hyaluronic acid, or platelet-rich plasma (PRP) to placebo using quantitative (T2 and T2* mapping) and morphological magnetic resonance imaging parameters in patients with mild or moderate osteoarthritis. MATERIALS AND METHODS: In a double-blinded, placebo-controlled, single-center trial, knees with mild or moderate osteoarthritis (Kellgren-Lawrence grade 1-3) were randomly assigned to an intra-articular injection with 1 of these substances: glucocorticoid, hyaluronic acid, PRP, or placebo. Cartilage degeneration on baseline and follow-up magnetic resonance imaging scans (after 3 and 12 months) was assessed by 2 readers using quantitative T2 and T2* times (milliseconds) and morphological parameters (modified Outerbridge grading, subchondral bone marrow edema, subchondral cysts, osteophytes). RESULTS: One hundred twenty knees (30 knees per treatment group) were analyzed with a median patient age of 60 years (interquartile range, 54.0-68.0 years). Interreader reliability was good for T2 (ICC, 0.76; IQR, 0.68-0.83) and T2* (ICC, 0.83; IQR, 0.76-0.88) measurements. Morphological parameters showed no significant changes between all groups after 3 and 12 months. T2 mapping after 12 months showed the following significant ( P = 0.001-0.03) changes between groups in 6 of 14 compartments: values after PRP injection decreased compared with glucocorticoid in 4 compartments (complete medial femoral condyle and central part of lateral condyle) and compared with placebo in 2 compartments (anterior and central part of medial tibial plateau); values after glucocorticoid injection decreased compared with placebo in 1 compartment (central part of medial tibial plateau). No significant changes were seen for T2 and T2* times after 3 months and T2* times after 12 months. No correlation was found between T2/T2* times and Kellgren-Lawrence grade, age, body mass index, or pain (Spearman ρ, -0.23 to 0.18). CONCLUSIONS: Platelet-rich plasma injection has a positive long-term effect on cartilage quality in the medial femoral compartment compared to glucocorticoid, resulting in significantly improved T2 values after 12 months. For morphological cartilage parameters, injections with glucocorticoid, PRP, or hyaluronic acid showed no better effect in the short or long term compared with placebo.

Imaging-guided subacromial therapeutic injections: prospective study comparing abnormalities on conventional radiography with patient outcomes.

OBJECTIVE: The purpose of this study was to compare abnormalities detected on conventional shoulder radiography with improvement in pain and shoulder function after subacromial injections. SUBJECTS AND METHODS: We conducted a prospective outcomes study including 98 consecutive patients after fluoroscopy-guided subacromial injections who returned outcome questionnaires and who underwent routine shoulder radiography. Numeric pain rating scale (NRS) data were collected before and, along with patient global impression of change (PGIC) data, at 1 week and 1 month after injection. Outcome differences were assessed using the Student t test and Mann-Whitney U test. Logistic regression analysis was done, including radiographic variables compared with the outcome improvement. The odds ratios with 95% CIs were identified for the significant predictors. RESULTS: A significant difference in overall improvement was found depending on the posterior acromial slope. Patients with a slope of more than 36° had significantly lower NRS and PGIC scores at 1 week and 1 month (p < 0.025) compared with those with a slope of 36° or less, with 86.4% of patients with a slope of more than 36° reporting significant improvement at 1 month. This was the only variable linked with improvement in the logistic regression analysis, with an odds ratio of 2.16 (95% CI, 1.11-4.22). Patients with calcific tendinitis had significantly lower NRS scores at both 1 week and 1 month (p = 0.03 and 0.05, respectively) and PGIC scores at 1 week (p = 0.05). CONCLUSION: A posterior acromial slope of more than 36° and the presence of calcific tendinitis on conventional shoulder radiography are associated with better outcomes. Patients with a slope of more than 36° showed the best improvement.

Interrater reliability of clinical tests to evaluate scapulothoracic motion.

BACKGROUND: Decreased scapulothoracic motion has been associated with various pathologies of the shoulder. Reliable and simple assessment methods of scapular mobility are, however lacking. The aim of this study was to evaluate the interrater reliability of four clinical tests to assess scapulothoracic motion in patients with a slightly restricted shoulder flexion. METHODS: A total of nineteen patients with a symptomatic slight restriction of shoulder flexion and twenty asymptomatic subjects were evaluated. The investigation consisted of four palpatory tests to assess scapulothoracic motion. A two-level rating scale (positive, negative) was utilised. Interrater reliability was evaluated using kappa coefficients. RESULTS: We found substantial to almost perfect (Kappa = 0.63-0.4) interrater reliability for the four tests. CONCLUSION: Our study demonstrates that the four mobility tests of the shoulder are a reliable and simple instrument to assess patients with a slightly restricted shoulder flexion. Future studies should be conducted to evaluate the validity of these tests and to establish their clinical usefulness.