Search Results (208)

Background: Endometriosis is a chronic gynecological condition marked by ectopic endometrial-like tissue, leading to inflammation, pain, and infertility. Diagnosis is often delayed by up to 10 years. Identifying non-invasive biomarkers could facilitate earlier detection. MicroRNAs, known for their stability in biological fluids and role in disease processes, have emerged as potential diagnostic tools. This pilot study investigated whether serum miRNA profiling can differentiate endometriosis from other causes of chronic pelvic pain. Methods: Serum samples from 52 patients (36 with laparoscopically confirmed endometriosis and 16 controls) treated for chronic pelvic pain at a University Endometriosis Centre were analyzed. High-throughput miRNA sequencing was performed. Feature selection reduced 4285 miRNAs to the 20 most informative MiRNAs. Machine learning models, including logistic regression, decision tree, random forest, and support vector machine, were trained and evaluated. Results: Among the tested machine learning models, support vector machine achieved the best overall performance (accuracy 0.71, precision 0.80), while logistic regression and random forest showed the highest AUC values (0.84 and 0.81, respectively), indicating strong diagnostic potential of serum miRNA profiling. Conclusions: This study demonstrates the feasibility of using serum miRNA profiling combined with machine learning for the non-invasive classification of endometriosis. The identified miRNA signature shows strong diagnostic potential and could contribute to earlier and more accurate detection of the disease. Full article

Ulcerative colitis (UC) is a chronic inflammatory disease that affects the colon, triggering persistent inflammation and ulceration, resulting in a severe impact on patients’ quality of life. Currently, the standard diagnostic methods for UC include invasive procedures such as colonoscopy and the use of non-specific inflammatory markers like C-reactive protein, which can be inconvenient or painful and lack specificity. This underscores the need for non-invasive and highly specific biomarkers for UC. MicroRNAs (miRNAs) are small non-coding RNAs, typically 22 nucleotides in length, which are well described as gene expression regulators. Several studies have reported their differential expression in various pathological conditions, including UC. Due to their role in gene regulation and stability in biological fluids, miRNAs present a promising opportunity as biomarkers. This systematic review explores the potential use of miRNAs as diagnostic biomarkers to distinguish between active and inactive ulcerative colitis. Following PRISMA guidelines and based on inclusion and exclusion criteria, seven studies, encompassing a total of 514 participants (181 with active UC and 116 with inactive UC), were included. Multiple miRNAs exhibiting differential expression between active and inactive UC were identified. Most notably, miR-21, miR-126, miR-146b-5p, and miR-223 exhibited consistent upregulation in active UC, suggesting their potential as diagnostic biomarkers. Supporting these findings is the fact that these miRNAs are involved in inflammatory pathways, further highlighting their relevance to the pathogenesis of UC. This review emphasizes the need for further validation studies with larger cohorts to confirm the utility of miRNAs as diagnostic tools for UC disease activity differentiation, which could enhance non-invasive disease monitoring and inform therapeutic decision-making. Future research should also evaluate the prognostic potential of these miRNAs for predicting treatment responses and long-term disease outcomes. Full article

Background: Chronic low back pain (CLBP) is the leading cause of disability both within the United States and globally. However, reliable diagnosis and treatment remains limited due to a lack of objective and image-based biomarkers. Modic changes (MCs) are visible vertebral endplate and bone marrow changes in signal intensity seen on MRI. MCs have emerged as promising correlates with degenerative disc disease and CLBP. Methods: This is a non-systematic literature review. Results: This review synthesizes current evidence on the classification, pathophysiology, and imaging of MCs, with a particular focus on their associations with patient-reported outcomes, including pain (Visual Analog Scale), functional status (Oswestry disability index and Roland-Morris Disability Questionnaire), and health-related quality of life (Short Form-36 and EuroQol 5-Dimension 5 Level). MC type 1 and 2 show significant correlations with symptom severity and predict positive response to basi-vertebral nerve (BVN) ablation, a minimally invasive intervention inhibiting the nerves’ ability to transmit pain signals. Conclusions: Across multiple trials, BVN ablation has shown significant sustained improvements in patient-reported outcomes among patients with MC, reinforcing their role as both a diagnostic and therapeutic biomarker. Full article

Background/Objectives: Diagnosis of Persistent Spinal Pain Syndrome Type 2 (PSPS-T2) currently lacks objective biomarkers. Therefore, this retrospective study aimed to investigate differences in glucose metabolism in the axial musculoskeletal system in PSPS-T2 patients by means of [¹⁸F]FDG PET-CT imaging. Methods: Nine PSPS-T2 patients (five females, four males; mean age of 53 ± 4.82 years) and nine age- and gender-matched healthy controls (five females, four males; mean age of 53 ± 3.91 years) were included. For each participant, 24 regions of interest (ROIs) were manually drawn, including areas of the vertebral endplates, the intervertebral discs, and the psoas muscles. For each ROI, the mean standardized uptake values (SUVs) were assessed. Group differences were evaluated using repeated measures ANOVA with Bonferroni-adjusted post-hoc pairwise comparisons. Additionally, Pearson correlation analyses examined associations between SUV_mean values and the Numerical Rating Scale (NRS) pain scores. Results: Results demonstrated significantly higher SUV_mean values in healthy controls compared to PSPS-T2 patients, particularly at the superior endplates of L4 and S1, the intervertebral discs at L4-L5 and L5-S1, and the posterior endplates of L4 and L5. Although PSPS-T2 patients exhibited higher SUV_mean values than controls in the psoas muscle, these differences were not statistically significant. Additionally, no significant correlations were found between SUV_mean values and NRS pain scores, suggesting that metabolic activity alone does not directly reflect pain severity. Conclusions: Despite the limited sample size of this pilot study, the metabolic fingerprint of the axial musculoskeletal system was shown to be distinctly different in PSPS-T2 patients compared to healthy controls. This could lead to an improved understanding of PSPS-T2 pathophysiology and might open new doors for better diagnosis and treatment strategies. Full article

Background: Chronic pain is closely associated with dysregulation of the autonomic nervous system, often reflected by reduced heart rate variability (HRV). While observational studies have demonstrated this association, the extent to which pain interventions modulate HRV and the impact of individual factors on HRV changes remain unclear. Objective: To evaluate the impact of pain interventions on HRV parameters through meta-analysis of randomized controlled trials (RCTs), and to examine whether intervention type and individual factors such as body mass index (BMI) moderate HRV responses. Methods: We conducted a systematic review of 23 RCTs and a meta-analysis of 21 RCTs (1262 subjects) involving patients with acute and chronic pain. HRV outcomes were extracted pre- and post-intervention. Both between-group (active vs. sham/control) and one-group (pre-post within active group) analyses were performed for time-domain indices—standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences (RMSSD), and percentage of successive normal-to-normal intervals > 50 ms (pNN50)—and frequency-domain indices—high-frequency (HF) and low-frequency (LF) components. Meta-regressions tested moderators including BMI, age, and pain phenotype. The protocol was registered in PROSPERO (CRD42023448264). Results: Twenty-three RCTs involving 1262 participants with a wide range of pain conditions were included. Meta-analysis of time-domain HRV parameters showed a trend toward improvement: SDNN (g = 0.435, p = 0.059) approached significance, while RMSSD (g = 0.361, p = 0.099) and pNN50 (g = 0.222, p = 0.548) showed smaller, non-significant effects. Frequency-domain analysis revealed a significant moderate reduction in the LF/HF ratio (g = −0.378, p = 0.003), suggesting a shift toward parasympathetic dominance. HF and LF showed small, non-significant changes. One-group meta-analysis confirmed significant improvements in vagally mediated HRV, with large effects for RMSSD (g = 1.084, p < 0.001) and HF (g = 0.622, p < 0.001), and a moderate effect for SDNN (g = 0.455, p = 0.004). Meta-regression identified BMI as a significant moderator: higher BMI was associated with attenuated improvements in HF and RMSSD and a slight shift toward sympathetic predominance. Conclusions: Pain interventions can significantly modulate autonomic function, as reflected in HRV improvements, particularly in vagally mediated indices. These effects are influenced by patient characteristics such as BMI. HRV may serve as a valuable biomarker for both treatment efficacy and autonomic recovery in pain management. In this context, HRV highlights its role as a biomarker for pain dysregulation and compensatory failure, reflecting shared top-down modulation between nociception and autonomic regulation. Full article

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that predominantly affects synovial joints, leading to inflammation, pain, and progressive joint damage. Despite therapeutic advancements, the molecular basis of established RA remains poorly defined. Methods: In this study, we conducted an untargeted plasma proteomic analysis using two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in samples from RA patients and healthy controls in the discovery phase. Results: Significantly (ANOVA, p ≤ 0.05, fold change > 1.5) differentially abundant proteins (DAPs) were identified. Notably, upregulated proteins included mitochondrial dicarboxylate carrier, hemopexin, and 28S ribosomal protein S18c, while CCDC124, osteocalcin, apolipoproteins A-I and A-IV, and haptoglobin were downregulated. Receiver operating characteristic (ROC) analysis identified CCDC124, osteocalcin, and metallothionein-2 with high diagnostic potential (AUC = 0.98). Proteins with the highest selected frequency were quantitatively verified by multiple reaction monitoring (MRM) analysis in the validation cohort. Bioinformatic analysis using Ingenuity Pathway Analysis (IPA) revealed the underlying molecular pathways and key interaction networks involved STAT1, TNF, and CD40. These central nodes were associated with immune regulation, cell-to-cell signaling, and hematological system development. Conclusions: Our combined proteomic and bioinformatic approaches underscore the involvement of dysregulated immune pathways in RA pathogenesis and highlight potential diagnostic biomarkers. The utility of these markers needs to be evaluated in further studies and in a larger cohort of patients. Full article

Background: Multiple myeloma (MM) is a heterogeneous plasma cell malignancy with non-specific symptoms and disease heterogeneity at clinical and biological levels. This non-specific set of symptoms, including bone pain, anemia, renal failure, hypercalcemia, and neuropathy, can mislead diagnosis as chronic or benign conditions, resulting in a delay in diagnosis. Timely identification is paramount to prevent organ damage and reduce morbidity. Methods: In this review, we present an overview of recent literature concerning the factors leading to the delayed diagnosis of MM and the impact of delayed diagnosis. This includes factors relevant to physicians and systems, diagnostic processes, primary healthcare services, and laboratory and imaging data access and interpretation. Other emerging technologies to diagnose NCIs include AI-based decision support systems and biomarker-focused strategies. Findings: Delayed diagnosis can lead to presentation at advanced disease stages associated with life-threatening complications and shorter progression-free survival. Patients are often seen by many physicians before they are referred to hematology. Understanding of clinical red flags for MM in primary care is inadequate. Our findings indicate that limited access to diagnostic tests, inconsistent follow-up of MGUS/SMM patients, and a lack of interdepartmental coordination delay the diagnostic process. Conclusions: Multimodal tools for early diagnosis of MM. Educational campaigns to raise awareness of the disease, algorithms dedicated to routine care and novel technologies, including AI and big data analytics, and new biomarkers may serve this purpose, as well as genomic approaches to the premalignant MGUS stage. Full article

Chronic pain is a multifactorial and complex condition that significantly affects individuals’ quality of life. The underlying mechanisms of chronic pain involve complex alterations in neural circuits, gene expression, and cellular signaling pathways. Recently, ncRNAs, such as miRNAs, lncRNAs, circRNAs, and siRNAs, have been identified as crucial regulators in the pathophysiology of chronic pain. These ncRNAs modulate gene expression at both the transcriptional and post-transcriptional levels, affecting pain-related pathways like inflammation, neuronal plasticity, and sensory processing. miRNAs have been shown to control genes involved in pain perception and nociceptive signaling, while lncRNAs interact with chromatin remodeling factors and transcription factors to modify pain-related gene expression. CircRNAs act as sponges for miRNAs, thereby influencing pain mechanisms. siRNAs, recognized for their gene-silencing capabilities, also participate in regulating the expression of pain-related genes. This review examines the diverse roles of ncRNAs in chronic pain, emphasizing their potential as biomarkers for pain assessment and as targets for novel therapeutic strategies. A profound understanding of the ncRNA-mediated regulatory networks involved in chronic pain could result in more effective and personalized pain management solutions. Full article

Background and Objectives: Chronic pain (CP), defined as pain persisting for over 3 months, is a significant cause of global disability and affects more than 20% of individuals in Western countries, including Italy. Substantial evidence indicates a higher prevalence of CP among women, who also experience greater sensitivity, increased frequency, and a longer duration of pain. The impact of CP on quality of life, daily functioning, and employment is profound, particularly for women. However, chronic pain research has insufficiently addressed sex and gender differences, contributing to suboptimal and inequitable care. This neglect limits the development of personalized treatment strategies and, when combined with an aging population and women’s longer life expectancy, highlights an increasing societal and economic burden. Materials and Methods: The authors conducted a narrative review of studies examining biological, psychological, or social determinants of sex-related differences in CP perception or treatment. Each thematic area was reviewed by at least two authors, who critically appraised the literature. Their analyses were refined through iterative group discussions to develop concise, evidence-informed recommendations for personalized and equitable pain management. Results: Sex differences in CP arise from a range of factors, including biological mechanisms such as hormonal and genetic influences, psycho-social factors such as depression and anxiety, and socio-economic determinants, such as income and education levels. These factors also affect sex-specific outcomes of analgesic treatments currently available. Identifying these risk factors and tailoring treatment strategies to sex differences can significantly improve CP management. Such a personalized approach is essential for advancing precision medicine in CP management. Even in the absence of molecular or genomic biomarkers, adopting a biopsychosocial model that considers sex and gender differences, symptoms, physiological indicators, medical history, lifestyle, and psychological aspects may substantially enhance patient outcomes. Conclusions: This review provides a comprehensive analysis of sex differences in CP perception, stressing the importance of individualized, interdisciplinary approaches in pain management. Addressing both the biological and psycho-social contributors to pain in men and women is critical for guiding healthcare professionals in implementing precision pain medicine strategies, ultimately fostering more equitable and effective care. Full article

Temporomandibular disorders (TMDs) impact quality of life and present diagnostic and treatment challenges. Biomarkers may serve as an additional tool to support diagnosis and monitor disease progression, offering supplementary information for treatment strategies in specific and selected patients. This systematic review aimed to assess the role of biomarkers in diagnosing TMD and guiding personalized treatment. It also examined key biomarkers linked to chronic temporomandibular joint (TMJ) pain and how therapies affect biomarker levels and clinical outcomes. A comprehensive search was conducted in PubMed, Scopus, and Web of Science to identify observational and interventional studies assessing the role of biomarkers in synovial fluid/tissue, saliva, and blood. The research was registered in PROSPERO, adhered to PRISMA guidelines, and employed Cochrane Risk of Bias tools. To assess the effect, only studies examining biomarker levels were considered. A total of forty-six studies met the inclusion criteria: three randomized controlled trials were rated as having some concerns, as were most of the observational studies. Elevated levels of interleukins (1ß and 6), tumour necrosis factor alpha, and prostaglandin E2 in synovial fluid were correlated with temporomandibular joint (TMJ) inflammation. Increased matrix metalloproteinases (2, 7, and 9) indicated cartilage deterioration, while oxidative stress markers such as malondialdehyde were higher in TMD patients. Treatments including hyaluronic acid, platelet-rich plasma, and low-level laser therapy effectively reduced inflammatory biomarkers and improved symptoms. Biomarkers show potential to contribute to the understanding of pathophysiological mechanisms in TMD and may support future diagnostic and therapeutic strategies for selected patients. After high-quality studies confirm these findings, this approach will enable personalized medicine by tailoring treatments to individual patient profiles, ultimately leading to improved outcomes and quality of life. Full article

The bidirectional relationship between chronic pain and poor sleep are well reported. Disrupted sleep and chronic pain, either alone or in conjunction, are often associated with poor post-surgical outcomes. However, the relationship between peripheral blood biomarkers and chronic pain and sleep disturbances after orthopedic surgery has not been extensively studied. The goal of this observational prospective study was to conduct an analysis on the relationship of blood cytokines and chemokines with chronic pain and sleep outcomes among US service members undergoing orthopedic surgery. Active-duty service members (N = 114) who underwent orthopedic extremity or spinal surgery were recruited, of whom 69 completed pre-surgery and 64 completed 6-week post-surgery surveys and blood draws. Blood cytokine and chemokine analyses were performed using multiplex immunoassays. Non-parametric correlations with blood cytokine and chemokine showed significant associations with both pre- and post-surgical pain scores whereas no significant correlations were observed with sleep disturbance scores. Increased pain intensity 6 weeks after surgery was positively associated with increased hepatocyte growth factor (ρ_s = 0.11; p < 0.05) and negatively correlated with interleukin-2r (ρ_s= −0.42; p < 0.001). This study found that inflammatory biomarkers are associated with pre- and post-surgical pain but not sleep disturbances. Full article

Background/Objectives: Chronic neuropathic ocular pain (NOP) can manifest concurrently with dry eye (DE) symptoms following ocular surgical procedures. Due to its low prevalence, NOP remains an underrecognized and underdiagnosed postoperative complication, leading to suboptimal management. This study evaluated the long-term evolution of symptoms, signs, and tear biomarkers in patients with NOP and DE after corneal refractive surgery (RS). Methods: Patients with chronic NOP and persistent DE-related symptoms after corneal RS were assessed in two visits (V1 and V2), at least two years apart. Symptoms (DE, pain, anxiety, and depression) were measured with specific questionnaires. Clinical examination included a slit-lamp ocular surface evaluation, corneal sensitivity measurement, and subbasal corneal nerve plexus evaluation. Basal tear samples were collected, and a 20-plex cytokine panel and Substance P (SP) were assayed. Results: Twenty-three patients (35.57 ± 8.43 years) were included, with a mean time between visits of 4.83 ± 1.10 years. DE symptoms, measured with the Ocular Surface Disease Index questionnaire, improved at V2 (p < 0.001), along with a reduction in anxiety and depression levels, measured with the Hospital Anxiety and Depression Scale (p = 0.027). Corneal staining also decreased (p < 0.001), while subbasal nerve plexus parameters and corneal sensitivity remained unchanged. Tear analysis revealed increased concentrations of fractalkine/CX3CL1 (p = 0.039), interleukin (IL)-1 receptor antagonist (Ra) (p = 0.025), IL-10 (p = 0.002), and SP (p < 0.001). Conclusions: Symptom improvement may result from better control of underlying pathologies or natural disease progression. However, the increased levels of SP and fractalkine/CX3CL1 suggest sustained neurogenic inflammation, while elevated IL-1Ra and IL-10 indicate a potential compensatory anti-inflammatory response. Full article

Endometriosis, affecting up to 10% of women in their reproductive years, is a chronic and multifactorial disease characterized by the presence of endometrial tissue outside the uterus. Traditionally associated with pain and infertility, recent studies highlight its systemic nature, implicating inflammatory, immunological, and hormonal dysregulation in its pathogenesis. This paper explores the emerging role of microRNAs (miRNAs) in the pathophysiology of endometriosis and its related infertility. Evidence suggests that dysregulation of specific miRNAs influences cellular proliferation, migration, and progesterone resistance, thereby contributing to the development and progression of endometriotic lesions. Additionally, altered miRNA expression profiles hold promise as non-invasive biomarkers for improving diagnostic accuracy and as potential targets for novel therapeutic interventions. Although current diagnostic methods, such as laparoscopy, remain the gold standard, the integration of miRNA-based approaches could reduce reliance on invasive procedures and enhance treatment outcomes. Ultimately, further research—particularly regarding the interplay between endometriosis and infertility—is crucial to fully elucidate these complex mechanisms and foster the development of more effective diagnostic and therapeutic strategies. Full article

Effective postoperative pain management remains a major clinical challenge in spinal surgery, with poorly controlled pain affecting up to 50% of patients and contributing to delayed mobilization, prolonged hospitalization, and risk of chronic postsurgical pain. This review synthesizes current and emerging strategies in postoperative spinal pain management, tracing the evolution from opioid-centric paradigms to individualized, multimodal approaches. Multimodal analgesia (MMA) has become the cornerstone of contemporary care, combining pharmacologic agents, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and gabapentinoids, with regional anesthesia techniques, including erector spinae plane blocks and liposomal bupivacaine. Adjunctive nonpharmacologic modalities like early mobilization, cognitive behavioral therapy, and mindfulness-based interventions further optimize recovery and address the biopsychosocial dimensions of pain. For patients with refractory pain, neuromodulation techniques such as spinal cord and peripheral nerve stimulation offer promising results. Advances in artificial intelligence (AI), biomarker discovery, and nanotechnology are poised to enhance personalized pain protocols through predictive modeling and targeted drug delivery. Enhanced recovery after surgery protocols, which integrate many of these strategies, have been shown to reduce opioid use, hospital length of stay, and complication rates. Nevertheless, variability in implementation and the need for individualized protocols remain key challenges. Future directions include AI-guided analytics, regenerative therapies, and expanded research on long-term functional outcomes. This review provides an evidence-based framework for pain control following spinal surgery, emphasizing integration of multimodal and innovative approaches tailored to diverse patient populations. Full article

Introduction: The monitoring of autonomic nervous balance during childhood remains underexplored. However, heart rate variability (HRV) is widely recognized as a biomarker of health risk across the lifespan. Juvenile idiopathic arthritis (JIA), a group of chronic inflammatory joint disorders, is associated with persistent inflammation and pain, both of which contribute to increased cardiovascular risk, commonly linked to reduced HRV. Among HRV parameters, very-low frequency (VLF) components have been associated with physiological recovery processes. This study aimed to assess HRV during sleep in patients with JIA. Methods: We studied 10 patients with JIA and 10 age-, gender-, and Tanner stage-matched healthy controls. All participants underwent polysomnographic monitoring following an adaptation night in the sleep laboratory. HRV was analyzed using standard time and frequency domain measures over 5 min epochs across all sleep stages. Frequency components were classified into low- and high-frequency bands, and time domain measures included the standard deviation of the beat-to-beat intervals. Group differences in HRV parameters were assessed using nonparametric tests for independent samples, with a significance level set at p < 0.05. Results: JIA exhibited greater sleep disruption than controls, including reduced NREM sleep, longer total sleep time, and increased wake time after sleep onset. HRV analyses in both time and frequency domains revealed significant differences between groups across all stages of sleep. In JIA patients, the standard deviation of the normal-to-normal interval during slow wave sleep (SWS) and total power across all sleep stages (p < 0.05) was reduced. In JIA patients, the standard deviation of the normal-to-normal interval during slow wave sleep and total power across all sleep stages were significantly reduced (p < 0.05). VLF power was also significantly lower in JIA patients across all sleep stages (p = 0.002), with pronounced reductions during N2 and SWS (p = 0.03 and p = 0.02, respectively). A group effect was observed for total power across all stages, mirroring the VLF findings. Additionally, group differences were detected in LF/HF ratio analyses, although values during N2, SWS, and REM sleep did not differ significantly between groups. Notably, the number of affected joints showed a moderate positive correlation with the parasympathetic HRV parameter. Conclusions: Patients with JIA exhibited sleep disruption and alterations in cardiovascular autonomic functioning during sleep. Reduced HRV across all sleep stages in these patients suggests underlying autonomic nervous dysfunction. Addressing sleep disturbances in patients with chronic pain may serve as an effective strategy for managing their cardiovascular risk. Full article