P < .001). High Age-CCI (Age-CCI ≥ 7) compared with the low Age-CCI (Age-CCI < 7) showed a 36% increase of mortality and readmission rates . The RCS curve analysis showed a continuous linear relationship between Age-CCI and the composite outcome risk (P for non-linearity = .671). The Kaplan–Meier survival analysis showed that patients with Age-CCI ≥ 7 had a poorer prognosis than those with Age-CCI < 7 (log-rank P < .001). Subgroup analyses showed the results remained stable. Age-CCI is independently associated with all-cause mortality and readmission in patients treated with TAVR, which may help clinicians risk-stratify patients and offer an opportunity to improve patient outcomes.Patients undergoing transcatheter aortic valve replacement (TAVR) have a high comorbid burden. Our objective was to assess the association between the age-adjusted Charlson comorbidity index (Age-CCI) and mortality and readmission rates within 1-year post-TAVR. Data were extracted from the Medical Information Mart for Intensive Care IV database (MIMIC-IV version 2.0). The primary endpoint was a composite outcome of all-cause mortality or readmission within 1-year after TAVR. To examine the associations of Age-CCI with outcomes, we used multivariable Cox proportional hazards regression, restricted cubic spline (RCS), and Kaplan–Meier curves. A total of 785 patients  with a median age of 84.0 years were assessed. More than half of our patients had an Age-CCI ≥ 7. After adjustment for potential confounders, we found that a 1 unit increase in Age-CCI was associated with a 10% increase in mortality and readmission rates after TAVR (HR = 1.10, 95% CI: 1.04–1.17,  Despite numerous improvements in TAVR procedures and expert experience, the rates of death or readmission after TAVR remain very high, with 1-year mortality rates of approximately 24% in high-risk patients and readmission rates ranging from 18.4% to 59.7%.–8 Moreover, the economic burden of health care is significantly increased by readmission and mortality.,10 Identifying high-risk populations is critical to making timely individualized interventions and maintaining TAVR cost-effective.With the rapid advancement of device technology, transcatheter aortic valve replacement (TAVR) is now indicated for low- and intermediate-risk patients, and it is increasingly becoming the main method for treating patients with aortic stenosis.,12 Therefore, cardiac teams need to assess chronic disease burden in the decision-making process for TAVR eligibility. The Charlson Comorbidity Index (CCI) is an indicator that quantifies comorbidity burden by aggregating individually weighted scores for 19 comorbidities. The Age-adjusted Charlson comorbidity index (Age-CCI), which incorporates age and comorbidities, outperformed CCI in terms of discriminating and predictive accuracy.,14The majority of TAVR patients have a significant burden of comorbidities. Furthermore, approximately half of the causes of death or readmission following TAVR are non-cardiac and related to baseline comorbidities. However, Hiltrop et al found no difference in CCI scores between survivors and deceased populations at 2 years follow-up post-TAVR. Another study also found that the CCI score was not independently associated with a higher risk of 30-day death but can be useful in addition to Logistic Euro Score (LES) and Society of Thoracic Surgeons (STS) risk models in informing decision making on the selection of patients for TAVR. Furthermore, it is unknown whether Age-CCI is associated with 1-year readmission rate in patients who underwent TAVR. Therefore, the goal of this study was to evaluate the burden of comorbidities in patients receiving TAVR, as well as the association of Age-CCI with adverse outcomes within 1-year after TAVR.The effect of CCI on outcomes following TAVR is still controversial. Higher CCI was independently linked to higher mortality for up to 6 years after TAVR in 1 study. We passed the exam named “Protecting Human Research Participants” and obtain the seniority to access these database (Record ID:48851221). The study complied with the principles of the Declaration of Helsinki. The institutional review boards of the Massachusetts Institute of Technology and Beth Israel Deaconess Medical Center approved the study, and informed consents were exempted due to all patients’ data were anonymized before the data were obtained. We present this article by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.The Medical Information Mart for Intensive Care IV (MIMIC-IV version 2.0) provided the information used in this study. The database was publicly available of patients hospitalized at the Beth Israel Deaconess Medical Center between 2008 and 2019.We identified patients who underwent endovascular TAVR using International Classification of Diseases, Tenth Revision, Clinical Modification procedural codes  and ICD-9-CM procedural codes of 35.05. If patients underwent repeat TAVR, only patients with the first procedure were included.Age, gender, previous cardiac surgery, biomarkers, and associated comorbidities were extracted. Identification of disease components in CCI based on ICD-9 and ICD-10 diagnosis codes included myocardial infarction, congestive heart disease, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatic disease, peptic ulcer disease, liver disease, diabetes with or without complications, paraplegia, renal disease, malignant tumors, and Acquired Immune Deficiency Syndrome (AIDS). Additionally, we analyzed conditions such as coronary artery disease, hypertension, atrial fibrillation/flutter (AF), pulmonary hypertension, anemia, and obesity that were not part of the CCI. Other variables were extracted including previous cardiac procedures, in-hospital procedures such as percutaneous coronary intervention, previous coronary artery bypass grafting, in-hospital complications, such as peri-valve leakage, conversion to surgical aortic valve replacement, acute kidney injury (AKI), blood transfusion, permanent pacemaker placement, transient ischemic attack/stroke, cardiogenic shock, and cardiac arrest.http://links.lww.com/MD/K823). The age-based scoring was 0 points for ages under 40, 1 point for each additional 10 years between 40 and 70, and 4 points for ages 70 and older. The final score is the sum of the comorbidity score and the age group score that corresponds. The burden of comorbidities increases with the score. This score divided patients into 2 categories based on their median: low (Age-CCI < 7) and high Age-CCI (Age-CCI ≥ 7).The calculated Age-CCI for each patient was used to measure the comorbidity burden. A total of 19 disease components of CCI were identified. Score weights for diseases used the original weights from Charlson  depending on their distribution, as determined by the Shapiro–Wilk test, and were compared using t tests or the Mann–Whitney U test as appropriate. Chi-square tests or the Fisher exact test were used to compare categorical data reported as numbers and percentages. Missing data were imputed with the corresponding median or mean value.P < .05 in univariable analysis were selected as adjustments that were recorded in the dataset and were not part of the CCI, nor were they in the causal chain between CCI and outcome. Model 1: unadjusted. Model 2: adjusted for age and gender. Model 3 adjusted for Model 2 plus red blood cell, mean corpuscular hemoglobin concentration, red blood cell distribution width, creatinine, chloride, hypertension, and atrial fibrillation/flutter. The variance inflation factor (VIF) was applied to examine the collinearity of the variables (acceptable collinearity VIF ≤ 5).A multivariable Cox proportional hazards model was used to assess the independent association between Age-CCI and the primary outcome, after testing the proportional hazards assumption. Results were presented as hazard ratios (HR) with 95% confidence intervals (CI). Variables with Kaplan–Meier survival curves were generated, and the log-rank test was utilized to compare the groups. A restricted cubic spline (RCS) was used to examine the functional relationship between Age-CCI and outcome. Additionally, we conducted subgroup analyses by age , gender, anemia , hypertension, atrial fibrillation/flutter, and renal disease. The continuous variable was transformed into a categorical variable using the clinical cut points or median value. The interaction was tested via a likelihood ratio test.P < .05 was considered statistically significant.All statistical analyses were performed using R software  and Stata statistical software . A 2-sided http://links.lww.com/MD/K821). Table The current study included 785 patients in total ; however, the prevalence of the other comorbidities did not differ significantly.Although the age of the patients did not significantly differ across groups, more male patients were found in the high Age-CCI groups. The high Age-CCI groups had significantly higher rates of myocardial infarction, congestive heart failure, cerebrovascular disease, chronic pulmonary disease, diabetes, peripheral vascular disease, liver disease, renal disease, paraplegia, coronary artery disease, anemia, atrial fibrillation/flutter, hypertension, and cancer  and coronary artery disease , while the most common non-cardiovascular comorbidities were anemia , renal disease , diabetes , and chronic pulmonary disease .P < .001). In multivariable adjustment analysis (Model 3), the association remained statically significant , showing that with every 1-unit increase in the Age-CCI, the risk of primary outcome increases by 10%. Similarly, the multivariate-adjusted risk of 1-year death increased significantly with a unit increase in Age-CCI .Data on 1-year mortality or readmission rates were available for 352 (44.8%) patients, of which 131 (16.7%) died within 1-year after discharge. Table P = .013) and 1-year mortality  after adjusting for all the variables in Model 3. Figure P < .001).We also transformed the Age-CCI from a continuous variable to a dichotomous variable for sensitivity analysis. An Age-CCI score ≥ 7 was associated with a higher risk of the primary composite endpoint . Although some subgroups did not show a significant association, this trend was observed in those subgroups.The risk associations between Age-CCI and the composite outcome were similar across subgroups defined by age, gender, anemia, hypertension, AF, and renal disease when Age-CCI was used as a continuous variable. No statistically significant interaction was observed Fig. . The subThe main finding of this study was that the Age-CCI was linearly associated not only with all-cause mortality, but also with readmission rate in TAVR populations, with the incremental risk of mortality and readmission an estimated 10% per 1-point increase in the Age-CCI score. Subgroup results suggested that this relationship was robust. These preoperative risk assessments did not adequately capture the risks associated with comorbidity burden and performed poorly in predicting hospitalization and 30-day mortality after TAVR. Therefore, it is critical to assess the comorbidity burden in TAVR patients.In this study, subjects with TAVR had a significant comorbidity burden, with more than half of the patients having an Age-CCI ≥ 7. This finding is in line with previous research suggesting that comorbidities are common in patients undergoing TAVR. Patients with low comorbidity burdens tend to be candidates for surgical aortic valve replacement. Previous studies have found weak associations between CCI and established preoperative risk scores such as the Society of Thoracic Surgeons (STS), Logistic Euro-SCORE (LES), and Euro-SCORE-II (ESII).,12 This may explain the current research findings, which show that the more complications, the higher the risk of readmission and mortality. In addition, our study found that patients with high Age-CCI had a longer length of hospital stay, which may also indicate critical illness, leading to high mortality and readmission rates. AKI is frequently found in patients following TAVR and is associated with increased mortality. In our study, patients with high Age-CCI had a significantly greater incidence of AKI, which may lead to higher readmissions and mortality. The effect of Age-CCI on mortality and readmission in the current study emphasizes the importance of comorbidities in TAVR recipients.In this era of newer technology providing safer procedures, we recognize that the mortality following TAVR is decreasing. Therefore, in this study, we analyzed not only deaths but also readmissions following TAVR. We found that mortality or readmission risk within 1-year following TAVR increased 10% for every 1-unit increment in the Age-CCI. Subgroup analysis suggested that the association between Age-CCI and poor outcomes was stable. Some subgroup results were not significantly correlated, possibly because of smaller sample sizes after stratification, but this trend was observed in these subgroups. Previous studies found that 30-day readmissions following TAVR were common and associated with baseline comorbidities, with more than 50% of readmissions due to noncardiac factors.,22 They discovered that increased mortality after 30 days was linked to greater CCI. But we should also be aware of studies with conflicting findings. Hiltrop et al analyzed 145 patients who received TAVR, of whom 61% via the femoral artery and 39% transapical, with a median [IQR] age of 84 [80–87] years and a median [IQR] CCI of 3 [2–4]. They found that CCI scores at baseline did not appear to differ between patients who died and patients who survived at 2 years of follow-up after TAVR. The difference in the number and characteristics of participants may be the main reason for the different results. Their patients had significantly lower comorbidities than our study population, including patients with both transfemoral and transapical approaches, whereas our study did not include patients with transapical approaches.In addition, our results also indicate that each 1-unit Age-CCI was associated with increased 1-year mortality. This finding is in line with previous reports.–25 However, in the real world, TAVR recipients tend to have multiple comorbidities, and analyses of isolated chronic conditions do not adequately capture the complexity of patients. Multiple comorbidities and multiple treatments may interact with each other, raising the chance of adverse outcomes. Given the harmful impact of comorbidity, we should evaluate and manage the entire person rather than focusing on a particular disease component.As in previous studies, comorbidities in the CCI component when evaluated alone were associated with poorer outcomes after TAVR. For example, chronic kidney disease, chronic lung disease, and atrial fibrillation were associated with poor long-term or short-term outcomes after TAVR.Our findings have certain clinical implications. The Age-CCI may be used as an adjunct to assess mortality or readmission rates after TAVR. An improved understanding of the burden of comorbidities may aid in preoperative risk stratification and shared decision-making. Establishing risk stratification can facilitate timely, individualized intervention, different follow-up plans, and better patient outcomes. Preoperative addressing modifiable patient comorbidity may serve as a strategy to improve postoperative outcomes and reduce cost. Further research is needed to explore the appropriate prevention and therapy of multiple comorbidities in patients with TAVR.Our study has several limitations. First, our sample size is limited, and we only considered the variables in the database for our analysis. Information on surgical risk scores, valve type, and echocardiographic results were not available. Further research with a large sample size is needed. Second, despite performing a multivariable cox regression model to adjust for many factors, unmeasured confounders may persist, and a prospective study should be considered to confirm our findings. Third, we only used the Age-CCI to quantify the comorbidity burden. Even though this is the most extensively researched comorbidity index for predicting mortality, the results might be different if other comorbidity scales were utilized. Lastly, we cannot view the findings as causative but as an association. Future prospective studies may aid in determining the causal relationship between Age-CCI and crucial outcomes after TAVR, such as quality of life.The Age-CCI was independently associated with an increased risk of readmission and mortality. This emphasizes the significance of investigating the burden of comorbidities and taking preventative measures to manage some modifiable comorbidities before surgery to reduce readmission and death following TAVR.Conceptualization: Bingyan Guo.Data Curation: Hua Yang, Limin Meng, Chao Chang, and Xiufeng Zhao.Formal analysis: Hua Yang, Limin Meng, Chao Chang, and Xiufeng Zhao.Investigation: Hua Yang, Limin Meng.Methodology: Shuanli Xin, Bingyan Guo.Supervision: Bingyan Guo.Writing – original draft: Hua Yang, Limin Meng.Writing – review & editing: Shuanli Xin, Bingyan Guo.


Transforaminal lumbar interbody fusion (TLIF) is an effective and popular surgical procedure for the management of various spinal pathologies, especially degenerative diseases. Surgeons have been pursuing minimally invasive technology as soon as TLIF was appeared. Currently, TLIF can be performed with transforaminal approaches by open surgery, minimally invasive surgery or percutaneous endoscope. We provide a detailed description of a new modified open TLIF with percutaneous pedicle screws, which we refer to as mini-open TLIF. The objective of this study was to present feasibility of this procedure and the preliminary results.The study is a prospective study. From January 2021 to March 2022, 96 patients  with neurological symptoms due to degenerative lumbar spine diseases were enrolled. Operation time, blood loss, ambulatory time, hematocrit and complications were recorded during perioperative period. Clinical symptoms were evaluated 1 week, 3 months and 12 months after surgery. Visual analogue scale (VAS) scores for lower back pain and leg pain and Oswestry disability index (ODI) were assessed. Magnetic resonance imaging was performed preoperatively and 12 months postoperatively to emulate cross-sectional area of paraspinal muscles. The lumbar interbody fusion rate was evaluated by CT scanning.P < 0.0001) and reached minimal clinically important difference. Atrophy rate of paraspinal muscles was 2.5% for symptomatic side and 1.2% for asymptomatic side. The cross-sectional area before and after the operation and atrophy rate had no statistically significant difference (P > 0.05).The mean operation time of single level was 112.6 min, and the mean operation time of multilevel was 140.1 min. Intraoperative blood loss of single level was 64.5 ml and was 116.3 ml of multilevel. The VAS and ODI scores before and after surgery were significantly different . Transforaminal lumbar interbody fusion (TLIF) has been proven as an excellent treatment option for various spinal pathological conditions, such as degenerative disk disease and deformity . SurgeonThis prospective study included 96 patients who suffered from degenerative lumbar disease with single- or multilevel disease (from January 2021 to March 2022). The inclusion criteria were as follows: (1) lumbar degenerative/isthmic spondylolisthesis 1 or 2; (2) lumbar disk herniation with segmental instability; and (3) lumbar foraminal stenosis with segmental instability. Patients were excluded for the following reasons: (1) lumbar spondylolisthesis grade 3 or above; (2) reoperation; (3) bilateral nerve root canal stenosis; and (4) tumors, infections and fractures involving lumbar vertebrae. Patients who were lost to follow-up were excluded.A total of 47 males and 49 females were recruited in this study, with an average age of 54.8 ± 17.5 years (range 22–89 years). Twenty-one patients were diagnosed with lumbar spondylolisthesis, 45 with lumbar disk herniation with segmental instability and 30 with lumbar foraminal stenosis with segmental instability. Fifty patients had single-segment lesions: L3–L4 in 5 patients, L4–L5 in 24 patients and L5–S1 in 21 patients. Forty-six patients had multi-segment lesions: L3–L5 in 18 patients, L4–S1 in 24 patients and L3–S1 in 4 patients  decompression, discectomy and cage insertion for interbody fusion and (b) percutaneous placement of pedicle screws. The side of the approach was usually based on the location of the preoperative radicular symptoms. According to the standard anteroposterior position, the incision of the lesion segment and projection of pedicle were determined under C-arm fluoroscopy and marked on the skin Fig. . The surThe following parameters were recorded: operation time, blood loss, postoperative ambulatory time, follow-up time, complications and visual analogue scale (VAS) and Oswestry disability index (ODI) scores for lumbar and lower extremity pain preoperatively, 1 week postoperatively, 3 months postoperatively and 12 months postoperatively. Preoperative and postoperative hematocrit (Hct), lateral radiography and computed tomography (CT) were used to evaluate intervertebral fusion [P < 0.05 was considered significant.VAS and ODI scores before and after surgery were compared by a paired-sample t-test. The cross-sectional area at operational segments before and after operation was compared as well. All statistical analyses were performed using SPSS 27.0. The data are presented as mean ± standard deviation, and 2 and that on the asymptomatic side was 2081.8 ± 238.6 mm2. There was no statistically significant difference. The CSA for lumbar muscles on the symptomatic side postoperatively which was measured by MRI 1 year after operation was 2077.9 ± 225.5 mm2 and that on asymptomatic side was 2076.1 ± 235.5 mm2. Atrophy rate was 2.5% for symptomatic side and was 1.2% for asymptomatic side, which had no statistically significant difference (P > 0.05). The properties of fat infiltration on symptomatic side were 22.14% ± 9.21% preoperatively and 22.09% ± 9.04% postoperatively. The properties of fat infiltration on asymptomatic side were 21.78% ± 8.71% preoperatively and 22.20% ± 9.19% postoperatively. The detailed paraspinal muscle data are presented in Tables This study included 96 patients  with lumbar degenerative diseases, with a mean age of 54.8 ± 17.4 years (range 22–89 years); the demographic characteristics of patients are shown in Table In the past decade, the technologies of tubular retractors and endoscopes have shown dramatic development . VariousP > 0.05) for limited subperiosteal dissection and Wiltse approach [MO-TLIF can be performed with or without visualization aids such as surgical loupes, or microscopes and can handle not only single-level but also multilevel diseases. In the operation of single-level, the paraspinal muscles are subperiosteally dissected from the spinous processes and laminae with a 3 cm incision. In comparison, the systematic review involving 28 studies and 1,475 patients published by Lei Zhu et al.  reportedapproach . MoreoveTo the best of our knowledge, few studies have reported endoscopic lumbar interbody fusion for multilevel diseases. MO-TLIF can be advantageously applied to treat multilevel lumbar degenerative diseases. The incision can treat the two segments by lengthening 1 cm  and 2 cm for three segments. The 49 patients who underwent multilevel operation reveal significant relief of low back pain and leg pain. Preoperatively, most patients presented with intermittent claudication and radicular pain in the lower extremities, and the mean VAS score for leg pain was higher than the mean VAS score for back pain. The postoperative VAS score (back pain and leg pain) and ODI both improved significantly compared to pre-surgery scores. Parker et al. revealed that MCID scores following TLIF are 2.1 points for back pain VAS, 2.8 points for leg pain VAS and 14.9 points for ODI. The VAS and ODI of MO-TLIF reached the MCID scores . The meaP > 0.05; Table P > 0.05). There are no statistical differences of CSA in postoperatively bilateral paraspinal muscles  and asymptomatic side was measured by MRI preoperatively and postoperatively Table . The CSAles Fig. . AtrophyIntraoperative blood loss was estimated by calibrated collection bags, which may have bias. The Nadler’s formula was used to evaluate the blood loss, which takes into account height, weight and sex for calculation –22. Howen = 10), dural tear (n = 4) and wrong surgical segment (n = 2). No neurological deficit, cage subsidence or screw loosening occurred. It is necessary to reconfirm segment by fluoroscopy after dissection. Ventral and the excessively thick lateral ligamentum flavum were removed. Part of dorsal ligamentum flavum was retained to keep spinal canal intact, thus reducing the possibility of epidural scar formation and shortening the operation time. This technique can also achieve decompression of contralateral central spinal canal and lateral recess by removing the root of spinous process.The main complications included wound infection  to determine the clinical efficacy of MO-TLIF. Finally, the blood loss calculation lacks universal assessment methodologies, which may cause a bias.Under appropriate patient selection and surgical indications, mini-open TLIF is effective and feasible for the treatment of lumbar degenerative diseases, especially multilevel diseases, with minor muscle damage and shorter operation time. It is an optional method of lumbar interbody fusion.


Cancer-induced bone pain (CIBP) has a considerable impact on patients’ quality of life as well as physical and mental health. At present, patients with CIBP are managed according to the three-step analgesic therapy algorithm proposed by the World Health Organization. Opioids are commonly used as the first-line treatment for moderate-to-severe cancer pain but are limited due to addiction, nausea, vomiting and other gastrointestinal side effects. Moreover, opioids have a limited analgesic effect in some patients. In order to optimize the management of CIBP, we must first identify the underlying mechanisms. In some patients, surgery, or surgery combined with radiotherapy or radiofrequency ablation is the first step in the management of CIBP. Various clinical studies have shown that anti-nerve growth factor (NGF) antibodies, bisphosphonates, or RANKL inhibitors can reduce the incidence and improve the management of cancer pain. Herein, we review the mechanisms of cancer pain and potential therapeutic strategies to provide insights for optimizing the management of CIBP. The skeleton is one of the most common metastatic sites in patients with solid tumors such as breast cancer, prostate cancer, kidney cancer and lung cancer , 2. The Bone plays a number of complex roles in the body including but not limited to exercise, support and protection of vital organs. Various cells, such as osteoblasts, osteoclasts, adipocytes, and macrophages maintain homeostasis and ensure the basic function of bone . Under pStephen Paget proposed the hypothesis of “seed and soil” to explain how bone remodeling induces tumor re-implantation and development during bone metastasis. Metastasis from a primary tumor site is a multi-step and multifactorial process, including primary site erosion, breakthrough of basement membrane, escape of nesting apoptosis, and adhesion, colonization and invasion in distant organs . NGF is commonly identified in prostate cancer, gastric cancer, and breast cancer , 19. RecIn addition to directly activating peripheral nociceptors, the low pH and hyperinflammatory state of the TME will lead to the remodeling of nociceptors in tumor tissue. Long-term stimulation with H+ ions and sustained inflammatory factors continuously activates nociceptors, leading to increased sensitivity of nociceptive neurons and amplification of their afferent nerve signals, which called as peripheral sensitization. Once peripheral sensitization occurs, as a result, even if the stimulation is not enough to trigger nociceptive signal transduction, this can still result in pain signal transduction in patients with cancer . ContinuThe complex microenvironment in tumor tissue is associated with long-term and high-intensity activation of peripheral high-density nociceptors and induce changes in the central nervous system through a variety of mechanisms, which is manifested in the increased responsiveness to peripheral stimuli, thus generating central sensitization and inducing cancer pain. Studies have shown that under stimulation by tumor tissue, glial cells in the spinal cord are activated, especially spinal microglia and astrocytes. The overactive state of spinal microglia and astrocytes is one of the key factors that activates central sensitization and leads to CIBP , 37–40. It is estimated that 20–85% of patients who receive neurotoxic chemotherapy will experience peripheral neuropathy , 45–47. Overall, the mechanisms underlying the occurrence and deterioration of CIBP are complex and involve tumor implantation, bone metabolism, enhancement of mechanical stimulation, activation and alteration of peripheral nerves, peripheral nerve remodeling, and activation/adaptive changes in the central nervous system. It will be vital to understand these mechanisms to facilitate the optimal management of CIBP in practice.Management of CIBP in patients with bone metastasis is an important issue, and the strategy of analgesia accompanies the life of patients, which is involved the three-ladder model of analgesia proposed by the World Health OrganizationNonopioids, such as nonsteroidal anti-inflammatory drugs (NSAIDs) are often the first-line therapy for CIBP. They are effective against mild-to-moderate pain; however, there is little evidence for the effectiveness of NSAIDs in patients with CIBP . While NWeak opioids, such as tramadol and codeine, are not commonly used to manage CIBP because there is limited evidence for their effectiveness. Low-dose morphine is associated with more rapid and effective analgesic effects than opioids , 54.For severe CIBP, strong oral and percutaneous opioids are the first choice for patients. Studies have shown that buprenorphine, oxycodone, fentanyl and morphine have similar analgesic effects and gradually achieve complete analgesia with adequate drug supply. Morphine is the first-line treatment for breakthrough pain and is associated with effective pain control . HoweverMethadone is an effective substitute for morphine, oxycodone, fentanyl and other opioid drugs, which shows incomplete cross tolerance with other opioid receptors. However, due to significant inter-individual differences in the plasma half-life of methadone, it should be used only under the supervision of professional doctors. Although morphine and methadone show similar analgesic effects after single dose administration, it is recommended to reduce the anodynia dose by one quarter to one twelfth when switching from another opioid to methadone to prevent side effects such as respiratory depression .In patients with a long-life expectancy and no important organ metastasis, surgical resection is the first choice for patients with bone metastases with only one site metastasis.For other metastatic spine tumors, patients with unstable spine, spinal cord compression or nerve function injury, tumor resection and reconstruction surgery are also should be chose firstly, for reducing compression on the spinal cord, which can relieve local pain by improving neural function . VariousFor long-bone metastasis, the Mirels predictive score is widely used in clinical practice . Based oFor pelvis metastasis, there is no widely recognized scoring system. Because the pelvic anatomy is complex and adjacent to important organs and blood vessels, the resection and reconstruction of pelvic metastasis must be performed by experienced surgeons. While this surgery can help to relieve CIBP, the effects of such a complex surgery can be associated with additional pain.Radiotherapy is a safe and effective strategy to relieve CIBP who are not suitable or cannot tolerate surgical treatment. Radiotherapy can significantly relieve CIBP. Studies have shown that 60% of patients with bone metastases experience significant pain relief after radiotherapy. Intraoperative radiotherapy is associated with particularly effective control of pain; however, it is worth noting that radiotherapy may lead to the occurrence of fracture or nerve injury in the spinal cord . CompareRadiofrequency ablation (RFA) includes microwave ablation and low-temperature ablation. RFA can be combined with radiotherapy and surgery. Research shows that RFA is associated with effective local pain control in around 64–77% of cases, which can relieve 70–100% of the pain related to bone metastases. After RFA treatment, PVP or PKP can prevent fracture and stabilize the surgical effect . HoweverBisphosphonates are pyrophosphate analogues that combine with hydroxyapatite on the bone surface, directly inhibiting the attachment, differentiation and maturation of osteoclasts, which reduces the rate of bone absorption. Bisphosphonates have become the standard of care for bone metastases and have been shown to reduce the incidence of hypercalcemia and the rate of SREs. Studies have shown that regardless of whether radiotherapy and chemotherapy are combined, bisphosphonate treatment reduces the occurrence of CIBP . HoweverThe RANKL/RANK signal pathway is a central to the regulation of osteoclast differentiation and activation. RANKL activates RANK binding on the surface of osteoclast precursor cells, and promotes osteoclast maturation. Denosumab, the most widely used RANKL inhibitor, prevents RANKL from combining with RANK, thus inhibiting the formation and activation of osteoclasts, result in reduced bone absorption and increased bone mass. Treatment with denosumab has been shown to inhibit tumor metastasis –77.It is worth mentioning that many studies have found that compared with bisphosphonates, Denosumab have more advantages in reducing SREs and alleviating pain , 78, 79.Many humanized anti-NGF antibodies have shown encouraging results in clinical trials. Moreover, anti-NGF antibodies has a significant inhibitory effect on CIBP, especially neural cancer pain. Additionally, experiments in mice show that NGF antibody treatment reduces bone damage caused by tumors, delays fracture time, and prolongs the use of tumor-carrying limbs, although the underlying mechanisms of these effects are unknown . Both exNeuropathic pain is an important component of CIBP. Therefore, in recent years, pregabalin has been increasingly used in the treatment of CIBP and is particularly effective especially for medium- and short-term CIBP , 81. TheAntidepressants including amitriptyline and duloxetine can also be used for the treatment of neuropathic pain. Data show that both of these drugs can help to improve quality of life in patients with CIBP .Traditional Chinese medicine can be used to treat pain, including CIBP. The advantages of traditional Chinese medicine include rich dosage forms, light toxicity and side effects, and improved tolerability compared with more established methods. For these reasons, it has gained traction as a treatment option for patients with CIBP. Studies have shown that astragalus, psoralen, scutellaria barbata, atractylodes macrocephala, and corydalis can significantly inhibit CIBP in patients with cancer –85. InseAcupuncture is effective for alleviating pain and can help to reduce the need for opioids . ElectriAlthough the mechanisms of treating cancer pain with traditional Chinese medicine are not yet fully elucidated, it is clear that this form of medicine has unique advantages for treating cancer pain compared with more commonly used methods. Going forward, it will be important to understand the mechanisms by which Chinese medicine is able to reduce CIBP, and to standardize usage and dosage to allow more widespread use.in vitro immune cell adoptive therapy can also relieve the pain caused by primary tumors and bone metastases (Injection of a TNF-α antagonist can partly block the mechanical hyperalgesia in oral cancer , 96. In tastases –100.The management of CIBP is a complex issue for patients and physicians. Active pain management, such as early surgical intervention for eligible patients. Radiotherapy and microwave therapy can be combined with surgical intervention to obtain a higher pain relief rate and promote the patient to recover the patient’s nerve and activity function as soon as possible. Early intervention with RANKL inhibitors, bisphosphonates or anti-NGF antibodies in patients who are not candidates for surgery may improve quality of life. Traditional Chinese medicine and acupuncture also have the potential to become important options for CIBP management. Overall, there is no single solution for managing CIBP in all patients. Only by fully elucidating the underlying mechanisms of cancer pain will it be possible to optimize the management of CIBP in real-world practice.DJ and ZQ conceived the manuscript and drafted the manuscript. YBZ and XDL contributed to data collection. YF, BZ, and XFZ reviewed the manuscript. All authors contributed to the article and approved the submitted version.


A third of patients with advanced cancer and bone metastasis suffer from cancer induced bone pain (CIBP), impeding quality of life, psychological distress, depression and anxiety. This study will evaluate the impact of an opioid rotation, comparing methadone rotation with other opioid rotation in patients with refractory CIBP.This open-label randomised controlled trial will recruit cancer patients with CIBP and inadequate pain control despite established baseline opioid and/or intolerable opioid side effects from cancer and palliative care services. Participants will be at least 18 years old, with a predicted prognosis of greater than 8 weeks, meet the core diagnostic criteria for CIBP, have a worst pain score of ≥ 4 of 10 from CIBP and/ or have opioid toxicity (graded ≥ 2 on Common Terminology Criteria for Adverse Events). Participants will have sufficiently proficient English to complete questionnaires and provide informed consent.Participants will be randomised 1:1 to be rotated to methadone to another opioid. The primary objective is to examine the impact of opioid rotation in improving CIBP by comparing analgesic efficacy, safety and tolerability in the two arms. Secondary objectives will assess changes in the intensity, duration and frequency of breakthrough pain, requirement of breakthrough analgesia, overall opioid escalation index, and time taken to observe improvement in pain reduction, pain interference and quality of life.Laboratory studies suggest the involvement of neuropathic involvement in the mechanism of CIBP, though there remains no clear evidence of the routine use of neuropathic agents. Methadone as an analgesic agent may have a role to play in this cohort of patients, thus warranting further exploratory studies.Australian New Zealand Clinical Trials Registry No: ACTRN12621000141842. Registered 11 February 2021.The online version contains supplementary material available at 10.1186/s12904-023-01160-1. Cancer induced bone pain (CIBP) is a common cancer pain syndromes with complex pathophysiology, comprising a mix of inflammatory nociceptive and neuropathic pain pathways . ApproxiThe characteristics of CIBP, with mixed mechanism pain and the combination of background and breakthrough (spontaneous and incident) pain leads to the challenges with its management, necessitating a multimodal approach . CurrentDespite increasing knowledge in the pathophysiology and mechanism of CIBP, there has been limited translation into clinical practice to guide the choice of available analgesic treatments . Laboratp < 0.001 [p < 0.001. These results provide preliminary evidence that methadone for refractory CIBP might provide benefits, but this requires confirmation by further exploratory studies as at this point there have been no other randomised controlled trial evidence for methadone in CIBP.Our department’s clinical experience in the use of racemic methadone as an alternative opioid in patients with refractory CIBP unresponsive to morphine or other opioids or those who exhibit dose limiting toxicity has not been substantiated by evidence. Our use of methadone is influenced by its known antagonistic effects at the N-methyl-D-aspartate (NMDA) receptor channel and inhibition of the reuptake of serotonin and noradrenaline . Our ret < 0.001 . On compIn this study we define refractory cancer pain as cancer pain that does not respond to standard opioid and/or co-analgesic therapy . This stThe secondary aim is to assess changes in the intensity, duration and frequency of breakthrough pain, requirement of breakthrough analgesia, overall opioid escalation index, time taken to observe improvement in pain reduction, pain interference and patient’s quality of life (QOL). We will additionally assess for correlations between trough levels of methadone at the end of the study period and analgesic response in the MR arm. The protocol is outlined according to the Standard Protocol Items: Recommendations for Interventional Trials guidelines .This is an exploratory, single site, open-label, randomised controlled trial with two parallel arms enrolling 50 cancer patients already established on a strong opioid with refractory CIBP. Refractory CIBP is defined as worst pain score rated at ≥ 4 of 10 on a numeric rating scale (NRS)  and/or cThe study will be conducted at an 850 bed metropolitan hospital in Melbourne, Australia. Patients with a solid tumour or haematological cancer diagnosis with a predicted prognosis of greater than 8 weeks will be recruited from the oncology and palliative services. Eligible patients 1) will be at least 18 years old; 2) have confirmed bone metastasis, with CIBP being the dominant pain. Bone metastasis will be confirmed through radiological investigations and patients must meet the core diagnostic criteria for CIBP as defined by The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society (ACTTION-APS) , stored in a locked drawer and accessed only at the point of randomisation. The participant will be enrolled and allocated by the clinician researchers.As this is an early exploratory study with a limited budget, participants will not be blinded to the interventions. Investigators conducting follow up assessments are also not blinded to the intervention to facilitate dose titration to mitigate the risk of toxicity.MR will be implemented using the rapid conversion Stop-and-Go method , 17. TheOpioid rotation with opioids other than methadone will be implemented based on established opioid conversion ratios . CliniciIn both intervention arms, participants will continue to use immediate release and/or rapid onset opioids (not methadone) for breakthrough analgesia. There will be no limitations set on the number of breakthrough analgesics used. Use of adjuvant co-analgesic medications such as NSAID, trazodone, acetaminophen, or Tramadol  are permParticipants will remain as an in-patient until stable opioid dose is achieved . Following discharge, participants will be followed up for a total of 14 days from initiation of study intervention. All follow up assessments will be conducted face to face or over the telephone.Data will be sourced from the clinical records, electronic prescribing records and directly from participants. Baseline and ongoing data collection are summarised in Table basic demographics .current analgesic use e.g. baseline opioid use converted to OMEDD, breakthrough and co-analgesic usepain types  and performance status.history of oncology-specific therapy, radiotherapy, denosumab and bisphosphonate use.We will collect the following data to ensure baseline comparability:a) Douleur Neuropathique 4 (DN4) is a screening tool for neuropathic pain consisting of interview questions (DN4-interview) and physical tests. A score of ≥ 4/10 suggests neuropathic pain .b) EuroQol Thermometer measures health status, ranging from worst to best possible health state .c) Hospital Anxiety and Depression Scale (HADS) is a self-rating scale to assess psychological distress in non-psychiatric patient .d) Australia-Modified Karnofsky Performance Scale (AKPS) measures the patient’s overall performance status or ability to perform their activities of daily living .e) Breakthrough pain Assessment Tool (BAT) assess the frequency, duration, severity and effect of breakthrough analgesia on breakthrough pain .f) Brief Pain Inventory (BPI) assesses pain interferences and patient satisfaction with pain relief . (0-no pain to 10-pain as bad as can be imagined) is used to rate pain on a defined scale [g) Numerical Rating Scale (NRS)ed scale .h) Common Terminology Criteria for Adverse Events (CTCAE) grades for opioid toxicities, evaluating for somnolence, respiratory depression, confusion, hallucinations, nausea, vomiting, constipation, pruritus/ itching, and dry mouth .i) Routine blood tests and trough methadone levelsWe collected routine haematology and biochemistry screens for all patients. We additionally elected to measure the trough level of methadone, which indicates the lowest concentration of methadone in the body after the drug has been broken down and metabolized by the body. Through levels are measured immediately before the next dose is given. Studies have indicated that for optimum efficacy, methadone trough levels of about 400–500 ng/ml are required . We thusThe primary outcome will be changes in worst and average pain intensity on day 14. A significant response is classified as ≥ 30% pain reduction and substantial response as ≥ 50% pain reduction. The proportion of responders in each group will be calculated.a) Breakthrough pain intensity, duration and frequencyb) Frequency of breakthrough analgesia administration at each time point (averaged over the preceding 3-days)c) Treatment safety and tolerability using composite CTCAE scoresd) Time taken to observe improvement will be calculated as the difference between baseline data and first date with ≥ 30% pain reduction.e) Opioid escalation index (OEI%) , a surrof) Changes in EuroQOL, HADS, total pain interferences score and patient satisfaction with pain relief.g) Correlation between analgesic response trough methadone levels at day 14.The following outcomes will be compared between the two intervention arms:Patients who developed severe adverse reactions likely to be secondary to MR or OOR, such as delirium will have their treatment discontinued and alternative analgesics prescribed as per usual clinical processes. Patients who develop complications unrelated to treatment such as pathological fractures or malignant spinal cord compression and those who require invasive analgesic techniques or radiation therapy during the study will be withdrawn. Data will.continued to be collected up to the point of withdrawal and included in the analysis plan. Alladverse events will be reported to the trail monitoring committee and participants will beoffered opportunities to seek support for any adverse outcome.This is an exploratory study. We chose to recruit 50 participants (25 per arm) to this study based on the absence of any preliminary data related to timing to pain reduction and change in pain intensity for those treated with methadone and assuming that methadone is equivalent to other opioids in relation to the expected proportion of patients reaching > 30% or 50% pain reduction . AdditioThe summary statistics will be reported as mean (SD) or median (IQR) for continuous data and N (%) for categorical data. The results of all regression models will be reported as point estimate with 95%CI as appropriate. Level of significance was mentioned as a standard procedure, but all results will be interpreted with respect to both statistical significance and clinical relevance/importance. Between group differences will be assessed using either Student T-test or Wilcoxon rank-sum test for continuous data or either Chi2 or Fisher’s exact test for categorical variables. Additionally, standardised difference between two groups will be calculated and values > 0.1 will be indicative of between group imbalances.A mixed effect model will be used to assess the longitudinal differences in pain reduction, opioids escalation and quality of life measures between methadone and other opioids groups. Survival analysis will be used to compare time to event outcomes (i.e. time taken to observe pain improvement). Kaplan-Meyer survival curves will be constructed and either log-rank test or Cox proportional hazard model will be used. Spearman correlation will be used to examine any correlations between reduction in pain intensity and QOL score, HADS and other relevant continuous outcomes.As stated in the study protocol, all data collected until patient’s withdrawal from the study or death will be included in the data analysis and for the basis for the primary analysis.p < 0.05 will be considered statistically significant for all tests.The sensitivity analysis for the primary outcome will be considered, subject to study completion rate, and will be performed using LOCF, worst/best case scenario imputations. This will be detailed in the final manuscript of the completed randomised controlled trial as appropriate. The analysis will be performed using Stata16  and p < In view of logistical and financial considerations, this study will be an open-label study with both participants and study investigator/ clinicians administering the intervention being aware of treatment allocation. Research statistician and research support staff assisting with data entry will be blinded to allocation.Following randomisation, the clinical trial pharmacist will be notified to ensure dispensing of the appropriate medication. The participant ID, date of request, preparation and dispensing will be recorded in a log maintained by the site pharmacist for each randomisation.Clinicians and research staff involved in the study will be trained on screening and approaching patients for recruitment, consent, data collection, coding and storage. Staff will also be trained on identifying risk, managing adverse effects and how to deal with any distress that the participants may display whilst completing the study and how to refer appropriately for support.A data monitoring committee will include an independent pain clinician, pharmacist and.researcher to provide ongoing oversight into early results and ensure adherence to the research protocol. Data will be stored in a secure database with information and measurements stored independently from identifiable personal information to ensure confidentiality. Findings of the study will be presented at national and international meetings and published in peer reviewed journals.This study is limited by it being a single site, non-blinded study with a small sample size. The research team’s exploratory work identified the lack of use of methadone as a primary analgesic in many potential collaborative sites . It is hoped that this preliminary work will increase the confidence of sites in considering enrolment in a subsequent multi-site study. Additionally, it is difficult in cancer pain studies to limit other confounding factors such as radiotherapy and the use of bisphosphonates that may influence pain outcomes and as such a pragmatic approach was used in the study design.CIBP continues to be a source of much suffering for cancer patients, warranting exploration of novel treatment options. Methadone as an analgesic agent may have a role to play in this cohort of patients, thus warranting further exploratory studies.Additional file 1: Appendix 1. Common Terminology Criteria for Adverse Events: Opioid Toxicity Assessment Version 5.0.


This study investigates the functional brain connectivity in patients with anterior knee pain (AKP). While biomechanical models are frequently employed to investigate AKP, it is important to recognize that pain can manifest even in the absence of structural abnormalities. Leveraging the capabilities of functional magnetic resonance imaging (fMRI), this research aims to investigate the brain mechanisms present in AKP patients.Forty-five female subjects  underwent resting-state fMRI and T1-weighted structural MRI. Functional brain connectivity patterns were analyzed, focusing on pain network areas, and the influence of catastrophizing thoughts was evaluated.Comparing patients and controls, several findings emerged. First, patients with AKP exhibited increased correlation between the right supplementary motor area and cerebellum I, as well as decreased correlation between the right insula and the left rostral prefrontal cortex and superior frontal gyrus. Second, in AKP patients with catastrophizing thoughts, there was increased correlation of the left lateral parietal cortex with two regions of the right cerebellum (II and VII) and the right pallidum, and decreased correlation between the left medial frontal gyrus and the right thalamus. Furthermore, the correlation between these regions showed promising results for discriminating AKP patients from controls, achieving a cross-validation accuracy of 80.5%.Resting-state fMRI revealed correlation differences in AKP patients compared to controls and based on catastrophizing thoughts levels. These findings shed light on neural correlates of chronic pain in AKP, suggesting that functional brain connectivity alterations may be linked to pain experience in this population.Etiopathogenesis of pain in anterior knee pain patients might not be limited to the knee, but also to underlying alterations in the central nervous system: cortical changes might lead a perpetuation of pain.• Anterior knee pain patients exhibit distinct functional brain connectivity compared to controls, and among catastrophizing subgroups.• Resting-state fMRI reveals potential for discriminating anterior knee pain patients with 80.5% accuracy.• Functional brain connectivity differences improve understanding of pain pathogenesis and objective anterior knee pain identification. A peculumping)” . Moreoveumping)” .In spite of its high incidence and abundance of clinical research, its pathogenesis is not clearly understood , 4. It iFunctional magnetic resonance imaging (fMRI) techniques have recently provided insights into the mechanisms underlying the development of chronic pain, and AKP is a paradigm of chronic pain, identifying pain centers that work as networks. This is done by studying the structural and functional connectivity (FC) of brain networks, measuring neural activity through blood oxygenation level-dependent (BOLD) activity. “Pain neuromatrix” has been defined as a group of brain regions that are activated together in a coordinated manner by painful stimuli, being considered the basis of the multidimensional experience of pain , 12. In The primary purpose of this study was to define FC changes in AKP patients compared with matched controls and between AKP patients with catastrophizing thoughts and AKP patients without catastrophizing thoughts. The objective of this study is to investigate the impact of chronic AKP on brain dynamics at rest. We hypothesized that chronic AKP may be associated with fMRI brain changes in interconnected networks, which may modulate the variable impairments accompanying this condition, and even explain the different responses to treatment. The second objective of this study was to evaluate the accuracy of fMRI to assess AKP.A total of 45 subjects were recruited and evaluated, 24 women with chronic AKP of ≥ 6 months duration, ranging in age from 18 to 44 years , and 21 healthy women without knee pain, ranging in age from 20 to 43 years (28.7 ± 7.5 years). Patients and controls were age-matched. All patients are females because AKP is a pathological entity typical of women. In addition, the fact that they are all females avoids bias in our results. In this way, Silberstein and Camfield  observedDemographic variables recorded were age, dominant hand, schooling, and levels of depression and anxiety. All patients completed a booklet with self-report questionnaires on pain intensity, anxiety, depression, kinesiophobia, and catastrophizing. Clinical pain intensity was obtained by asking subjects to rate their pain on a visual analog scale (VAS) . Anxiety0; voxel size 1 × 1 × 1 mm3; and duration of 6 min. The resting-state fMRI T2*-weighted two-dimensional echo-planar BOLD sequence was acquired with the following main parameters: echo time 35 ms; repetition time 2,000 ms; 256 temporal dynamics ; pixel size 1.8 × 1.8 mm2; slice thickness 5 mm; and overall duration 9 min. This sequence allows to explore networks FC by sampling the brain hemodynamic response during neuronal activation at the resting-state.MRI data were acquired on a 3-T scanner  using an 8-channel head coil with parallel acquisition technology (SENSE). All participants were instructed at the beginning of the acquisitions to avoid movements, keep their eyes closed, stay awake and think of a blue sky. The acquisition protocol consisted of a high spatial resolution T1-weighted three-dimensional gradient-echo sequence with the following parameters: echo time 3,000 ms; repetition time 6,200 ms; flip angle 10All images were preprocessed using the CONN  and SPM1The intensity level of BOLD time-series z-score was normalized and images were spatially registered towards a standardized MNI space. Segmentation, , was applied. Then, brain parcellation was performed using the Functional Magnetic Resonance Imaging of the Brain, FMRIB, Software Library Harvard–Oxford probabilistic atlas, which provides 91 cortical and 15 subcortical regions of interest (ROIs) plus 26 cerebellar regions defined by the Automated Anatomical Labelling, AAL, atlas. Six commonly characterized networks were obtained by seed-areas on known networks: SN, DMN, Dorsal Attention Network (DAN), SMN, Visual Network (VN), and Cerebellar Network (CN).The DMN comprises the medial prefrontal cortex, parietal lobe, and posterior cingulate cortex, and is mainly activated during introspection. On the other hand, the SMN is composed of the basal ganglia, thalamus, posterior insula, and somatosensory cortex, and is essential for body sensation awareness and the generation of appropriate motor responses. Additionally, the SN is formed by the anterior cingulate cortex, anterior insula, rostral prefrontal cortex, and the supramarginal gyrus. This network is responsible for processing sensory stimuli and generating affective responses. The VN is constituted by the cuneal cortex, intracalcarine cortex, occipital fusiform cortex, and lingual gyrus. The DAN is formed by the frontal eye field and the intraparietal sulcus, which are crucial for attentional processes. Finally, the anterior and posterior cerebellar areas form the CN. Each of these networks plays a distinct and vital role in the brain's functioning and interactions, contributing to various cognitive functions and perceptual processes.On the other hand, the CEN is a network that encompasses some of the areas described in these networks, such as the dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, anterior cingulate cortex, anterior insula, motor supplement area, and posterior parietal cortex. This network is a fundamental part of the system of brain networks involved in cognitive processing and control in the human brain.Before image processing, main confounder effects (24 parameters for head movement obtained from the ART-repair program and intensity effects that do not correspond to the gray matter) were included in a linear regression model, with a 0.008–0.09 Hz bandpass filtering to obtain BOLD time-series signal free of unwanted effects.versus controls, and catastrophizing patients versus patients without catastrophizing. Effect sizes represent Pearson correlation coefficients (r) with a Fisher's z-transformation, which are represented as ß coefficients.The ROI-to-ROI analysis, atlas-based, was performed representing the level of partial correlation between all the pairs of brain ROIs. Using a general linear model to estimate the strength of connectivity between brain areas, using a partial correlation analysis between the averaged BOLD signal from each pair of brain ROIs. Conducting two different group analyses: AKP patients p < 0.001 uncorrected to control for cluster spread, and a cluster-level threshold of p < 0.05 corrected for false discovery rate (FDR), for multiple comparisons across the whole brain [In the statistical analysis, significant clusters were determined by two thresholds, one at connection level and one at cluster level. The significance level was defined by a connection-level threshold of le brain . The conversus those without, following the same statistical model as in the previous analysis.The first analysis was a between-group comparison to discover significant unbiased resting-state fMRI differences between patients and controls, by means of an ANCOVA statistical analysis adding as covariates the variables that show significant differences between patients and controls, with the aim of making sure that these differences are due to FC and not to these. The second analysis compared the FC of patients with catastrophizing Finally, we explored the potential of a multivariate classification using the value of the correlation between the regions we found significant in the ANCOVA analysis to differentiate AKP patients from controls. These correlations were extracted from the ROI.mat matrix resulting from the CONN software. For this purpose, 6 supervised learning classifiers were used.The supervised classification approach allowed us to utilize the correlation between brain regions, to predict the group of each patient. We employed a set of well-established supervised learning classifiers to perform the classification task. The chosen classifiers were logistic regression, k-nearest neighbors, decision tree, linear discriminant analysis, support vector classification, and Gaussian naive Bayes. These classifiers were implemented using the Scikit-learn library, a widely-used machine learning library in Python .To assess the performance of the classifiers, we employed the k-fold cross-validation method. We divided the sample into ten subsets and conducted k iterations, with each iteration using one subset for testing and the remaining subsets for training. This approach allowed us to robustly evaluate the classifiers' performance across different training and testing sets. We evaluated the models based on two common metrics: accuracy and the area under curve at receiver operating characteristics analysis (ROC-AUC) Accuracy measures the proportion of correctly classified samples, providing an overall performance measure. The ROC-AUC represents the classifier's ability to discriminate between the AKP and control groups, with a higher ROC-AUC indicating a better discriminatory power.The methodology followed in this study, including the CONN steps of preprocessing, denoising and connectivity measures implementation of supervised classification models and the evaluation using k-fold cross-validation and accuracy/AUC metrics, is illustrated in Fig. The demographic variables collected show significant differences between patients and controls in the level of schooling and level of anxiety Table . As for p-FDR < 0.05) were found between AKP patients and matched healthy controls  rather than less positive FC.Significant correlation differences between regions (ls Table . For mosp-FDR < 0.05) in FC  and ROC-AUC (0.821) Table .Table 4The main finding of our study is the presence of altered FC in AKP patients during rest, compared with matched controls, in brain areas associated with pain dimensions . Moreover, significant differences in FC were found in AKP patients showing catastrophizing compared with those without catastrophizing ideas. Therefore, etiopathogenesis of pain in AKP patients might not be limited exclusively to the knee, but also to underlying alterations in the central nervous system. In short, AKP should not be considered as a single musculoskeletal pathology. In this way, cortical changes might lead a perpetuation of pain.Previous studies found nodes involved in the development of chronic pain in the DMN, SMN, CEN, and SN. In our study, the anterior insula, an important area of the SN, shows decreased correlation with the rostral prefrontal cortex, an area that is also part of the SN, and with the superior frontal gyrus, an area of the CEN. The insular cortex is often activated bilaterally during noxious somatosensory stimulation and has been suggested to play an important role in pain processing . AfferenThe rostral prefrontal cortex is involved in a large number of cognitive processes and executive functions such as prospective and working memory. It has been related to the medial frontal gyrus in prospective memory tasks . Thus, tOn the other hand, previous studies  have shoIn this study, we found a decreased correlation of the anterior cerebellar network with the upper motor area, a crucial region for proper motor planning. Previous studies in chronic low back pain condition showed decreased resting-state brain activity in S1, supplemental motor area, M1 and cerebellar lobules IV-V for those subjects suffering from pain. This indicates that under the condition of chronic pain there is an impaired motor response to painful stimuli, which may indicate that chronic pain patients are overresponsive to sensory inputs that potentially signal danger to the body, thereby inducing maladaptive overgeneralized motor responses .versus non-catastrophizing) has been demonstrated. This could explain the great variability in the pain experience among different subgroups of AKP patients. Pain catastrophizing is a psychological construct that includes cognitive, emotional and behavioral processes  that amplify perceived painful sensations and predispose to the perpetuation of pain [Connectome differences between different subsets of AKP patients  was applied, enhancing the consistency and robustness of the results. However, it is crucial to recognize that FC measures provide valuable insights into brain networks related to AKP but do not offer definitive causal explanations. A more comprehensive approach, considering additional relevant factors such as pain intensity or duration, and incorporating longitudinal studies, would be necessary to establish a clearer understanding of the role of FC in the etiopathogenesis of pain in AKP patients.To maintain control over the error rate, a threshold of Lastly, it is essential to acknowledge that pain is a complex and multifaceted phenomenon influenced by various biological, psychological, and environmental factors. Relying solely on FC to explain the entire etiology of pain in these patients may oversimplify the underlying mechanisms. A comprehensive and integrative approach is needed to grasp the full complexity of AKP etiopathogenesis.In conclusion, our data support the general idea that chronic pain has a disruptive effect on the functional brain network. Our study demonstrates that FC is altered in patients with AKP compared to matched control subjects, having a generalized impact on global brain function. Furthermore, it is shown that depending on the level of catastrophizing thoughts presented by the patients, new alterations in FC appear. It remains to be determined whether these extremely variable symptoms of AKP are related to fMRI imbalance, although the present study is a first step in that direction. The use of the results of brain alterations in a clinical decision support system could help the clinician to identify this disease, which is mostly diagnosed by discarding others. This could be a first step towards the objectification and identification of pain.


Elbow pain (EP) in overhead sports is a common phenomenon. Swimming is classified as an overhead sport, but a lack of attention regarding EP in swimming has created a gap in the knowledge around elite freestyle swimming in Tianjin, China. The purpose of this study was to identify the distribution and prevalence of EP among elite freestyle swimmers in Tianjin, China. The methodology involved a total of 311 qualified participants who volunteered to undertake all measurements. The main findings showed that 183 of the elite freestyle swimmers in this study had EP , with 147 in slight pain and 36 in critical pain. The characteristics of a heavier body weight, taller height, longer left/right forearm length, and longer weekly average training hours serve as contributing factors to the occurrence of EP issues. Gender, age, weekly average training hours, and left/right forearm length are the primary factors correlating with and influencing the assessment scores. In conclusion, swimmers with longer weekly training hours, older ages, heavier bodyweight, and longer forearm lengths should receive greater attention in relation to EP. Regular assessments at a high frequency serve as a means to identify the risk of EP. Elbow pain (EP) is a common sports injury in various overhead sports . As it iIn China, research on and exploration of EP in swimming are in their initial stages . As a poThere are a few Chinese researchers who have initiated investigations into the condition of EP in swimming. Such studies are valuable for assessing the health status of elite swimmers’ upper limbs, highlighting specific risks that require attention, and providing information for targeted interventions aimed at preventing EP ,5,10,11.In summary, regional sampling evaluation is one of the primary methods for studying EP in swimming athletes, given the state of development of sports science in China. Regular assessment of athletes’ physiological parameters over time is a necessary injury prevention strategy to safeguard their health and professional safety ,23. EvalThis study received ethical approval from the University of Malaya Ethical Approvals Sub-Committee, with reference number UM.TNC2/UMREC_1951 . All subThe subjects in this study were swimmers from three different competitive-level organizations . This study was conducted from February to September 2022 in Tianjin Evergrande Olympic Aquatic Sports Center, China. A total of 503 elite freestyle swimmers responded to join this study voluntarily. Recruitment information was obtained by telephone and e-mail. Based on the inclusion and exclusion criteria, a total of 311 swimmers were enrolled after excluding 192 athletes.The inclusion criteria were: (1) Achieved the title of elite swimmer in freestyle swimming  time in 50 m freestyle swimming under 24.50 s for males and under 27.20 s for females) ; (2) ageThe exclusion criteria were: (1) At the stage between competition and/or retirement; (2) having suffered from any injuries in the last six months, such as fractures, impingements, surgery, or injuries during physical therapy.α/2 = 1.96, π = 0.58, and a permissible error of 10% (δ = 0.1π) in formula No formal sample size calculations were conducted at the beginning of this study due to the pragmatic approach. The final sample size was decided based on a predefined time frame of seven months. This decision was made following the principle of convenience or opportunistic sampling , taking One of the researchers (WH.L.) evaluated all 311 participants in two steps, namely, basic demographic and anthropometry measurement  and an EThe ULFE is a test that assesses whether participants have EP and the degree of pain based on elbow joint actions in 13 motion scenarios. The participants were instructed to perform the motions in the order specified by the ULFE. After completing each motion, they were then required to report their perceived pain scores to the researcher. Details of the self-marking in the scoring category can be found in The BPDE is a test that assesses whether participants have EP and the degree of pain based on elbow joint actions in 10 daily scenarios. The participants were instructed to perform the motions in the order specified by the BPDE. After completing each motion, the subjects were required to report their perceived pain scores to the researcher. The details of the self-marking in the scoring category can be found in The ULFE and BPDE in this study are questionnaires designed based on the FMS scale to screen EP patients under both real-life and training conditions. According to the literature, the reliability of the Functional Movement Screen (FMS) scale is 0.81  and 0.81 , respectively, while the odds ratios are within the 95% confidence limits for the injury predictive value ,28,29,30p-value was less than 0.05.SPSS 26.0 software was used for the data analysis. The Kolmogorov–Smirnov and Shapiro–Wilk tests were first used to determine all normality and homogeneity variance levels ,32 Appe. Box–Coxp-value was set at less than 0.05.The Pearson correlation method was used to assess the correlation between the UFLE and BPDE scores and all variables . Then, mn = 1) and “tennis elbow” (n = 2), respectively.All 311 eligible subjects completed all measurements. The demographic findings in Based on the scoring categories of the UFLE and BPDE, the specific pain categories were determined for all 183 EP patients. Among the two pain categories and the EP patients’ anthropometric characteristics, it was found that female EP patients with critical pain had higher values than EP patients with slight pain in terms of age, height, and weight by approximately 0.5 years, 1 cm, and 0.5 kg, respectively. Male EP patients with critical pain had higher values than EP patients with slight pain in terms of age and height, but lower values in terms of weight, with the difference accounting for approximately 1 year, 0.5 cm, and 1 kg, respectively.Both male and female EP patients with critical pain had longer left forearm lengths compared to those with slight pain, by approximately 2 and 8 mm, respectively. However, when comparing the right forearm length, female EP patients with critical pain had longer lengths than those with slight pain, by approximately 6 mm, while male EP patients with critical pain had shorter lengths than those with slight pain, by approximately 1 mm. All EP patients with critical pain were right-handed (accounting for 100%), while only four in five of EP patients with slight pain were right-handed.p-values of less than 0.05. The correlation between gender and UFLE and BPDE scores yielded r-values of −0.299 and −0.152, indicating negative correlations. The correlation between weight and BPDE scores was positive, with an r-value of 0.146. Organization and left and right forearm lengths demonstrated positive correlations with the ULFE and BPDE scores, with r-values of 0.648/0.725, 0.409/0.515, and 0.399/0.514, respectively.The results of the Pearson correlation analysis  indicatep-values of less than 0.05. Gender exhibited a negative correlation with the ULFE and BPDE scores, with β-values of −21.649 and −13.823, respectively. The effects of age, average weekly training hours, organization, and right forearm length showed positive correlations with the ULFE and BPDE scores, with β-values of 0.731/0.484, 0.607/0.572, 9.605/11.431, and 0.518/0.521, respectively.The results of the multiple regression analysis  indicatep-values of less than 0.05. The odds ratio (OR) for the gender factor in ULFE scores ≥ 35  and BPDE scores ≥ 30  as the cut-off threshold was calculated to be less than 1 (OR = 0.376), which indicates a protective factor. This suggests that male swimmers tend to have lower assessment scores and lean toward the “slight pain” category. For the left/right forearm length factor, calculated in ULFE scores ≥ 35  and BPDE scores ≥ 30  as the cut-off threshold, the ORs were both greater than 1 the (OR = 1.168/1.177), indicating a risk factor. This implies that the longer the forearm length of EP swimmers, the more severe the intensity of their pain sensations.The elbow pain predictor results of the binary logistic regression  indicateIn this study, we obtained precise results regarding the number of EP patients, pain categorization, anthropometric characteristics, and distribution among elite freestyle swimmers in Tianjin, China. We also examined the contributing factors to EP. The observed high prevalence rate of EP  raises concerns about the occupational health development of elite swimmers in China.The significant majority of male compared to female EP patients among the total number of 183 EP patients indicates that a significant number of male elite swimmers in China may be struggling with EP without finding appropriate solutions. This phenomenon also highlights the current state of occupational health development among Chinese swimmers, which exhibits a gender disparity with better occupational health levels observed among female athletes . TherefoThis study’s evidence of a correlation between age, height, weight, right forearm length, and organization with the scores of the two EP assessments (UFLE and BPDE) indicates that the root cause of EP problems may lie within these factors. Regarding age, healthy athletes tend to be younger than EP patients. This suggests that the occupational health level of athletes declines with increasing age . TherefoThe results of pain categorization in EP patients show that the number of subjects with slight pain was approximately four times that of those with critical pain. This suggests that these subjects did not promptly report their EP and did not receive effective intervention measures to alleviate their EP discomforts. Therefore, we recommend that coaches and relevant professionals conduct frequent assessments of the occupational health of swimming athletes, aiming to detect and treat EP issues at an early stage to prevent the risk of deterioration . FurtherIn summary, despite the prevalence of EP issues among elite freestyle swimmers in Tianjin, China, potential solutions to reduce the number and risk of EP cases include improving training management strategies, optimizing athlete selection criteria, increasing the frequency of athlete occupational health assessments, and providing timely rest and intervention measures. Additionally, the anthropometric data of EP patients can support the establishment of a sports injury detection system in Chinese swimming teams in the near future.The sample inclusion and exclusion criteria may have overlooked some subjects who also suffer from EP, such as butterfly, backstroke, breaststroke, and synchronized swimmers. Additionally, young athletes under the age of 18 and disabled athletes were not included in the evaluation scope. Consequently, results based on such inclusion and exclusion criteria are preferred. Furthermore, factors such as ligament and tendon injuries, as well as shoulder strength, may contribute to EP among swimmers. These aspects were not investigated in the current study, potentially accounting for variations in the results. Therefore, it is advisable for future research to consider the correlation between these factors and elbow pain.The high prevalence of EP issues among elite freestyle swimmers in Tianjin, China, necessitates increased attention from professionals. Special focus should be directed toward young male athletes within the EP swimmer cohort. Regular proactive assessments would benefit these swimmers. Organizational level and training duration emerged as pivotal factors impacting the elbow joint health of swimmers. Athletes of older age, longer forearm length, higher body weight, and taller stature should be prioritized for observation and assessment, and these traits characterize the EP swimmer profile. Finally, it is important to acknowledge the limitations of this study, including the limited sample range and the technical diversity of swimming. We acknowledge that the current inclusion criteria excluded young athletes (under 18 years old) and disabled athletes, and it is unknown whether EP exists in swimmers primarily practicing backstroke, breaststroke, and butterfly. Therefore, we plan to address these topics in future research.