To analyze the pattern and appropriateness of pain medications in older adults receiving home care.PMAS) was applied to evaluate inappropriateness (i.e. a score ≤67) of pain medication.We performed a prospective cross-sectional study in patients ≥65 years old having chronic pain and receiving home care in Berlin, Germany. Data on prescribed pain medications were collected using self-reported information, nursing documents, and medication plans during interviews at home. Pain intensity was determined with the numeric rating scale (NRS) and the Pain Assessment In Advanced dementia (PAINAD) scale. The Pain Medication Appropriateness Scale score (SPMAS was 47.6 (range 0–100) with 58 (18.0%) of patients achieving appropriate values. Half of the patients were treated with scheduled, while 29.9% were only treated with on-demand medications. Cognitive status had no effect on appropriateness of pain treatment.Overall 322 patients with a mean age of 82.1 ± 7.4 years  were evaluated. The average pain intensity scores during the last 24 hours were 5.3 ± 2.1 and 2.3 ± 2.3 on NRS and PAINAD scale . Sixty (18.6%) patients did not receive any pain medication. Among the treated patients, dipyrone was the most frequently prescribed analgesic (71.4%), while 50.8% and 19.1% received systemic treatment with opioids and non-steroidal anti-inflammatory drugs, respectively. The observed median SWe observed substantial deficits in dosing patterns and appropriateness of pain medication in older adults with pain receiving home care. This applied to both patients with and without severe cognitive impairment. The global population has experienced a demographic change over the last century towards an aging population . In GermWhile pain itself is not a disease, rather a symptom to a multitude of underlying health disorders, chronic pain is regarded by some as a disease in its own right . The impUncontrolled pain substantially affects daily activities such as sleeping, housework and social relationships, and despite a plethora of available analgesic drugs, pain remains inadequately treated in most elderly patients , 12. On The elderly population is challenging in terms of its complexity and heterogeneity where comorbidity and polypharmacy complicate frailty . Thus, iWe set out to assess the pattern of prescribed pain medications and their appropriateness in older adults receiving home care. We performed a prospective cross-sectional study in Berlin, Germany, and included patients independently from their cognitive status; thus patients with cognitive impairment were also enrolled.ACHE study (“Development of a Model for PAin Management in Older Adults ReCeiving Home CarE”) in Germany. ACHE is an observational cross-sectional study conducted in the home care setting in Berlin, Germany, from May 2017 to April 2019. The study complies with the declaration of Helsinki and was approved by the ethical committee of the Charité, Universitätsmedizin Berlin (EA1/368/14). Written informed consent was obtained by all the patients or their legal guardians in case of cognitive impairment.The current analysis is a pre-specified analysis of the recently completed Older adults receiving home care were mainly recruited through ambulatory nursing services  and wereData were obtained through face-to-face interviews in the patients’ own homes by five trained research assistants with different educational and professional qualifications including backgrounds in pharmacy, medical education, social science, nursing, or occupational therapy. Data on pain characteristics, pain management strategies, demographics as well as the level of care were collected and were based primarily on patients’ self-report, caregiving relatives, nurses and, if available, medication plans . Drug-rePain management was evaluated by using the Pain Medication Appropriateness Scale (i.e. PMAS) originally designed to detect problems in pain therapy in nursing homes . The PMAThe German PAINAD scale consists of five items that focus on characteristic behavior due to pain in patients with advanced dementia as a physical indication of pain suffering . For each item considering different behavioral patterns, there is a scale from 0 to 2 and total scores between 0 and 10 are possible.A checklist for special types of pain was also applied. Functional status was evaluated by the Barthel-Index (BI) , 28.Only medications that were prescribed by the treating physicians were considered for PMAS analysis, including both scheduled and on-demand medications; dosing intervals were also considered. Furthermore, we adapted the PMAS according to current national guidelines of pain management as well as high risk drugs avoided in geriatric patients , 30 S1 . In addiPMAS) reflects a percentage considering the possible points (Spossible), as well as the applicable points  according to the formula ) than in subjects without any pain medication . Patients who received only on-demand pain medication achieved lower SPMAS values compared to patients treated only with scheduled analgesics . Patients managed by both scheduled and on-demand medication (n = 84) obtained the highest SPMAS . Age, sex, cognitive state, school education, professional qualification, functional state, and pain intensity did not significantly affect appropriateness of pain medication.The observed median Sf of ≤67 , only 58PMAS . Patients who achieved an SPMAS ≤67 were treated with an average of 1.1 ± 0.8 (range 0–5) analgesic drugs, while patients with an SPMAS >67 received 2.1 ± 0.8 (range 1–4) medications. A total of 134 (51.1%) patients received only one analgesic, the majority of them had an SPMAS ≤67. Nevertheless, there were 10/58 (17.2%) patients who were adequately treated with monotherapy  of patients received adequate pain treatment according to the suggested Salue >67 . Our resalue >67 , 43. A malue >67 . In theialue >67 .One strength of our study is related to the fact that we included also patients with severe cognitive impairment (18.9%). This is in contrast to previous studies that either included only a very small number of these patients  or excluPMAS in the current study is not surprising. A combination of two or more analgesics with complementary mechanisms of action is projected to provide greater pain relief [PMAS >67). In addition, the combined prescription of fast-onset, short-acting, on-demand analgesics with scheduled analgesics for breakthrough pain is useful for optimal pain control [PMAS. In analogy to regularly-administered medications, clear information regarding the dose , the dosing interval and the duration of treatment should be provided to patients when on-demand medications are prescribed [The observed positive correlation between the number of analgesics and Sn relief . However control . This isescribed .As a case in point, we noticed that for 40.6% of prescribed on-demand analgesics, the dosing interval was unknown. In these cases, we could not assess whether these analgesics were adequately dosed by physicians. As a result, no additional points for adequate dosing intervals were considered during evaluation.PMAS, non-pharmacological pain treatment is not considered. The potential of this treatment modality should not be underestimated, especially in the elderly where side effects of medications, drug-drug interactions, and comorbidities can impede the use of pharmacological treatments [Our study has some limitations. First, we analyzed only a relatively small sample because access to this study population is very difficult to achieve in Germany. Second, the patients were interviewed/observed only once, i.e. at a single occasion. Third, no interrater reliability validity was done in our study. However, interrater reliabilities in our previous studies using a similar overall approach were found to be satisfactory and highly significant , 35. Theeatments . The comeatments , 49. Fureatments , 50 and eatments . Nevertheatments , wherebyeatments , 52. In eatments .We observed substantial deficits related to lack of treatment, inadequate dosing patterns and overall high frequency of inappropriate use of pain medications in older adults with pain receiving home care. Therefore, interventional strategies to improve treatment by implementing a multidisciplinary network approach involving physicians, pharmacists, nurses and patients, possibly supported by modern eHealth tools  is highlS1 FigIn consideration of all patients for whom the PAINAD sum score was available (n = 81), an appropriate four class categorization was not possible (A). For further explorative data analyses, we excluded patients with a total sum score of 0 on the PAINAD-scale (n = 57). Thus, we got a boxplot indicating four classes of the PAINAD sum score (B) as described in (DOCX)Click here for additional data file.S1 TablePMAS, Pain Medication Appropriateness Scale; NSAIDs, non-steroidal anti-inflammatory drugs; PRISCUS list, Potentially Inappropriate Medications in the Elderly.(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 TableWith regard to the highest level of sensitivity and specificity, a PAINAD score greater than 0.5 was chosen to determine cognitively impaired patients with pain-associated physical expressions. ROC, Receiving Operating Characteristic.(DOCX)Click here for additional data file.


To evaluate the feasibility and safety of treating painful osseous metastases using image‐guided percutaneous thermal microwave ablation.This is a retrospective study of patients treated from December 2016 to December 2019 in one institute. A total of 50 patients  with 56 osseous metastatic lesions underwent image‐guided percutaneous microwave ablation. There were 7 patients with multiple and 43 patients with single metastases. The numbers of patients with primary cancer were as follows: lung, 13; liver, 17; kidney, 10; prostate, 1; breast, 3; osteosarcoma, 1; and thyroid, 5. Seventeen patients had cancer combined with soft tissue masses. The radiological images for the ablative procedures were obtained by CT, fluoroscopy with ultrasound, and fluoroscopy alone in 16, 11, and 23 patients, respectively. Pain severity was estimated using the visual analogue scale before and after treatment . Radiological evaluations were performed at baseline and 3 months after the procedure.In all patients, pain reduction occurred from the first day after treatment. Pain did not recur during the 3 months of follow up. The mean total ablation time per microwave electrode was 3.99 ± 2.48 min . The mean power of the microwave electrode was 66.40 ± 12.08 W. The average volume of bone  cement after ablation was 2.82 ± 0.81 mL. There were no significant differences in visual analogue scale pain scores for different imaging techniques or ablation energies. No procedure‐related complications occurred.Image‐guided percutaneous thermal microwave ablation of osseous metastases relieves pain and improves mobility. CT remains the first choice for percutaneous ablation. Fluoroscopy combined with ultrasound is effective for cases with soft tissue masses; fluoroscopy is also suitable for combination with vertebroplasty. However, further investigations are required. (A) Microwave ablation probe. (B) Temperature probe in the vertebral body and in the vertebral pedicle . (C) Metastatic tumor. The thick white line of the ablation probe tip represents the source of microwave needle emission. The orange region represents the heating range of the microwave. Bone metastases are common, painful complications in patients with advanced cancerManagement of osseous metastatic disease requires multidisciplinary input. In addition to continually evolving medical therapy regimens, surgical techniques, and radiation technologies, treatment options now include emerging minimally invasive interventionsDue to these patients' short life expectancy and poor quality of life, a minimally invasive therapeutic approach is desirable. Recently, image‐guided ablation techniques have emerged and produced satisfactory results in the management of osseous metastatic painet al. reported microwave ablation of 102 spinal metastases in 69 patients under CT or fluoroscopy. Follow‐up imaging at 20–24 weeks demonstrated no locoregional progression in 59 of the 61 surviving patients. Two complications were documented; one of them was S1 nerve thermal injury. Westbroek reported a case performed under fluoroscopy with the resultant complication of thermal injury to the spinal cord.Khan et al. reported successfully treating 20 spinal metastases (17 patients) with MWA (with cementoplasty in 9 cases). They reported pain relief in 16 of 17 patients, with significant pain reduction 1 day, 1 week, and 1, 3, and 6 months after ablation without any major complications. However, CT requires a large operational space, is time‐consuming, and has some radiation effects on patients and surgeons.Kastler Ultrasound‐guided thermal surgery is now widely used in the management of lung, liver, and kidney cancers and has achieved satisfactory results. It provides real‐time visualization of applicator placement and intraoperative monitoring of the extent of ablation. However, it is not widely used in bone and soft tissue tumors and few reports exist of fluoroscopy combined with ultrasound‐guided microwave ablationThe purpose of our research was to answer the following three questions: i) whether using various image‐guided procedures  for microwave ablation in osseous metastases is safe; ii) whether using various image‐guided procedures is useful in controlling metastatic osseous pain; and iii) whether there are any differences between the three image‐guided percutaneous microwave ablation procedures for treating painful osseous metastases.All patients provided informed consent for participation and image publication, and were selected by an interdisciplinary team of radiation and medical oncologists and an orthopaedist , who performed image‐guided percutaneous MWA of osseous metastases between December 2016 and December 2019. This study was approved by the institutional review board. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Inclusion criteria were as follows: (i) patients who experienced refractory pain with a visual analogue scale (VAS) score of ≥4; (ii) lesions that did not respond to chemotherapy and/or radiotherapy; (iii) life expectancy >3 months; and (iv) ineligibility for surgical excision. Exclusion criteria were as follows: (i) active infections; (ii) lesions affecting key nerve roots or vascular bundles; and (iii) when the correlation between imaging findings and clinical symptoms was uncertain.A total of 50 patients  with 56 osseous metastatic lesions received image‐guided percutaneous MWA. All patients had previously received standard treatments: 39 received surgery on the primary site, 24 received chemotherapy, and 16 received chemotherapy and radiotherapy. There were 7 patients with multiple and 43 patients with single metastases. In addition, the numbers of patients with primary cancer were as follows: lung, 13; liver, 17; kidney, 10; prostate, 1; breast, 3; osteosarcoma, 1; and thyroid, 5. A total of 17 patients had cancer combined with soft tissue masses.All patients underwent pre‐procedural contrast‐enhanced CT scanning and/or MRI to evaluate the size and location of and the relationships among lesions, nerves, and vascular bundles and to determine the ideal location of the antenna and scope of MWA.Ablation was performed with an MWA system . CT‐guided surgery, fluoroscopy combined with ultrasound, and fluoroscopy were performed for 16, 11, and 23 cases, respectively. The choice of guidance with CT, tomography (X‐rays), or ultrasound with tomography depended on the type of lesions and associated soft tissue masses. Throughout the procedure, 12 patients were consciously sedated using continuous intravenous infusion of fentanyl citrate  and received local anesthesia composed of a subcutaneous injection of 2% lidocaine hydrochloridein situ for the osteoplastic procedure. Illustrative cases of each image‐guided procedure are shown in Figs n = 1) and vertebrae (n = 24). The amount of bone cement injected under image guidance was determined based on tumor size. In the case illustrated in Fig. An 11‐gauge bone biopsy needle was inserted into the proximal edge of the lesion under image guidance. The choice of ultrasonic probe was adjusted according to the depth of the lesion: a high frequency linear ultrasound probe was selected for the detection of superficial sites, including superficial masses and blood vessels, while a convex array transducer was used for deep tumors and deep blood vessels . Subsequently, the needle shaft was withdrawn, and the biopsy needle was advanced into the lesion. Once the appropriate position was confirmed, core biopsy samples were obtained. A 15‐gauge or 14‐gauge MWA antenna  was coaxially inserted into the tumor until the tip of the antenna was adjacent to the edge of the lesion. Technical success was defined as the ability to place the antenna accurately into the tumor and to calculate the ablation zone 2–3 mm beyond the extent of the tumor in an oval configuration; if the distance from a neurovascular bundle was <5 mm, the above requirements were not adhered to. Concurrently with ablation, a thermometer needle was placed in the normal tissue to ensure that the temperature remained below 43°C. Because the temperature probe only reflected the temperature at its tip, two to three probes were placed simultaneously to monitor the temperature at different sites, such as deeper intraoperative positions. After ablation, the antenna was withdrawn, and, if required, the introducer was left Before the ablation treatment and at follow up, the VAS was used to evaluate the pain severity. Pain intensity was rated on a continuous scale from 0 to 10Continuous data for pain intensity was recorded using the VAS. The score was determined by measuring the distance (mm) on the 10‐cm line between the “no pain” anchor and the patient's mark using a ruler, providing a range of scores from 0 to 10; a higher score indicated a greater pain intensity. The following cut‐off points pain using the VAS have been recommended: no pain, 0; mild pain, ≤3; moderate pain, 4–6; and severe pain, 7–10t‐test was applied to evaluate VAS scores before and after the procedure; P < 0.05 was considered statistically significant.SPSS 24.0  was used for data analyses. Continuous variables are shown as mean ± standard deviation. Student's A total of 35 men and 15 women were included in this study. The mean total ablation time per MW electrode was 3.99 ± 2.48 min (range: 1–15 min). The mean power of the MW was 66.40 ± 12.08 W (range: 40–80 W). Approximately 40% (20/50) of cases (25 sites) underwent the osteoplastic procedure; the mean volume of bone cement injected was 2.82 ± 0.81 mL.Based on the results obtained, the three questions posed by this study were answered in the following manner.(1) Whether using various image‐guided procedures  for microwave ablation in osseous metastases is safe: None of the patients had complications related to the three image‐guided procedures, such as neurovascular bundle injury. Two patients who underwent ablation procedures assisted by fluoroscopy combined with ultrasound developed symptoms of fever on postoperative days 1 and 3 that lasted for 24–48 h. This was attributed to post‐ablation syndrome. Illustrative emulation of intraoperative ablation and monitoring is shown in Figs (2) Whether using various image‐guided procedures is useful in controlling metastatic osseous pain: VAS scores for the assessment of pain were recorded preoperatively and postoperatively . All patients achieved satisfactory pain relief. The preoperative VAS scores ranged from 6 to 10, with an average of 8.75 ± 1.03 before CT‐guided operation, 8.33 ± 1.50 before fluoroscopy combined with ultrasound, and 8.66 ± 1.41 before fluoroscopy. Average VAS scores 24 h after ablation procedures guided by these imaging modalities were 2.37 ± 1.08, 2.00 ± 1.26, and 2.17 ± 1.19, respectively. The mean reductions in VAS scores were calculated from 1 week to 3 months after the procedure. The postoperative VAS scores for lung, liver, prostate, breast, thyroid, kidney, and bone metastases were significantly lower than the preoperative scores . No significant differences in VAS scores were observed among the different primary lesions. The lesions were divided into osteolytic and osteolytic combined with osteoblastic groups through imaging analysis, such as X ray, CT, and MRI. Although patients in the osteolytic group had better postoperative pain improvement, there was no statistical significance in the changes of VAS curves between the two groups. The VAS score curves are shown in Fig. (3) Whether there are any differences between the three image‐guided percutaneous microwave ablation procedures for treating painful osseous metastases: No significant differences in VAS scores were observed among the different imaging techniques and ablation energies. In patients who also had soft tissue masses, there was no difference in the VAS scores between CT and fluoroscopy with ultrasound. The VAS score curves are shown in Figs Bone metastasis is common and occurs in approximately 20% of patients with canceret al.via the nerve endings, decreased osteoclastic activity and coagulative necrosis of the tumor cells, and resultant decrease in the production of nerve‐stimulating cytokines such as interleukins and tumor necrosis factorSome studies that have used MWA to treat patients with painful metastases have demonstrated promising resultset al.Percutaneous MWA can be currently performed under imaging guidance. Fluoroscopy‐guided percutaneous ablation is suitable for combination with vertebroplasty due to its low resolution of soft tissueet al. introduced low‐milliampere CT fluoroscopy during CT‐guided ablationCT‐guided proceduresTo overcome these shortcomings, we performed selected fluoroscopy combined with ultrasound‐guided surgery in cases of osseous metastasis with soft tissue masses. Although fluoroscopic positioning is not precise, it produces little radiation. Ultrasound has relatively poor accuracy in bone tissue detection and is generally used in soft tissue tumor ablation; however, it provides real‐time visualization of applicator placement and is both universally available and of low costOsteolytic metastases can cause pathological fractures, and an impending fracture should be treated before the fracture occursWith respect to the functional evaluation of this treatment, most patients exhibited improved functional performance. Pusceddu reported that 98% of patients with large lesions obtained overall functional improvement 6 months after the procedure. Only 1 patient experienced a worsened functional outcomeMost researchers have suggested sedation combined with local anesthesiaThe present study has some limitations. First, this study had no control group and only a small number of cases were included. Second, this is a retrospective analysis from only one institution and the data might be limited by referral bias.Image‐guided percutaneous MWA of osseous metastasis significantly relieved pain and improved mobility; however, the decision to use a combination of bone cement in weight‐bearing bones should be taken on a case‐by‐case basis. CT is the preferred imaging modality for percutaneous ablation, while fluoroscopy combined with ultrasound is effective for cases with soft tissue masses. The hyperechoic area arising during the operation and the thermal monitoring system provide real‐time intraoperative monitoring of the extent of ablation. Fluoroscopy is suitable for combination with vertebroplasty. Further research with larger study populations is needed to assess the utility of image‐guided percutaneous MWA and to validate the findings of this study.


The postoperative PCA requirement, pain scores, opioid-related side effects, and blood cortisol levels were recorded. TEAS treatment resulted in a twofold decrease in the analgesic requirement and decreased pain level reported by the patients. In addition, a significant reduction of cortisol level was reported in the TEAS group at 24 h postoperatively compared to the sham and control groups. We conclude that TEAS is a safe and effective option for reducing analgesic consumption and postoperative pain following inguinal hernia repair. Given the rising rate of opioid-related adverse drug events during postsurgical pain management, a nonpharmacologic therapy that could decrease analgesic medication requirements would be of immense value. We designed a prospective, placebo-and-randomized controlled trial to assess the clinical effect of transcutaneous acupoint electrical stimulation (TEAS) on the postoperative patient-controlled analgesia (PCA) requirement for morphine, as well as side effects and recovery profile after inguinal hernia repair. Seventy-one subjects undergoing inguinal hernia repair with a standardized anesthetic technique were randomly assigned to one of three analgesic treatment regimens: PCA + TEAS ( Opioid analgesia remains the mainstay for postsurgical pain management, yet the consequences of its use incur risks for patients before and after discharge . Opioid Transcutaneous electrical acupoint stimulation (TEAS) is a non-invasive, safe, and comfortable treatment modality, which combines the effects of transcutaneous electrical nerve stimulation (TENS) with acupuncture point stimulation. TEAS excites the afferent nerves at an acupuncture point with low-voltage impulses. It is based, in part, on traditional Chinese analgesic methods and is known to suppress the transmission and perception of injurious stimuli . The curMost prior assessments have shown a beneficial effect of TENS or electroacupuncture (EA) in reducing pain intensity after hernia surgery ,16,17. Hhttps://doi.org/10.1186/ISRCTN76428396). All participants provided written informed consent before randomization and after being informed on the potential benefits, risks, alternatives, and responsibilities of the study.This prospective, three-armed, single-blinded, placebo-controlled randomized controlled trial was conducted at Wroclaw University Hospital, Wroclaw, Poland, from September 2017 to November 2020. The study was conducted in accordance with the Helsinki Declaration to protect the participants and was approved by the ethics committee of Wroclaw Medical University (No. KB-599/2017). The study protocol was registered at the ISRCTN registry . An independent, blinded statistician generated the block randomization scheme. The table was managed by an independent researcher who was not involved in the recruitment, treatment, or assessment. The participants were blinded to the type of treatment. Mock TEAS was provided with the same lamplight as real TEAS, so the participants were not able to predict the allocated group based on the appearance of the treatment .Power analysis was performed to determine the number of patients per group sufficient to detect a decrease of 30% or more in the PCA opioid analgesic requirements during the first 24 h after surgery, based on the results of the previous studies ,18,19. EA standard premedication of 7.5 mg oral midazolam was administered in every patient 30 min prior to entering the operating room. Thereafter, standard patient monitoring, including continuous electrocardiography, pulse oximetry, and indirect blood pressure (measured every 5 min), was applied and maintained until the end of anesthesia. Three-minute preoxygenation with 100% oxygen preceded the induction phase in every patient. Then, 1–3 mcg/kg fentanyl, followed by 2–3 mg/kg propofol and 0.6 mg/kg rocuronium, was applied through the peripheral vein to induce general anesthesia. Individually selected, an appropriate size endotracheal tube (ET) was placed via direct laryngoscopy. After confirmation of proper ET placement, mechanical ventilation was commenced, and anesthesia maintained by sevoflurane 2–4 vol.% mixed with 60% oxygen, titrated to achieve 0.9–1.2 MAC. Continuous monitoring of capnography was used to ensure proper respiratory function and gas exchange. During the surgery, additional boluses of fentanyl (1–2 mcg/kg) were administered in the presence of the patient’s reactions to pain stimuli . Depending on the time of surgery, an additional bolus of 25% of the initial dose of rocuronium was applied. For basic pain control, 1 g of metamizole was given to every patient before completion of the surgery. After cessation of sevoflurane administration and achieving an adequate level of consciousness and responsiveness, the patient was extubated. After the surgery, every patient was monitored and carefully observed for at least 30 min in the recovery room.The surgical technique was the Lichtenstein tension-free method. Hernia patients, according to the classification of Nyhus, were type II or IIIb.On a patient’s arrival in the postanesthesia care unit, the PCA device was connected to the patient’s intravenous line and programmed to deliver 1 mL bolus doses of morphine (1 mg) “on-demand”, with a minimal lockout interval of 10 min and a maximum 4 h dose of 15 mg according to a standardized hospital protocol. PCA therapy was initiated in the postanesthesia care unit when the patient was sufficiently alert to understand and operate the PCA device. If the patient required pain medication prior to starting PCA therapy, an incremental dose of metamizole 1 g intravenously was administered by the postanesthesia care unit nursing staff. The postoperative PCA analgesic therapy was supplemented with TEAS/sham therapy, which started when the patient arrived in the postanesthesia care unit.Stimulation was performed using four portable coin-sized electro-stimulators . A point-detection function in the device confirmed the correct localization of the stimulator. The TEAS group received mixed frequency stimulation  in continuous mode for 30 min at intervals of 2 h. The device was automatically shut off at the end of each 30 min treatment interval. The intensity of the stimulation was adjusted to each individual to maintain a slight twitching of the regional muscle and achieve De-Qi sensations, such as soreness, distention, and heaviness. To minimize the arousal effect of electrical stimulation on the patient’s quality of rest and sleep, the intensity of stimulation was reduced by 50% during sleep hours. In both groups, electro-stimulators were applied bilaterally to LI4 (He Gu) and ipsilateral to hernia to two ashi points located within a diameter of 5 cm from the incision site . The poiTotal morphine dose received in the postoperative period (mg) using patient-controlled analgesia (PCA) device .The number of PCA demands  and delivered bolus doses after surgery. Score on the Visual Analogue Scale prior to the surgery and at 4, 8, 12, 16, and 20 h after surgery. The scale of 0 to 10, where 0 represents the complete absence of pain and 10 represents the worst pain intensity. Moreover, opioid-related side effects and the requirements for supplemental medications  were recorded during the postoperative observation period. The patients’ whole blood was collected between 8 and 10 a.m. on the day before the surgery and 24-h later within the same timeframe. After collection and the samples were transferred to an appropriate collection tube. After being centrifuged at 10,000 rpm for 10 min, serum was transferred into a new cryotube to freeze the samples at −80 °C until the analysis. Cortisol level was detected by an enzyme immunoassay using the ELISA kit . The 5 µL of serum samples were resuspended in 5 µL Dissociation Reagent, and 490 µL of the Assay Diluent included in the ELISA kit to prepare final serum dilution 1:100. Then cortisol levels were analyzed according to the manufacturer’s instructions. The absorbance was measured at 490 nm on microtiter plate reader BioTek ELX800 . Cortisol levels were analyzed in a total of 21 patients (7 in each arm). The standards and samples were prepared in duplicate, and the results are presented as means. Intra-assay variances between data points within an assay were between 1 and 5%. The levels of cortisol are shown as ng/mL. All adverse events were closely monitored through reports by participants or direct observation by personnel and by asking the patients about adverse events during the observation period. All adverse reactions were recorded, and additional treatment was offered if required. t-test (t-test for Independents Samples by Groups) was used to compare the mean values in two groups, and in the case of three groups-one-way analysis of variance (ANOVA). HSD Tukey’s test (Tukey honest significant difference) and Kruskal–Wallis ANOVA were used for multiple comparisons (post hoc tests). In addition, a multivariate analysis, ANOVA for factorial designs , was performed where the main effects and their interactions (relationships between independent variables) were analyzed. The significance level was set at 5%. All data were analyzed using Statistica v.13.3 . Quantitative variables were reported using the mean and SD (M ± SD) for normally distributed data or median (Me), the lower quartile (Q1), and the upper quartile (Q3) and the range (min–max) for skewed data. Shapiro–Wilk’s test was used to verify the normality of distributions. In the one-way analysis, the Student’s The datasets analyzed for the present study were collected directly from the patients and will not be publicly shared due to conditions of ethical approval. The datasets are available from the author upon reasonable request.p > 0.05).The recruitment and follow-up of the trial participants are presented in p < 0.001; The total morphine dose (mg) received in the postoperative period using PCA device in the first 24 h was significantly decreased in the TEAS group  compared with the sham  and control groups  . Although we have also observed a reduction in the cortisol level at follow-up compared to baseline in the study group, the difference did not reach statistical significance (p = 0.063). In TEAS-treated patients, the cortisol level at 24 h postoperatively was significantly lower compared to sham (p = 0.024) and control group (p = 0.001)  .On the follow-up interview, nearly 90% of the study patients reported that their postoperative pain was “satisfactorily” treated, and there were no significant differences among the three groups. No patient complained that the electrical stimulation produced by the TEAS device was uncomfortable. In one patient in the study group and two patients in the sham group, skin irritation (redness and itching) was observed; however, the severity of these symptoms was mild, and no subjects reported discomfort nor required specific treatment. Sedation, pruritus, vomiting, and other side-effects were not reported.With more than 20 million patients yearly, inguinal hernia repair is among the most commonly performed surgeries worldwide . The proThe results of this study clearly document the opioid-sparing effect of TEAS. We have found that the use of TEAS resulted in over 50% decrease in narcotic analgesic usage. Moreover, our results indicate that the level of pain was significantly lower in the study group compared with the sham and control groups. In the present study, a combination of the LI4 acupuncture point and peri-incisional ashi points were found to augment PCA analgesia in the postoperative period . Our resNot only points selection but also the frequency of stimulation and treatment timing play a critical role in determining the outcome of the intervention. In humans, low-frequency (2 Hz) electrostimulation applied at the acupoints exerts antinociceptive effects mainly by enhancing the release of met-enkephalin (M-ENK) and β-endorphin (β-EP) ,30. The Pain initially stimulates the hypothalamic-pituitary-adrenal system to produce cortisol and travel to tissue targets, including wounds and injured nerves. Therefore, in the stimulation phase of acute pain, cortisol levels are elevated . Our stuDuration of electrical stimulation can influence the effectiveness of TEAS. Continuous stimulation leads to the development of accommodation (or habituation) to the electrical current . In contInterestingly, no patients in the study group reported that stimulation adversely influenced their quality of hospitalization. Notably, an earlier study has shown that over a third of all patients complained that cutaneous electrodes and wires had an adverse impact on their quality of sleep . We haveSince it has been implied that acupoint stimulation exerts a placebo effect with respect to its analgesic qualities , it was There are some limitations to this study. First, we only collected data on pain control in the short-term postoperative period. The effect of TEAS on long-term pain management after surgery needs further investigation. Second, although we tried to minimize the risk of patient bias by setting up a sham-group and providing the participants with the same devices as the true group, the limitation included lack of proper electrical stimulation. Third, it is necessary to study the effect of TEAS on postoperative analgesic consumption and pain control in large-scale multi-center studies and other types of surgery in the future.Another factor analyzed in the study included the incidence of nausea after the surgery. Although there were no subjects reporting nausea in the study group, no statistically significant difference was found between the three arms of the study. The results are presumably secondary to the relatively low incidence of nausea in the trial. In conclusion, the postoperative use of TEAS resulted in a twofold decrease in the analgesic requirement. In addition, when TEAS was used as an adjunct to PCA, it produced a significant decrease in the level of pain reported by the patients. The evidence suggests that acupoint stimulation exerts its action through the neuroendocrine system. Adding the fact that it is easy to employ TEAS in a postoperative setting and that multiple stimulation sessions are possible, we conclude that TEAS is a safe and effective option for reducing analgesic consumption and postoperative pain following inguinal hernia repair. Further large-scale prospective randomized controlled trials are warranted to establish the TEAS-based treatment regimens for enhanced recovery after surgery.MS, SA, PP, AA, WG, BB, MN, and JR are inventors on submitted patent applications .


BackgroundPatients with loin pain hematuria syndrome (LPHS) can find relief via multiple modalities, few provide long-term pain control like renal auto-transplantation (RAT). This study evaluates the intermediate effectiveness of the RAT procedure’s ability to achieve long-term pain control and quality of life improvement.MethodsAll patients with suspected LPHS were seen by a multi-disciplinary team (MDT) composed of urologists, interventional radiologists, and transplant surgeons. Clinical history and physical exam, lab values, imaging findings, and response to renal hilar block (RHB) were used to determine LPHS and candidacy for potential RAT. Preoperative, one-year, three-year, and five-year postoperative pain assessment scores and quality of life surveys were administered to each LPHS and potential RAT patient.ResultsEighty-four LPHS patients were referred for the evaluation of and consultation for the option of RAT. Sixty-four of these patients underwent RHB of which 60 (93.8%) had a positive response, defined as a temporary reduction of pain score by >50%. Forty-six of the 60 patients who responded favorably proceeded to RAT. At the one-year follow-up, there was a 75% reduction in pain with 88.9% of patients experiencing a 50% reduction in pain. At one year, the mean Beck Depression Inventory (BDI) decreased by 65.4%, from an average of 23.7 to 8.2. Similarly, at three years (n = 5) and five years (n = 3), the mean pain scores were 2 and 1.ConclusionsThe MDT evaluation of potential LPHS patients with our protocol and treatment results in an improvement in pain and depression scores in these selected patients. Loin pain hematuria syndrome (LPHS) was first described in 1967 as otherwise unexplained severe flank pain with gross or microscopic hematuria ; it is tSurgical or other procedure-based therapies include percutaneous regional nerve block, surgical sympathectomy, renal capsulotomy, vascular pedicle denervation, ureterolysis, nephrectomy, and renal auto-transplantation (RAT) ,7-9. PreOne reason for the treatment failures of LPHS is the difficulty in establishing the correct diagnosis . We propIn this paper, we report our intermediate-term results for patients in whom this standardized MDT evaluation was performed, followed by RAT.We defined LPHS as chronic (> 6 months), unbearable flank pain with or without hematuria in the absence of infection, nephrolithiasis, or upper tract obstruction. An MDT, consisting of a urologist, interventional radiologist, and transplant surgeon, was created to evaluate and treat patients with suspected LPHS. All candidate patients, of all genders, went through the same, standardized evaluation protocol. They were first evaluated by our senior urologist to rule out other causes of flank pain and hematuria. If the urologic evaluation was consistent with probable LPHS, patients were then referred to interventional radiology for an RHB.Prior to RHB, the interventional radiologist graded and recorded pain reported by the patient using a standard visual analog scale (VAS), where 10 is the worst pain and 0 is no pain. Patients were positioned prone, and the renal artery was identified by non-contrast computed tomography (CT). A 21 G needle was advanced adjacent to the ipsilateral renal artery. A 50/50 mixture of 2% lidocaine and 0.5% bupivacaine was administered with a total volume of 20 mL . A post-Prior to surgery, baseline quality of life and pain assessment geared towards LPHS patients developed by our MDT was filled out. Patients also completed the Medical Outcomes Study Questionnaire Form 36 Health Survey (SF-36)  and the Pain score, BDI, and QOL of 50 patients were summarized before and after surgery. Pain score and BDI were summarized as mean (standard deviation (SD)), median (interquartile range (IQR)), and range. QOL was summarized as frequency and percentage at each level (ordered from not acceptable to very good). The exact Wilcoxon signed-rank test was used to compare scores before and after surgery when both were available where QOL, an ordered categorical variable with five levels, was treated as a numerical.Between 2013 and 2020, we evaluated 84 patients for LPHS through a near equal mixture of urology and transplant referrals using our standardized MDT methodology. Of these, 64 patients qualified for an RHB after initial evaluation by our urologist. The mean duration of chronic pain prior to RAT was 5.1 ± 7.4 years. Sixty patients had >50% reduction in pain scores following the RHB. The mean patient age was 32.3 years, and 73% of the patients were female  had a >50% reduction in pain; this is considered a positive response. For patients who responded to RHB (>50% reduction in pain), there was an overall decrease in pain by 86% (6.6 ± 1.7 down to 0.9 ± 1.2).Of the 60 patients with a positive response to RHB, 10 (17%) did not undergo RAT; four were denied by insurance, four patients chose alternative therapies (simple nephrectomy (3), intrathecal pump (1)), and two were not candidates for auto-transplant (horseshoe kidney (1), solitary kidney in a morbidly obese patient with three renal arteries (1)).Of the 50 remaining patients, 46 underwent RAT and the other four are awaiting their scheduled surgery. Of the 46 patients who underwent RAT, 16 patients (36%) were previously diagnosed with depression and 28 (57%) were taking pain medications chronically. The pain was described as burning by 13 (29%), aching by 27 (60%), stabbing by 39 (87%), and/or dull by 21 (46%). There were no patient deaths or graft loss for all 46 patients that underwent a RAT. The donor nephrectomy portion of the surgery was performed laparoscopically in the standard fashion. Two patients were converted to open nephrectomy because of adhesions from prior surgery. After preparation on a back table, the kidneys were then placed into the patient through a standard lower quadrant transplant incision. Mean operative time was 281 ± 51 minutes.Of the 46 patients that received RAT, 27 (59.6%) patients have at least one year of follow-up after surgery. Nine patients were lost to follow-up and did not complete the one-year questionnaire. One-year pain assessment was 1.6 ± 2.5 with a mean pain score decrease of 75%. All 27 patients had a sustained improvement in their pain with 85% having a >50% improvement. Mean BDI score  one year after RAT decreased from 23.7 preop (moderate depression) to 8.2 postop . There were significant shifts in the quality of life, pain affecting the quality of life, and BDI scores  of patients would undergo another RAT if similar symptoms arise with the other one patient opting for ‘maybe.’Chronic flank pain, often described as loin pain hematuria syndrome, remains an elusive diagnosis that has proven difficult to understand and difficult to treat. When we began our protocol seven years ago, we were motivated by the remarkably dismal outcome of treatments for patients with LPHS. Medical management seemed to be relatively ineffective and carried a tremendous burden since opioids were frequently a staple of those regimens-in an era when we, as a medical community, were trying to decrease our patients’ usage of opioids. Percutaneous ablative techniques were widely disparate, inconsistently applied, and often yielded only transient improvement. Surgical solutions included nephrectomy-often the untimely removal of a functioning kidney in a young patient-and auto-transplant, which had a wide range of success rates yielding a predicted outcome that was often no better than a flip of a coin.We believed that by the creation of a standardized protocol, employed consistently by a multidisciplinary team, we could both predict and achieve durable results in a greater portion of these patients. We have now demonstrated the success of that program by reporting consistently excellent results at one year and showing a durable trend of success at three and five years.Our experience now demonstrates that successful treatment for LPHS relies on appropriate diagnosis and the predictive ability of our standardized protocol performed by a multidisciplinary team of clinicians. Our patients have all been previously evaluated by urologists/nephrologists who then refer the patients to our center for LPHS assessment. We report successful screening and triage of patients to RAT through an MDT approach developed at our tertiary referral center. Clinical evaluation by an experienced urologist focuses on eliminating alternative causes of pain and hematuria and identifying appropriate clinical symptoms and history for LPHS. RHB by the interventional radiologist is a critical step in the work-up as it temporarily anesthetizes the renal nerves, predicting the success of RAT.Prior reports have shown a 25% and a 88% rate of success utilizing RAT for pain control in LPHS, which is an unacceptably low rate of success considering the magnitude of surgery -11. The In addition to the reduction in pain scores, our patients’ mental health and quality of life were also improved. Not surprisingly, chronic pain is frequently accompanied by an adverse impact on mental health and overall quality of life. In our cohort, patients went from being moderately depressed (mean score of 23.7) preoperatively to minimally depressed at one year (mean score 8.2). Likewise, there was an observed improvement in the quality of life from “not acceptable” to “very good.” Each of these improved measures is consistent with the overall improvement of these patients’ well-being.When we examine the three- and five-year data, the trends appear to hold up, suggesting a durable response. Patients reported a BDI score of 8.2 at three years and 13.2 at five years. An increase in BDI score is noted in the five-year patient population; however, according to surveyed patients, the increased scores are attributed to disease processes not associated with loin pain. The observed sustained improvement in quality of life affirms the aforementioned statement with a majority of three- and five-year patients reporting ‘very good.’Although success rates for RAT in the existing literature are low, it is unclear from these reports how the diagnosis of LPHS was made. MDT with protocolized evaluation can help appropriately select patients for RAT with prediction for successful outcomes. A transplant program that has a high-volume live donor kidney transplant program with excellent results as defined by the Scientific Registry of Transplant Recipients (SRTR)  is anothA limitation of this study is the smaller number of patients with three- and five-year follow-up data. Early in the study period, we treated fewer patients and had a greater number of patients rejected for treatment by insurers. In addition, there were patients who were lost to follow-up, in part because of the large geographical referral patterns, as well as early lapses in protocol or patients who opted out of the study.In conclusion, RAT should be considered an excellent treatment option for appropriate patients after standardized evaluation by a multidisciplinary team. This study confirms that when MDT is used with an RHB as part of the workup protocol, RAT is highly successful with a durable reduction in pain and depression scores and patients’ quality of life.


Total knee arthroplasty (TKA) is known to be a painful orthopedic procedure and moderate to severe pain is common, especially immediately postoperatively and during active motion. The aim of the present study was to compare epidural analgesia (EA) and adductor canal block (ACB) techniques with regard to early period pain levels, need for additional opioids, and ambulation and functional scores in patients who had undergone primary TKA.P < .05.Approval for the study was granted by the Changji Branch of the First Affiliated Hospital of Xinjiang Medical University. Written informed consent will be obtained from all of the participants. Inclusion criteria included the following: planned unilateral TKA; spinal anesthesia; American Society of Anesthesiologists physical status classification score of I to III. Prospective assessment will be done for 100 patients who are scheduled for unilateral primary TKA surgery in our academic hospital by a single senior surgeon between August 2020 and December 2021. Patients were randomized to ACB treatment or EA treatment by a computer random number generator. The primary outcome was visual analog scale pain scores in the immediate postoperative period. Secondary outcomes included postoperative opioid use, length of hospital stay, activity level during physical therapy, and knee range of motion. Results were evaluated in a confidence interval of 95% and at a significance level of We hypothesized that standard ACB would be as effective as EA for postoperative pain management following TKA.This study protocol was registered in Research Registry (researchregistry5775). Therefore, postoperative pain management is of utmost importance for patient outcome and satisfaction, and many studies have reported that multimodal pain management was necessary.,5The prevalence of knee osteoarthritis is increasing world-wide due to the aging population. A standard surgical intervention for advanced knee osteoarthritis is total knee arthroplasty (TKA), and demand for this surgery is rising.,7 EA consisting of a local anesthetic agent and an opioid has been a regular regimen used for postoperative analgesia after TKA. However, some studies have indicated that the benefit of EA must be weighed against the frequency of its adverse effects such as urinary retention, hypotension, pruritus, and motor block that delays mobilization.,8–10 FNB has traditionally been the gold standard for analgesia following TKA, but FNB significantly impairs quadriceps motor function, which may interfere with rehabilitation and delay discharge. ACB has emerged as an alternative to FNB after TKA. ACB offers the advantage of sparing the motor nerve supply to most of the quadriceps muscle, which may facilitate physiotherapy after TKA and may lead to a reduction in falls after surgery. ACB is commonly integrated into a multimodal pain protocol to improve pain management after TKA.–14Patient-controlled analgesia, local infiltration analgesia, epidural analgesia (EA), femoral nerve block (FNB), and adductor canal block (ACB) are some methods that may manage the postoperative pain and shorten the physiotherapy duration, but the most efficacious remains unclear.,9,15 there have been limited studies directly comparing ACB to EA in terms of postoperative pain control and ambulation after primary TKA.–18 Thus, the aim of the present study was to compare EA and ACB techniques with regard to early period pain levels, need for additional opioids, and ambulation and functional scores in patients who had undergone primary TKA. We hypothesized that standard ACB would be as effective as EA for postoperative pain management following TKA.However, while studies exist comparing FNB to EA and FNB to ACB,22.1Approval for the study was granted by the Changji Branch of the First Affiliated Hospital of Xinjiang Medical University (CJ97440). Written informed consent will be obtained from all of the participants. Prospective assessment will be done for 100 patients who are scheduled for unilateral primary TKA surgery in our academic hospital by a single senior surgeon between August 2020 and December 2021. Our study was registered in Research Registry (researchregistry5775) prior to the enrollment start. All surgeons, recovery room and floor nurses, research assistants, statisticians, and patients were blinded to group allocation. Only the anesthesiologists performing the blocks and operating room nurses were not blinded.Inclusion criteria included the following: planned unilateral TKA; spinal anesthesia; American Society of Anesthesiologists physical status classification score of I to III. Exclusion criteria included the following: unwillingness to participate in the study; general anesthesia; contraindications for the application of ACB such as localized infection and neurological disease in the lower extremity; history of epilepsy; arrhythmia; alcohol or drug dependency; known allergy to local anesthetics; insufficient co-operation for the completion of the visual analog scale (VAS) for pain scores; patients who had an inability to communicate verbally or who were unwilling to give informed consent; American Society of Anesthesiologists physical status classification score of IV.2.2Patients were randomized to ACB treatment or EA treatment by a computer random number generator. Every participant received a consecutive study number from 1 to 100 and received the treatment assigned according to the randomization list. The randomization key was first broken when all enrolled patients had completed the study . Sedation using propofol and intravenous fluid therapy during surgery was administered at the discretion of the anesthetist.An epidural catheter was placed laterally at the L3/4 or L4/5 level using a 17-gauge Tuohy needle and inserted upward by 5 cm. A test dose of 1% lidocaine (50 mg) was initially injected, and the sensory block was tested after 10 min by applying ice to the ipsilateral thigh. Then, continuous epidural infusion for management of postoperative pain using the catheter that was inserted preoperatively for use during the TKA operation. 20 mL of 0.3% ropivacaine were administered and 0.2% ropivacaine was infused at 5 mL/h for 36 h.Under ultrasound guidance as above, a 10-cm, 18-gauge Tuohy needle was introduced into the adductor canal. Following dilation of the adductor canal with normal saline, a 21-gauge nerve catheter was threaded up to 3 to 5 cm beyond the needle tip. The guidewire was removed upon the catheter exiting the needle tip while threading to avoid inadvertent advancement of the catheter out of the space. The catheter was then manipulated and normal saline injected to confirm the catheter tip location within the adductor canal on ultrasound visualization, with peri-arterial spread as the endpoint. Up to 5 to 10 mL of normal saline was used in total per catheter placement. 20 mL of 0.3% ropivacaine was then injected via the catheter, following which a continuous infusion of 0.2% ropivacaine commenced at 5 mL/h for 36 h and then removed.2.4All of the operations were performed by a single senior surgeon, using a tourniquet and a medial parapatellar approach. Cruciate-retaining implants were used in all cases, as none of the patients were inflammatory arthritis or required posterior cruciate ligament resection and the patella was not changed in any patient. Intra-articular analgesic infiltration was not applied to any patient. For deep vein thrombosis prophylaxis, 40 mg enoxaparin sodium was applied subcutaneously once a day for 4 weeks after discharge.Preoperative prophylactic intravenous 1 g cefazolin were administered to all patients and postoperative antibiotics were continued for 24 h. In patients with a known allergy to penicillin, 500 mg vancomycin was preferred for prophylaxis. If serum creatinine levels were normal, a dose of 75 mg diclofenac sodium in 100 cc saline was given 8 hourly, for patient controlled analgesia. Otherwise infusion of 1000 mg paracetamol was administered. In both groups, 50 mg tramadol was given as rescue analgesia at the request of the patient inpresenceof intolerable pain despitethe use of standard analgesic regimen.2.5The primary outcome was VAS pain scores in the immediate postoperative period (postoperative day 0 through 3). VAS scores were recorded by nursing staff, blinded to treatment group, every 6 h throughout the hospital stay. VAS scores on each postoperative day were averaged, and the daily averages were used for analysis. Secondary outcomes included postoperative opioid use, length of hospital stay, activity level during physical therapy, and knee range of motion. Total opioid consumption was calculated by converting opioids consumed to morphine equivalents. Length of hospital stay was calculated by measuring the time from the completion of surgery through discharge for each patient. Activity level during physical therapy was recorded by measuring the steps taken in daily physical therapy sessions. Knee range of motion was measured by the surgeon using a goniometer in the office at 3 weeks postoperatively.2.6The sample size calculation was based on a pilot study that we conducted on 20 patients. In this prior study, the mean difference and standard deviation of the VAS scores on postoperative day 0 between the ACB and EA groups were 0.42 and 0.21, respectively. From this, it was determined that 50 subjects would be required to reach an α value of 0.05 and a power of 90%. It was estimated that the attrition rate due to canceled surgery or reasons of late patient ineligibility could be up to 20% and, therefore, to account for this, the final sample size selected was n = 120 (60 per group).2.7t test was used for comparison of continuous variables and Pearson Chi Square test was used for comparison of categorical variables. Results were evaluated in a confidence interval of 95% and at a significance level of P < .05.Statistical analyses were conducted using SPSS v22.0 software . Conformity of the data to normal distribution was tested with the Kolmogorove–Smirnov test. Independent two samples 3–5 ACB has been demonstrated to be an effective alternative to the FNB, providing similar analgesic efficacy while sparing the motor strength significantly. However, there have been no studies directly comparing ACB to lumbar EA following TKA. Thus, the aim of the present study was to compare EA and ACB techniques with regard to early period pain levels, need for additional opioids, and ambulation and functional scores in patients who had undergone primary TKA. We hypothesized that standard ACB would be as effective as EA for postoperative pain management following TKA.Patients undergoing TKA have moderate to severe pain postoperatively. Among the techniques developed for analgesia, the use of regional anesthesia techniques such as FNB has proven efficacious. The drawback of FNB is that they tend to result in motor blockade of the quadriceps muscle and potentially delay postoperative mobilization, as well as increase the risk of falls.Conceptualization: Lianzhou Zhu.Data curation: Li Yang.Formal analysis: Lianzhou Zhu, Li Yang.Funding acquisition: Lianzhou Zhu.Investigation: Lianzhou Zhu, Li Yang.Methodology: Hanjuan Cui.Resources: Zhengkai Wang.Software: Zhengkai Wang.Supervision: Zhengkai Wang.Validation: Hanjuan Cui.Visualization: Zhengkai Wang.Writing – original draft: Lianzhou Zhu, Li Yang.Writing – review & editing: Zhengkai Wang.


Patients with secondary pain due to mucositis after chemotherapy require treatment with morphine. Use of electronic video games (EVGs) has been shown to be an effective method of analgesia in other clinical settings.The main objective of this study was to assess the association between the use of EVGs and the intensity of pain caused by chemotherapy-induced mucositis in pediatric patients with cancer. The secondary objective was to assess the association between changes in pain intensity and sympathetic-parasympathetic balance in this sample of pediatric patients.Clinical records were compared between the day prior to the use of EVGs and the day after the use of EVGs. The variables were variations in pupil size measured using the AlgiScan video pupilometer , heart rate variability measured using the Analgesia Nociception Index (ANI) monitor , intensity of pain measured using the Numerical Rating Scale (score 0-10), and self-administered morphine pump parameters.P=.003), lower demand for additional pain relief medication , lower scores of incidental pain intensity , lower scores of resting pain , and higher basal parasympathetic tone as measured using the ANI monitor . No variation in pupil size was observed with the use of EVGs.Twenty patients  who met all the inclusion criteria were recruited. EVGs were played for a mean of 2.3 (SD 1.3) hours per day, resulting in statistically significant changes. After playing EVGs, there was significantly lower daily morphine use (before vs after playing EVGs: 35.9 vs 28.6 µg/kg/day, The use of EVGs in pediatric patients with chemotherapy-induced mucositis has a considerable analgesic effect, which is associated physiologically with an increase in parasympathetic vagal tone despite lower consumption of morphine. Pediatric patients with cancer may experience chronic pain associated with the development of the illness itself, which is caused by compression or infiltration of nearby organs or nerves or by pathologic bone fractures. However, in this population, it is very common to observe acute pain specifically associated with the diagnostic or therapeutic procedures necessary for treatment . ChemothAcute nociception has been found to be associated with changes in the sympathetic-parasympathetic balance, including the response of pupil dilation and respiratory variations involving heart rate. A positive association has been proven between the magnitude of these vegetative changes and pain intensity .Given the impact of acute pain associated with chemotherapy-induced mucositis, it is very important to administer adequate analgesia. Some of the recommended measures include lidocaine mouthwash and regulated use of analgesics, particularly strong ones such as morphine, with a patient-controlled analgesia (PCA) pump, which allows the patient to administer additional doses of morphine during peaks of intense pain . HoweverDistraction has been widely used to reduce the intensity of pain and improve function in individuals with pain, especially young individuals . So-callGiven these considerations, the main objective of this study was to assess the association between the use of EVGs and the intensity of pain , which was caused by chemotherapy-induced mucositis, in a sample of pediatric patients with cancer. As a secondary objective, the study assessed the associations of changes in pain intensity with vegetative changes in the sympathetic-parasympathetic balance assessed using a Analgesia Nociception Index (ANI) monitor  and variations in pupil size assessed using AlgiScan  in this sample of pediatric patients. We hypothesized that EVG use is significantly and negatively associated with pain intensity ratings and morphine consumption. We also hypothesized that EVG use is positively associated with vagal tone.We designed an analytic observational study with a quasi-experimental pre/posttest methodology.Participants in this study were children and adolescents with pain secondary to mucositis, who were receiving treatment in our tertiary hospital in relation to cancer . In ordeThe study included all patients aged between 4 and 17 years, who were hospitalized at the children’s oncology ward of the hospital and who received treatment between January 2016 and December 2017 for acute pain caused by grade 3 or 4 mucositis in the context of treatment for cancer [Potential participants were invited when a PCA pump  with morphine for pain relief was indicated. At that point, the goals of the study were explained. Patients were included in the treatment protocol for acute pain at the children’s pain service, which involved a PCA pump that administered morphine chloride  with the following parameters: continuous perfusion at 0-1 mL/h and a bolus on demand of 1-2 mL every 5 minutes, up to a maximum of 10 mL in 4 hours.If a patient was under 12 years old, one of the parents or guardians was considered responsible for signing the consent form.Those interested in taking part were offered the possibility of playing video games on PlayStation Vita  on demand, with a range of different alternatives available depending on the patient’s preference and age as follows: age-rated puzzles, sports, platforms, and strategy games.After 24 hours of established analgesia, patients were usually visited by members of the children’s pain service at 9 am for 30 minutes to compile information on the variables adopted . The study was approved by the Ethics Committee at La Paz University Hospital on May 21, 2015 (code: PI-1217).With regard to demographic and descriptive variables, information on age and sex was collected for descriptive purposes.Participants were asked to report their pain intensity using the NRS-11 (scores 0-10). Participants were asked to rate their average pain intensity during the past 24 hours by choosing a single whole number between 0 (no pain) and 10 (pain as bad as could be), which best represented the pain during most of the day under rest conditions  and especially when patients tried to swallow even their own saliva . The NRS-11 has been found to provide valid and reliable scores when used in young people, including children as young as 6 years of age [In addition to this information, we developed a survey to collect information about the following: (1) PCA use in the previous 24 hours ; (2) ANI parameters ; and (3) parameters for pupil dilation (in mm) according to the pupillometry index at three time points .Finally, information was collected about the amount of time spent playing EVGs, with children’s relatives asked to report the daily total minutes played.t test was performed for ordinal variables .We first calculated percentages, means, and SDs of the study variables for descriptive purposes. A Wilcoxon test was performed for categorical variables , and a Student Of 25 patients invited to join the study, 20 (80%) agreed to participate in the study. Of these 20 patients, 12 had acute lymphoblastic leukemia, five had received a bone marrow transplant, and the remaining three had acute myeloid leukemia. One 6-year-old girl showed clinical signs of probable septic shock that required admission to the pediatric intensive care unit, and she was excluded from the study.Of the remaining 19 patients, 10 were girls and nine were boys, with a mean age of 11.5  years. EVGs were played for a mean of 2.3 (SD 1.3) hours per day. P=.001) (P=.01)  . Similar (P=.01) .P=.003), with a 44% decrease in the number of on-demand boluses .The parameters of the electronic PCA pump showed a 20% decrease in the daily consumption of morphine on the day the video games were played   . HoweverP=.009) .To the best of our knowledge, this is the first clinical trial to study the efficacy of playing video games to reduce the pain associated with chemotherapy-induced mucositis related to the treatment of young patients with cancer. The results were as expected. This is to say that as hypothesized, participants reported lower levels of pain intensity after playing video games , and we observed a highly remarkable reduction in the peak of pain, along with a 44% decrease in the need for additional morphine boluses to control incidental pain, resulting in a 20% decrease in the daily total dose of morphine administered. This is of particular importance as a reduction in the dose of morphine would logically result in a reduction in common morphine-associated side effects, such as paralytic ileus, nausea or vomiting, and pruritus .Interestingly, the effect was so intense that it influenced the sympathetic-parasympathetic balance of the patients. A sympathetic-parasympathetic imbalance is caused by the presence of a harmful stimulus that tends toward sympathetic activation, while physiological recovery is achieved by the parasympathetic system .The patients included in this study had secondary pain caused by mucositis. Chemotherapy-induced mucositis causes acute pain with a high intensity regarding pain sensation , as can Our results are consistent with evidence-based medicine, which has shown that EVGs are effective in pediatric patients as both psychological therapy and treatment for boosting physical function . In factAs analgesia, video games have been proven to be useful in reducing pain among children, especially in the case of pain associated with procedures for venipuncture , wound cThe mean duration of video game use in this study was close to 3 hours per day, which is the value established in several studies as the threshold after which video games start to be more harmful than beneficial to health . Thus, tVideo games have already been shown to be effective in pediatric oncology patients, encouraging physical rehabilitation during the patient’s recovery phase after disease remission  and alloThe ANI monitor measures parasympathetic activity through the analysis of respiratory sinus arrhythmia, assessing heart rate variability induced by each respiratory cycle . In conscious patients, the ANI indicates acute pain and stress levels. Normal values are higher than 50, and higher levels indicate higher parasympathetic-sympathetic balance. This device has been used successfully to measure the level of nociception during different painful situations, including surgery in children . HoweverIf the results of this study are confirmed in future work, the clinical implications of the findings would be great, as EVGs could be included as part of the nonpharmacological treatment plan for cancer-related mucositis in pediatric patients.This study has some limitations that should be considered when interpreting the results. First, the sample size was small. Additional research with a larger sample size would be needed to help determine the reliability of the findings. Second, although the study design allowed for the evaluation of concurrent associations among the scores of the study variables, we were not able to test for causal associations. Thus, clinical trials with control groups are needed to evaluate the causal influence of the use of video games on outcome variables.Despite the limitations of this study, the findings provide important additional information on the potential value of using video games to reduce pain and suffering, as well as enhance health recovery by increasing vagal tone in a very safe and efficient way. The use of video games for a mean of approximately 2 hours in children with intense mucositis relieved their pain by 30%, with a 14% increase in vagal tone, and at the same time, it reduced the daily dose of morphine by 20%.The findings are consistent with a biopsychosocial model of pain, supporting the use of medical or physical and psychosocial interventions to prevent or manage pain in young patients ,24. Addi


Fibromyalgia syndrome (FM) is a multifactorial disorder whose pathogenesis and diagnosis are poorly understood. This study investigated differential serum proteome profiles in patients with FM and healthy pain-free controls and explored the association between serum proteome and clinical profiles in patients with FM. Twenty patients with FM  and 20 healthy pain-free controls were recruited for optimized quantitative serum proteomics analysis. The levels of pain, pressure pain threshold, sleep, anxiety, depression, and functional status were evaluated for patients with FM. We identified 22 proteins differentially expressed in FM when compared with healthy pain-free controls and propose a panel of methyltransferase-like 18 (METTL18), immunoglobulin lambda variable 3–25 (IGLV3–25), interleukin-1 receptor accessory protein (IL1RAP), and IGHV1OR21-1 for differentiating FM from controls by using a decision tree model (accuracy: 0.97). In addition, we noted several proteins involved in coagulation and inflammation pathways with distinct expression patterns in patients with FM. Novel proteins were also observed to be correlated with the levels of pain, depression, and dysautonomia in patients with FM. We suggest that upregulated inflammation can play a major role in the pathomechanism of FM. The differentially expressed proteins identified may serve as useful biomarkers for diagnosis and evaluation of FM in the future. The prevalence of FM was reportedly between 0.2 and 6.6%, predominantly affecting women in the general population5. The diagnosis of FM continues to be based mainly on clinical history taking and patients’ complaints. Currently, no specific laboratory measure or specific biomarkers are available for the diagnosis of FM.Fibromyalgia syndrome (FM), manifesting as chronic widespread pain throughout the body, is associated with long-term pain and impaired quality of life, which can result in tremendous medical and socioeconomic burden8. Neuroimaging and neuroendocrine research have revealed that altered central nervous system structure and function occur in patients with FM11. Patients with FM also exhibit a wide spectrum of associated symptoms such as sleep disturbance, depression, anxiety, fatigue, other pain disorders, and cognition problems12. These symptoms add significant heterogeneity and difficulty in the clinical management of FM. Furthermore, the linkage of relevant biological pathways with clinical symptom profiles is poorly understood. Therefore, FM treatments currently available are primarily symptomatic and usually require a multidisciplinary approach13. Exploration of potential biomarkers that correlate with the clinical profiles of FM can be valuable for evaluating the patients with FM.FM has been recognized as a multifactorial disorder involving genetic, biological, and environmental factors. Although the pathogenesis of FM is poorly understood, altered central pain processing and pain sensitization are key elements in the pathogenesis of FM15 and serum or plasma17. Proteomics analyses of the cerebrospinal fluid (CSF) in FM revealed dysregulation of proteins involved in lipoprotein lipase activity, inflammatory signaling, energy metabolism, and neuropeptide signaling18 as well as of proteins related to pain19. However, none of the respective candidates were replicated in salivary and blood proteomics studies. Moreover, CSF proteins are not ideal for clinical diagnosis. More extensive proteomics analysis in easily accessible specimens for FM detection is required. For this purpose, the present study investigated differential serum proteome profiles in patients with FM and healthy pain-free controls by using an optimized serum proteomics analysis workflow. We further explored the underlying molecular mechanism and the correlation between serum proteome and clinical profiles in patients with FM. These data can clarify the FM pathogenic mechanism and can help provide insights to objectively evaluate patients with FM and to develop specific treatments for FM.Proteomics analysis based on modern liquid chromatography–mass spectrometry (LC–MS) has enabled systematic profiling of proteome expressions in various specimens to identify disease-associated proteins. A few proteomics studies on FM have identified potential protein biomarkers in salivaIn this study, we adopted the commercially available multiple affinity removal system (MARS) Hu-14 column, which utilizes antibodies targeting the top 14 high-abundance serum proteins to selectively remove high-abundance proteins and generate depleted serum samples for proteomics analysis. The SDS-PAGE analysis of raw and depleted serum samples in Supplementary Fig. 2.A total of 20 patients with FM and 20 healthy pain-free controls were recruited for quantitative serum proteomics analysis. The demographic data and clinical profiles are summarized in Table To achieve in-depth profiling of serum proteome, we used a tandem mass tag (TMT)-based quantitation strategy, which integrated optimized MARS Hu-14 depletion, gel-assisted digestion, TMT tagging, high-pH reversed-phase (Hp-RP) StageTip fractionation, and LC–MS/MS analysis  indicated several altered pathways, including acute phase response signaling, liver X receptor–retinoid X receptor (LXR–RXR) activation, and synaptogenesis signaling pathways  parameters Fig. . For sym22. However, these changes are difficult to use as clinical biomarkers because most of them lack specificity. One advantage of using proteomics to investigate potential biomarkers of FM is the ensemble feature of proteomics. The novelty of the present study is using machine learning to explore the complex proteomics and locate potential biomarkers in patients with FM. Using a decision tree model, we could successfully differentiate patients with FM from controls based on the expression levels of METTL18, IGL3-25, and IL1RAP, yielding an accuracy of up to 0.97. We developed a diagnostic panel and decision tree by using a combination of more than two candidate proteins, which yielded better specificity and sensitivity in the diagnosis of FM. This panel may serve as an objective diagnostic tool for FM in the future. However, it is difficult to claim the proteomic difference exhibited in present study is associated with FM or chronic pain. Further study to compare the proteomic profile between FM and patients with other well-characterized chronic pain disorders should be considered.Among the possible factors that underlie FM pathophysiology, a proinflammatory status and a decreased antioxidant capacity are commonly reported in patients with FM23. Furthermore, FM is common in patients with primary immunodeficiency24. Primary immune deficiency states are well known to predispose patients to autoimmunity. This finding reinforces the hypothesis that FM is associated with dysregulated immune response.We found that METTL18, known as histidine protein methyltransferase 1 homolog, is an efficient candidate protein for differentiating patients with FM from controls. However, data regarding the biological function of METTL18 are scant. The most well-known protein database, UniProt, suggests that METTL18 acts as a protein methyltransferase and participates in fundamental protein modification and heat shock protein binding. Nevertheless, the role of METTL18 in FM pathophysiology requires further study. A significant downregulation of immunoglobulin G-associated proteins  was noted in the present study. Although relevant data are scant, an unexpectedly high prevalence of immunoglobulin deficiency in FM was reported. reported the plasma proteomic signature in patients with FM and also found differentially expressed proteins to be mainly involved in inflammatory (LXR–RXR) and coagulation pathways16. Our results suggest that inflammation plays a role in the pathophysiology of patients with FM, as seen in another study25. Subtyping of FM according to unique inflammatory features as inflammatory FM has been proposed26. The role of inflammation in FM pathogenesis, as least in certain subtypes, should be further studied.After performing further pathway analysis for candidate proteins , IL-6, and IL-828. Studies have suggested that serum IL-6 is elevated in patients with FM and is correlated with disease severity29. In contrast with present data, we observed decreased IL-6 upstream activation based on candidate proteins’ expression  of FM39. The inconsistency in results might also be due to the use of different types of body fluids and assays.In one large cross-sectional study, serum CRP, a proinflammatory systemic biomarker, was significantly elevated in patients with FM40. Fibrin, as a final product in the coagulation cascade appearing at the neurovascular interface, could be associated with further inflammatory responses, including immune cell migration to the brain. Dysregulation of the coagulation and fibrinolysis system has been observed in several CNS diseases, such as multiple sclerosis and Alzheimer’s disease42. In the present study, we found alterations in the regulation of several coagulation and fibrinolysis factors, including platelet glycoprotein Ib alpha chains, thrombospondin-1, platelet glycoprotein V, prothrombin, thrombospondin-2, fibrinogen alpha chains, and platelet glycoprotein Ib alpha chains, in patients with FM. Other studies have seldom mentioned the altered coagulation function in patients with FM. Future studies should explore the pathogenic effects of altered coagulation on symptoms or neuroinflammation in patients with FM.Neuroinflammation in CNS has been suggested to be involved in the FM pathogenesis. Evidence shows the potential linkage of coagulation and fibrinolysis at the neurovascular interface to neuroinflammation and degeneration44. For clinical applications, more specific treatments targeting inflammation may be considered for FM management. We found that TNF-α may be a potential upstream activation molecule in patients with FM . Nonsteroidal anti-inflammatory drugs and steroids targeting anti-inflammation yielded inconsistent results in the treatment of FM22. These FM subtypes may specifically involve different underlying biological pathways. Using this concept, we analyzed the correlation between serum protein expression patterns and symptom profiles in patients with FM. We found that the expression level of the Ig heavy chain V-I region HG3 was positively correlated with pain intensity in patients with FM. Growing evidence suggests that immunoglobulin therapy can be a potential treatment for chronic pain, including FM, complex regional pain syndrome, and pain associated with specific autoantibodies49. The analgesic immunoglobulin G might be associated with the modulation of cytokine expression and function50.The subtyping of FM into phenotypes according to pain, sleep, and psychological symptom profiles has been suggested51. The level of dysautonomia was correlated with symptom severity in patients with FM. In this study, we found the level of FGA, a subunit of fibrinogen, to be significantly correlated with altered sympathetic–parasympathetic balance in HRV. Fibrinogen expression can reportedly differentiate patients with FM from controls in a proteomics study16. Fibrinogen is a protein involved in acute systemic responses to inflammation, stress, and coagulation. We suggest that fibrinogen levels can act as a surrogate marker to evaluate the level of dysautonomia in patients with FM. IL6 is also a primary regulator of fibrinogen synthesis. Intervention to IL-6 associated pathway may be a candidate strategy in managing dysautonomia in patients with FM.The level of type II cytoskeletal 80 was negatively correlated with the depression level. The roles of these proteins in the symptom profiles of FM are of potential interest to researchers. A dysfunctional hypothalamic–pituitary–adrenal axis and dysautonomia are common in FM16 and label-free-based17 shotgun proteomics strategies were applied in serum or plasma samples to screen FM-associated proteins, enabling the identification of 266 proteins. The present study utilized the TMT-based proteomics approach and extensive peptide fractionation by Hp-RP StageTip, identifying 890 serum proteins, which is the largest serum proteome result in FM to date. Distinct serum proteomics profiles can be found in patients with FM compared with controls. Compared with approaches used in other studies, the approach used in the present study enabled a wider range of proteomic profiles to be investigated in patients with FM.The serum is an easily accessible clinical specimen and thus is ideal for disease detection. However, identification of potential protein biomarkers in serum by using MS-based proteomics analysis is extremely challenging because of the wide dynamic ranges of serum proteins and the masking effect of high-abundance proteins. To overcome these limitations, two-dimensional gel electrophoresis25.Limitations of the present study should be addressed. First, the sample size of the present study is relatively small. A large study is required to confirm our results. Second, recruited patients with FM and controls were all Han Chinese. Our results should be revisited in patients with FM of other ethnicities. Third, a cross-sectional study cannot identify the temporal relationship between symptoms and proteomics profiles. Interactions between proteins and biological pathways are complex, and primary and secondary pathophysiological changes in experimental participants cannot be differentiated in proteomics data. A longitudinal proteomics study in patients with FM may help clarify this. Fourth, because those affected by FM are predominantly women, the present study included only women to enhance the study population homogeneity. Finally, the symptomatic duration of patients with FM was not taken into account, because the syndrome onset time is often difficult to determine in patients with FM. Pathophysiological changes in FM have also been suggested to be associated with syndrome durationIn conclusion, patients with FM have differential serum proteomics pattern compared with healthy pain-free controls. We suggest that upregulated inflammation plays a major role in the pathogenesis of FM, as observed from the serum proteomics analysis. Combining the levels of METTL18, IGLV3-25, IL1RAP, and IGHV1OR21-1 can successfully differentiate FM patients from healthy pain-free controls. Differentially expressed proteins may serve as potential biomarkers for diagnosis and clinical evaluation of FM in the future.52. We included women with FM aged > 20 years. The WPI was used to access the range of pain involved area. The SSS was used, including categorical scales for cognitive symptoms, unrefreshed sleep, fatigue, and a number of somatic symptoms. The diagnosis was established by a clinical specialist. Twenty healthy pain-free women were recruited as the control group. Each participant provided informed consent prior to inclusion. The study was approved by the Joint Institutional Review Board of Taipei Medical University (TMU-JIRB No.: N201702062). All methods herein were performed in accordance with relevant guidelines and regulations. The CONSORT flow diagram for participants’ recruitment was shown in Supplementary Fig. Major psychiatric disorders, such as schizophrenia or schizoaffective disordersSubstance or alcohol abuseKnown concurrent malignancyMajor rheumatic diseases such as systemic lupus erythematous, Sjogren’s syndrome, rheumatoid arthritis, and ankylosing spondylitisPregnancyTwenty women who fulfilled the American College of Rheumatology 2010 diagnostic criteria for FM were recruited from clinics in the university hospitalVisual analog scale (VAS) of pain and pressure pain threshold (PPT)53Fibromyalgia impact questionnaire (FIQ)55Pittsburgh sleep quality Index (PSQI)57Beck depression inventory version II (BDI-II)59Beck anxiety inventory (BAI)Five-minute heart rate variability (HRV)For each patient with FM, measurements were taken by using the following scales:The details of these questionnaires and measurements are listed in Supplementary Information.g for 10 min. After centrifugation, the serum supernatants were collected, aliquoted, and stored at − 80 °C until use.To prevent interference from concurrent FM medications on proteomics analysis, patients with FM were asked to terminate use of medications for at least 2 weeks prior to serum collection. However, oral acetaminophen 3,000 mg/24 h was allowed for relief of pain when the patient was prevented from taking their usual pain medications during this period. Forty-milliliter blood samples from patients and controls were drawn in the early morning and after an overnight fast. The blood was disposed in ethylenediaminetetraacetic acid–free tubes and left undisturbed at ambient temperature for 30 min to allow clotting. The clot was removed through centrifugation at 1,30060 to collect peptides for subsequent 10-plex TMT labeling . For each TMT experiment, peptides from four FM patients were individually labeled with TMT127N, TMT128N, TMT129N, and TMT130N, while peptides from 4 controls were labeled with TMT127C, TMT128C, TMT129C, and TMT130C, respectively. TMT126 were labeled with reference peptides from the pooling of 40 samples. Five batches of 10-plex TMT experiments were performed for 20 patients with FM and 20 healthy pain-free controls. In each batch, 9 TMT-labeled samples were combined for Hp-RP StageTip fractionation61 to generate six reversed-phase fractions, followed by duplicate analysis using LTQ Orbitrap Fusion mass spectrometers equipped with the Dionex Ultimate 3000 nanoLC system and a NanoSpray interface (Thermo Fisher Scientific). Protein identification and quantification were performed using Proteome Discoverer 2.1 (Thermo Fisher Scientific). The details of experiments, LC–MS/MS acquisition, and proteome identification or quantitation are included in Supplementary Information. The mass spectrometry proteomics data have been deposited in the jPOST repository62 with the dataset identifier PXD013905.Figure 63. The chi-squared test was used to determine the frequency difference in categorical variables between the two groups. PLS-DA64 was applied to visualize how efficiently significant candidates could distinguish patients from controls. The variable importance in the projection value of each protein in the PLS-DA model indicated its contribution to the classification of patients and controls. Eighty percent of patients with FM and healthy pain-free controls were randomly selected and used to train a decision tree by using the classification and regression tree analysis65 for distinguishing patients with FM from healthy pain-free controls and for developing decision rules for the diagnosis of FM. The remaining 20% of patients were used to validate decision rules.We used the Mann–Whitney U test to compare differences in demographic data and clinical profiles between controls and patients with FM as well as to evaluate the significance of protein fold changes between patients with FM and healthy pain-free controls66. All data processing and statistical analysis were performed using R (Version 3.5.1)67.The age and BMI of each patient were used as control variables to calculate the partial correlation between each significant protein fold change and the clinical data of patients with FM by using the R package “ppcor”68 for the enrichment analysis of dysregulated cellular functions, disease annotations, networks, pathways, and upstream regulators.The significant candidate proteins in patients with FM were submitted for IPA (Qiagen Bioinformatics)Supplementary Information.