Purpose:Knee osteoarthritis is one of the leading causes of chronic musculoskeletal pain and disability worldwide. Although intra-articular ozone therapy has demonstrated analgesic effects, the optimal concentration for maximizing pain relief while preserving functional improvement remains uncertain. Our aim is to determine whether different low-dose ozone protocols differ in their ability to reduce pain and improve functional performance in patients with knee osteoarthritis. Patients and Methods:This retrospective comparative study included 45 patients aged 40-80 years with Kellgren-Lawrence grade II-III knee osteoarthritis. Patients were retrospectively classified into three groups according to the ozone protocol documented in their medical records: 1 μg/mL, 5 μg/mL, and 10 μg/mL, with 15 patients in each group. All patients received intra-articular ozone injections once weekly for 3 consecutive weeks. Outcomes were assessed at baseline and at week 4 using the Visual Analogue Scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the 2-minute walking test. Results:The study included 45 patients, 7 men and 38 women, with a mean age of 59.62 ± 8.08 years. VAS, WOMAC pain, WOMAC physical function, and WOMAC total scores improved significantly in all three groups after treatment. WOMAC stiffness scores improved numerically in all groups but reached statistical significance only in the 5 μg/mL group. No significant between-group differences were found for changes in pain, stiffness, physical function, or total scores. The increase in 2-minute walking test distance was significantly greater in the 1 μg/mL group than in the 10 μg/mL group. No adverse events were documented in any group. Conclusion:Intra-articular ozone therapy was associated with short-term improvements in pain and functional outcomes in patients with knee osteoarthritis, with generally comparable results across the ozone concentrations evaluated. Because of the retrospective design, causal conclusions cannot be drawn, and the difference favoring the lowest concentration in walking distance should be considered exploratory. Prospective studies with larger sample sizes and longer follow-up are needed to confirm these findings.
Introduction:The optimal timing of paravertebral block (PVB) for metabolic and bariatric surgery (MBS) remains uncertain. Drawing on the concept of preemptive analgesia-which suggests that blocking nociceptive signals before surgical stimulus may limit central sensitization-we designed this study to test whether a preoperative PVB reduces 24-hour opioid consumption more effectively than a postoperative PVB in patients undergoing laparoscopic sleeve gastrectomy (LSG). Methods:This single-center retrospective cohort study enrolled patients aged ≥18 years undergoing LSG with bilateral T8 PVB between January and October 2025. Patients were categorized into Pre (PVB before anesthesia induction) and Post (PVB after surgery) groups. The primary outcome was 24-hour postoperative opioid consumption (morphine milligram equivalents, MME). Secondary outcomes included time to first rescue analgesia, rescue analgesia requirement, postoperative nausea and vomiting (PONV), time to first ambulation, and length of hospital stay. Propensity score matching (PSM, 1:3 nearest-neighbor matching with a caliper width of 0.2) was performed to control for confounders. Results:After PSM, 233 patients were analyzed (Pre, n=168; Post, n=65). Median 24-hour MME consumption was 104.1 (IQR 64.8-147.3) in the Pre group and 91.2 (IQR 50.4-158.4) in the Post group (P=0.425). No significant differences were observed in any secondary outcomes, including time to first rescue analgesia (3h vs 4h, P=0.182), PONV incidence (70.2% vs 73.8%, P=0.585), time to first ambulation (2.5h vs 2.5h, P=0.681), or length of hospital stay (3 vs 4 days, P=0.865). Conclusion:In patients undergoing LSG within a multimodal analgesic protocol, preoperative PVB was not associated with reduced 24-hour opioid consumption or improved early recovery outcomes compared to postoperative PVB in this retrospective cohort. These findings suggest that PVB timing may be guided by logistical considerations without compromising analgesic efficacy, but prospective studies are needed to confirm this observation.
Introduction:Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of neurotoxic chemotherapy agents. Despite its substantial global burden, the prevalence of chronic CIPN (persisting for ≥3 months after completion of chemotherapy) remains uncertain. We aimed to estimate the global prevalence of chronic CIPN and assess variations based on chemotherapy regimen, cancer type, geographic region, and human development index (HDI). Methods:A systematic search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus was conducted from database inception to May 2025. A random-effects model with Freeman-Tukey transformation was used for meta-analysis. The primary outcome was the global prevalence of chronic CIPN. Subgroup analysis explored prevalence by time since chemotherapy completion, geographic region, chemotherapy regimen, cancer type, and study design. Results:A total of 197 studies from 36 countries (72,794 patients who received chemotherapy, 26,258 with chronic CIPN) were included. The pooled global prevalence of chronic CIPN was 44.50% (95% CI 40.77-48.25). Subgroup analyses revealed significant variation by geographic region, chemotherapy class, and cancer type. Chronic CIPN prevalence was 54.37% (95% CI 48.24-60.45) at 3-12 months post-chemotherapy, 37.12% (95% CI 30.15-44.26) at 12-24 months post-chemotherapy, and 40.36% (95% CI 34.72-46.08) at ≥24 months post-chemotherapy. Conclusion:Chronic CIPN affects a substantial proportion of cancer survivors, with prevalence influenced by time since completion of chemotherapy, geographic region, chemotherapy type, and cancer type. These findings highlight the need for targeted surveillance, prevention, and management, particularly for high-risk populations.
Haipeng Xu,1,* Yuqian Li,2,* Xinlei Xu,2 Haohao Ni,2 Yunxing Xie11Department of Tuina, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People’s Republic of China; 2The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunxing Xie, Email 19817189161@163.comPurpose: To evaluate prediction models for acute postoperative pain (AOPP) and chronic postsurgical pain (CPSP) after cancer surgery, prioritizing pain phenotype and cancer type.Patients and Methods: Four databases were searched through February 2026. Risk of bias was assessed with PROBAST. AUCs were synthesized on the logit scale using multilevel random-effects models with estimates nested within studies and CR2/Satterthwaite cluster-robust inference. AOPP and CPSP were analyzed separately; cancer-specific estimates were nested within each phenotype, and mixed-pain estimates were secondary. Bivariate random-effects models synthesized sensitivity, specificity, and SROC curves.Results: Twenty-nine studies reported 53 models. For AOPP, pooled AUCs were 0.83 (95% CI 0.76– 0.88; 95% prediction interval [PI] 0.54– 0.95) in training and 0.80 (0.76– 0.83; PI 0.66– 0.89) in validation. For CPSP, corresponding AUCs were 0.79 (0.75– 0.83; PI 0.62– 0.90) and 0.75 (0.70– 0.80; PI 0.50– 0.91). Validation sensitivity/specificity were 0.75/0.80 for AOPP and 0.72/0.72 for CPSP. In cancer-specific validation analyses, AOPP gastrointestinal-cancer models yielded AUC 0.80; CPSP estimates were 0.72 for breast, 0.82 for lung, and 0.80 for other cancers, although the lung estimate included only three studies. Heterogeneity remained substantial. Eight studies were at low risk of bias, seven reported external validation, and calibration parameters were insufficient for pooling.Conclusion: Current models show moderate average discrimination, but wide prediction intervals, high risk of bias, sparse independent validation, and incomplete calibration reporting preclude routine use. AOPP research should prioritize early perioperative prediction and actionable analgesic thresholds; CPSP research requires standardized long-term outcomes and multicenter external validation.Keywords: postoperative pain, cancer surgery, clinical prediction model, machine learning, meta-analysis
Jie Zhuang,1,2,* Dorota Duhova,1,2,* Yimeng Xu,1 Zekai Hu,3 Jinxiang Wang,2 Lifeng Qian,4 Lei Fang1,21Department of Rehabilitation Medicine, the second Rehabilitation Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3School of Meidicine, Shanghai University, Shanghai, People’s Republic of China; 4Department of Rehabilitation Medicine, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lifeng Qian, Department of Rehabilitation Medicine, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, 314000, People’s Republic of China, Email cxqianlifeng@126.com Lei Fang, School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China, Email fanglei586@126.comAbstract: Peripheral neuropathic pain (PNP) arises from lesions or diseases of the somatosensory system and remains difficult to treat because peripheral nerve injury is coupled to spinal, thalamic, cortical and affective network changes. Repetitive transcranial magnetic stimulation (rTMS) can engage cortical pain-modulation circuits without implantation or systemic drug exposure, but the field needs a clearer account of which peripheral neuropathic phenotypes, targets and trial designs can convert transient neuromodulation into clinically durable benefit. This narrative, non-systematic review synthesizes randomized trials, systematic reviews, consensus guidance and mechanistic studies through June 2026. The most defensible clinical signal is high-frequency stimulation of the primary motor cortex (M1) contralateral to the painful region. A 2026 meta-analysis assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework included nine randomized sham-controlled trials and 435 patients, and reported reduced pain intensity after rTMS (SMD, − 1.11; 95% CI, − 1.72 to − 0.49). A separate 2026 pathology-stratified review found that postherpetic neuralgia (PHN) had the most consistent phenotype-specific evidence, whereas diabetic neuropathy (DNP), radiculopathy, brachial plexus injury and other peripheral neuropathies remained less certain. We propose an aetiology-stratified translational framework that separates three decisions often conflated in earlier reviews: confirmation of PNP, selection of cortical target and stimulation schedule, and documentation of multidomain response. At present, rTMS should be investigated as an adjunct to, rather than a replacement for, guideline-supported pharmacotherapy. Future studies should pre-specify sensory phenotype, mood and sleep status, target localization, maintenance schedules and responder definitions so that the feasibility and value of a phenotype-stratified rTMS framework can be tested reproducibly rather than assumed from short-term analgesic effects.Keywords: postherpetic neuralgia, diabetic neuropathy, motor cortex stimulation, cortical plasticity, neuromodulation, phenotype stratification
Purpose:To evaluate the feasibility, safety, and preliminary clinical effect of ultrasound-guided acupotomy (UA) compared with conventional physical therapy (CPT) in patients with degenerative lumbar spinal stenosis (LSS). Patients and Methods:This single-center, pilot randomized controlled trial included 50 participants with degenerative LSS, randomized in a 1:1 ratio to receive either UA or CPT (transcutaneous electrical nerve stimulation and microwave diathermy). Both groups underwent eight treatment sessions over 4 weeks. Feasibility was assessed through recruitment, attrition rates, and protocol adherence, while safety was monitored through adverse events (AEs). Clinical outcomes, including the Visual Analog Scale (VAS), Zurich Claudication Questionnaire (ZCQ), Oswestry Disability Index (ODI), maximum walking distance, and EuroQol 5-Dimension (EQ-5D), were measured at baseline and at weeks 5, 8, and 12. Results:The attrition rate was 8.0% (UA: 0% [n=0] vs CPT: 16.0% [n=4]), and protocol adherence was 98.3% (UA: 100% [200/200 sessions] vs CPT: 96.5% [193/200 sessions]). No serious intervention-related AEs, specifically iatrogenic neural or vascular injuries, occurred. Minor AEs in the UA group were mild and resolved spontaneously. At follow-up assessments, the UA group exhibited statistically significantly greater improvements in VAS, ZCQ, and EQ-VAS scores compared to the CPT group (p < 0.05). Significant intergroup differences in ODI and EQ-5D were observed only at weeks 8 and 12, respectively. Regarding VAS scores, improvements in the UA group were sustained over time, whereas the CPT group showed a gradual decline in therapeutic effects. Conclusion:UA demonstrated feasibility, acceptable short-term procedural safety, and tolerability for degenerative LSS, suggesting potential short-term benefits in pain relief and functional recovery compared with CPT. These exploratory results warrant future large-scale confirmatory clinical trials.
Fibromyalgia (FM), a chronic centralized pain syndrome, has been associated with lower urinary tract pain and lower urinary tract symptoms (LUTS) in women, but quantitative evidence remains limited. We searched PubMed/MEDLINE, Embase, Web of Science Core Collection, and CINAHL from January 1990 to December 2025 for observational studies. Fourteen studies involving 17,139 women were included. Random-effects meta-analysis showed increased odds of lower urinary tract pain (OR = 2.92, 95% CI: 1.41-6.06) and lower urinary tract symptoms (OR = 2.83, 95% CI: 1.98-4.03), but the certainty of evidence was very low. For lower urinary tract pain, the association was concentrated in studies using validated interstitial cystitis/painful bladder syndrome definitions; the clinician-based FM subgroup yielded a more conservative estimate (OR = 1.45, 95% CI: 1.15-1.83), whereas the larger self-reported estimate (OR = 5.84, 95% CI: 2.16-15.79) may have inflated the overall pooled estimate. The overall LUTS association appeared to be driven predominantly by urgency-related storage symptoms, including overactive bladder (OR = 2.65, 95% CI: 1.88-3.74) and urge urinary incontinence (OR = 2.95, 95% CI: 1.05-8.28); no significant association was found for stress urinary incontinence (OR = 1.00, 95% CI: 0.63-1.59). Heterogeneity was substantial for both primary outcomes (I 2 = 79.07% and 79.05%). Outlier exclusion reduced the lower urinary tract pain OR to 1.66, while LUTS heterogeneity remained substantial (I 2 = 73.50%). These findings are preliminary and hypothesis-generating and require confirmation in prospective studies with standardized outcome assessment.
Xinyi Hu, Lin HuangThe Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of ChinaCorrespondence: Xinyi Hu, The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China, Email hxy17858655767@163.com
Shuai Hou,1,2 Ruizhu Zhou,2,3 Liuxuan He,2 Mengling Cheng,4 Xiaolu Fan51Department of Rehabilitation, Xianning Central Hospital, Xianning, Hubei, People’s Republic of China; 2School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 3Department of Cosmetic Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of China; 4School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning, Hubei, People’s Republic of China; 5Department of Rehabilitation, The Third People’s Hospital of Hubei Province, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Xiaolu Fan, Department of Rehabilitation, The Third People’s Hospital of Hubei Province, Wuhan, Hubei, People’s Republic of China, Email 15971460262@163.comObjective: Inflammatory and neuropathic pain arise from different peripheral insults but share nociceptive and affective features. Whether they recruit common or model-specific brain-wide activation patterns remains unclear. We compared regional neuronal activation and interregional co-activation in mouse models of these pain states.Methods: Inflammatory pain was induced using complete Freund’s adjuvant (CFA), whereas neuropathic pain was induced by spared nerve injury (SNI). Nociceptive, anxiety-like, and depression-like behaviors were assessed. Recent neuronal activation was quantified by c-Fos immunohistochemistry across 50 subregions within seven major brain divisions. Images were registered to the Allen Mouse Brain Atlas. Hierarchical clustering and interregional c-Fos covariance analysis were used to compare activation patterns and identify candidate network hubs.Results: Both models developed persistent nociceptive hypersensitivity and anxiety-like behavior, without detectable depression-like behavior. CFA increased c-Fos expression in 28 regions and SNI in 34 regions, with 20 regions commonly activated across both models. These shared regions encompassed sensory, affective, and motivational systems. The CFA co-activation network showed relative prominence of thalamic and hypothalamic hubs, including the paraventricular thalamus and dorsomedial hypothalamus. In contrast, SNI exhibited a more distributed sensory and corticolimbic hub profile involving the primary somatosensory cortex, secondary motor cortex, central amygdala, and hippocampal CA3. Model-associated activation was also detected in comparatively understudied regions, including the dorsal endopiriform, lateral septal, and basomedial amygdalar nuclei.Conclusion: CFA and SNI were associated with overlapping regional recruitment but differently organized brain-wide c-Fos co-activation patterns. Although these descriptive patterns do not establish directed connectivity or causal circuit function, they identify candidate regions and network organizations for mechanistic studies of chronic pain.Keywords: inflammatory pain, neuropathic pain, activation patterns, brain networks
Purpose:MEST (Muscle Enhancement and Support Therapy) is a device for intramuscular placement of bidirectional barbed polydioxanone filaments. Placement of these filaments into the vastus medialis obliquus has been reported to reduce knee pain and improve quadriceps function in patients with knee osteoarthritis. However, clinical evidence remains limited and is based primarily on a small number of controlled trials in selected populations. This study evaluated the real-world clinical outcomes and safety of the MEST procedure across Kellgren-Lawrence (KL) grades I-IV. Patients and Methods:In this retrospective study, 62 patients with knee osteoarthritis who underwent the MEST procedure between March 2025 and February 2026 were analyzed. Pain intensity, functional outcomes, patient-reported overall improvement, effusion grade, and adverse events were assessed at 4, 8, and 12 weeks. The primary outcome was the change in numeric rating scale (NRS) pain score from baseline to 8 weeks. Factors associated with treatment response, defined as ≥2-point NRS reduction at 8 weeks, were also evaluated by logistic regression. Results:NRS scores decreased from 5.8 ± 1.7 at baseline to 2.5 ± 2.4 at 8 weeks (Padj < 0.001), and 50 patients (80.6%) achieved a ≥2-point reduction. At 8 weeks, walking and stair climbing improved in 54 (87.1%) and 38 patients (61.3%), respectively, and 55 patients (88.7%) rated the procedure as effective or very effective. In multivariable analysis, moderate-to-severe baseline effusion was associated with a lower response likelihood (odds ratio, 0.22; 95% confidence interval, 0.05-0.94; P = 0.041). No serious adverse events occurred. Conclusion:The MEST procedure was associated with clinically meaningful pain reduction and favorable patient-reported outcomes across KL grades I-IV, with no serious adverse events. In an exploratory analysis, moderate-to-severe baseline effusion grade was associated with a lower likelihood of response, suggesting that baseline effusion warrants further investigation as a potential marker of treatment response.
Objective:To identify the core acupoint prescription and Kellgren-Lawrence (K-L) grade-dependent compatibility patterns of acupuncture for KOA through complex network analysis, and to predict the potential molecular mechanisms underlying the core prescription via network pharmacology. Methods:Literature was retrieved from PubMed, EMbase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and SinoMed (inception to September 3, 2025). Frequency, association rule, complex network, and K-L grade subgroup analyses were applied. Potential targets of the core prescription were identified via network pharmacology and intersected with disease targets from OMIM, Therapeutic Target, GeneCards, and DrugBank. A protein-protein interaction (PPI) network was constructed, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential molecular mechanisms. Results:We included 522 studies, yielding 582 prescriptions involving 123 acupoints. The core prescription comprised 24 acupoints, including Dubi (ST35), Neixiyan (EX-LE4), Liangqiu (ST34), Xuehai (SP10), Zusanli (ST36), Yanglingquan (GB34), Yinlingquan (SP9), among others. K-L subgroup analysis revealed ST35, GB34, SP9, and SP10 as universal core acupoints. The mild-to-moderate subgroup mainly used local acupoints, while the moderate-to-severe subgroup centered on ST35, with increased distal acupoint usage and higher degree values. Network pharmacology analysis identified 77 overlapping targets. Core targets included tumor necrosis factor (TNF), interleukin 6 (IL6), interleukin 1 beta (IL1B), tumor protein p53 (TP53), matrix metallopeptidase 9 (MMP9), signal transducer and activator of transcription 3 (STAT3), transforming growth factor beta 1 (TGFB1), caspase 3 (CASP3), and B-cell lymphoma 2 (BCL2), which were enriched in inflammation and immunity, cartilage metabolism, and tissue repair pathways. Conclusion:The core acupoint prescription for KOA features local acupoints combined with distal ones, exhibiting distinct patterns across K-L grades. Our computational findings suggest that core acupoints may potentially delay knee joint degeneration by synergistically regulating inflammation, cartilage metabolism, apoptosis, and tissue repair, although these predictions require experimental validation. These findings provide preliminary evidence and a theoretical basis for standardized clinical point selection and further mechanistic research.
Purpose:Black communities face high rates of unmanaged pain due to anti-Black racism in the healthcare system. However, a gap currently exists in the understanding of how anti-Black racism impacts pain management conversations (ie where a pain management plan is discussed with a healthcare professional) with youth in Canada. The purpose of this study was to gain a rich understanding of the experiences of anti-Black racism in a group of Black youth and their caregivers who had pain management conversations with healthcare professionals. Patients and Methods:A qualitative narrative inquiry study, an approach well-suited to centering participant voices, was conducted through interviews with five Black caregiver-youth dyads (youth 12-18 years, M = 14.5 years; caregivers M = 46.8 years; ten participants total) using open-ended questions and prompts to explore how anti-Black racism impacted youths' pain management experiences. Caregiver accounts were used to further contextualize the youths' narrated experiences. Data were analyzed through thematic narrative analysis to identify common themes in their stories of pain management conversations. Results:Two overarching themes were generated from the interviews: "The Healthcare System Rendering Black Youth as Invisible" and "Healthcare Professionals Dismissing Black Youth". The first theme captured how Black youth and their caregivers had often felt ignored within healthcare settings, particularly through adultification and the normalization of inequitable pain care. The second theme reflected how participants had been emotionally invalidated, overlooked, and felt forced to advocate for themselves or their youth due to inadequate support and communication from healthcare providers and intergenerational experiences of anti-Black racism within health contexts. Conclusion:These findings provide nuanced insights into the pain management experiences of a group of Black youth and caregivers, centering their voices and lived realities.
Purpose:To report the short-term outcomes of lumbar sympathetic radiofrequency ablation (LSRA) in patients with peripheral arterial disease (PAD) who were refractory to conservative management or unsuitable for revascularization, and to generate preliminary evidence to inform the design of future prospective investigations. Patients and Methods:A retrospective, self-controlled analysis was conducted on consecutive patients with PAD who underwent LSRA at our institution between July 2025 and March 2026. Pain intensity (Faces Pain Scale-Revised, FPS-R), toe skin temperature, and perfusion index (PI) were measured preoperatively and on postoperative day 7. Complications were documented. Normality of between-condition differences was assessed using the Shapiro-Wilk test. Wilcoxon signed-rank tests were used as the primary analysis for non-normally distributed variables, with paired t-tests as sensitivity analysis. Effect sizes (Cohen's d for paired samples) with 95% confidence intervals were calculated. Results:Sixteen patients were included, comprising 14 cases of atherosclerotic occlusive disease and 2 cases of thromboangiitis obliterans. At postoperative day 7, FPS-R scores decreased from 5.88±1.36 to 3.75±1.24 (V=91, p=0.001; Hedges' g=1.48, 95% CI 0.77-2.17, large effect), toe skin temperature increased from 35.06±1.04 °C to 35.95±0.78 °C (t=-5.06, p=0.00014; Hedges' g=-1.20, 95% CI -1.82 to -0.56, large effect), and PI increased from 2.92±1.71 to 3.94±1.71 (V=0, p=0.0005; Hedges' g=-2.02, 95% CI -2.87 to -1.16, large effect). One patient (6.25%) experienced lumbar artery injury requiring embolization, with successful resolution; no other major complications were observed. Conclusion:In this preliminary, short-term, retrospective pilot study of carefully selected PAD patients, LSRA was associated with improvements in pain, toe skin temperature, and perfusion index at postoperative day 7. These findings require validation in prospective, controlled trials with longer follow-up.
Purpose:Low back pain (LBP) is a heterogeneous pain condition with a measurable genetic contribution, but the genes, brain cell types, and spatial tissue contexts through which inherited risk is expressed remain unclear. We aimed to define cell-type-specific and spatially contextualized genetic mechanisms underlying LBP. Methods:FinnGen R12 LBP GWAS summary statistics (42,521 cases and 353,224 controls) were integrated with brain single-nuclei eQTL data across eight major brain cell classes. We evaluated genome-wide polygenic signal using LDSC, prioritized genes using MAGMA and PoPS, and performed brain cell-type-specific eQTL-anchored Mendelian randomization, primarily based on single-instrument Wald ratio estimates, followed by Bayesian colocalization. Spatial genetic mapping was conducted using gsMap in an E16.5 murine embryonic atlas and two adult human lumbar spinal cord Visium sections. Selected candidates were assessed by RT-qPCR in neuronal-like and astroglial-like inflammatory cell models. Results:LDSC supported interpretable polygenic signal for LBP. MAGMA and PoPS showed partial gene-level convergence, with TCF4 and TMEFF2 supported by both approaches. Across 1641 tested gene-cell type exposures, significant eQTL-anchored MR associations were concentrated in excitatory neurons, oligodendrocytes, inhibitory neurons, and astrocytes. Integrated eQTL-anchored MR, colocalization, and gene-prioritization evidence highlighted CLEC18A, QPRT, and GMPPB as higher-priority non-MHC candidates with moderate, but not strong, colocalization support. gsMap localized LBP-associated enrichment to neuroaxis-related embryonic regions, including brain, spinal cord, sympathetic nerve, and dorsal root ganglion, and to neuronal-like niches in adult lumbar spinal cord. RT-qPCR showed model-dependent expression changes, with QPRT and LGI4 preferentially responsive in neuronal-like SH-SY5Y cells and GMPPB and DPYSL5 responsive in astroglial-like U251 cells. Conclusion:These findings support neuronal and glial regulatory programs as plausible contributors to LBP genetic susceptibility and highlight CLEC18A, QPRT, and GMPPB as higher-priority non-MHC candidates with moderate colocalization support. The results provide a spatially contextualized framework for candidate prioritization in LBP, while emphasizing the need for larger cell-type-specific eQTL resources and functional validation before therapeutic or mechanistic conclusions can be drawn.
Ying Shen,1,* Rui Chen,1,* Lijiang Lv1,21The Third School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Research Institute of Tuina (Spinal Disease), Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lijiang Lv, The Third School of Clinical Medicine, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang, People’s Republic of China, Email lvlijiang0288@163.com
