1.Traditional Chinese medicine understanding and treatment strategies for hypertension com plicated by chronic low back pain from perspective of kidney deficiency syndrome.
Zheng-Rong LUO ; Yin-Qiu GAO ; Xing-Jiang XIONG ; Pin LYU ; Xiao-Chen YANG
China Journal of Chinese Materia Medica 2025;50(4):1121-1131
In China, the number of chronic pain patients has exceeded 300 million, making chronic pain the third major health problem after tumors and cardiovascular diseases. Particularly concerning is the gradual emergence of hypertension and chronic low back pain as public health problems that threaten public health and increase the global economic burden. Modern research shows that the incidence of coexisting hypertension is higher among patients with chronic low back pain. Additionally, evidence indicates that the use of NSAIDs for pain relief can have adverse effects on blood pressure, and some antihypertensive medications may trigger symptoms of low back pain. Thus, addressing chronic pain in hypertensive patients while stabilizing blood pressure is one of the important research questions in the modern treatment of hypertension among middle-aged and elderly individuals. From ancient to modern traditional Chinese medicine(TCM) theory, kidney deficiency has been regarded as the core pathogenesis of low back pain. Recent clinical practices and literature indicate that kidney deficiency plays a crucial role in the modern pathogenesis of hypertension. Both hypertension and chronic low back pain are closely associated with kidney deficiency in TCM theory, revealing a potential mechanism linking the two conditions. Combining the theories of " kidney-essence-marrow" and " nourishing water to moisten wood", a therapeutic strategy centered on tobifying kidney was proposed, including selecting single drugs with kidney-tonifying effects as well as compound formulations and elaborating modern research evidence. The aim is to achieve stable blood pressure control in hypertension patients with chronic low back pain while providing a new treatment perspective for chronic low back pain. This article systematically elaborates on the understanding of hypertension combined with chronic low back pain from both TCM and modern medicine, as well as the therapeutic strategy involving kidney-tonifying drugs, to offer useful references for clinical practice.
Humans
;
Hypertension/complications*
;
Low Back Pain/complications*
;
Drugs, Chinese Herbal/therapeutic use*
;
Kidney/drug effects*
;
Medicine, Chinese Traditional
;
Chronic Pain/drug therapy*
2.Effects and mechanisms of Yuxuebi Tablets combined with ibuprofen in treating chronic musculoskeletal pain through "integrated regulation of inflammation and pain-related oxylipins".
Ao-Qing HUANG ; Wen-Li WANG ; Guo-Xin ZHANG ; Ying LIU ; Na LIN ; Chun-Yan ZHU
China Journal of Chinese Materia Medica 2025;50(13):3763-3777
This study adopted a three-dimensional "effect-dose-mechanism" evaluation system to screen the optimal regimen of Yuxuebi Tablets(YXB) combined with ibuprofen(IBU) for chronic musculoskeletal pain(CMP) intervention and elucidate its pharmacological mechanism, so as to provide a scientific basis for the clinical application of the regimen. The experiments were conducted using 8-week-old ICR mice, which were randomly divided into sham operation(sham) group, model(CFA) group, IBU group, YXB group, stasis paralysis tablets combined with ibuprofen low-dose group(IBU-L-YXB), stasis paralysis combined with ibuprofen high-dose group(IBU-H-YXB), stasis paralysis tablets combined with ibuprofen high-dose with ibuprofen discontinuation on the 10th day of administration(IBU-10-YXB), and stasis paralysis tablets combined with ibuprofen high-dose with ibuprofen halving on the 10th day of administration(IBU-1/2-YXB) group. An animal model was established using the CFA plantar injection method. On D0(the second day post-modeling), the success of model establishment was assessed, followed by continuous drug administration for 18 consecutive days from D1 to D18. During this period, mechanical pain threshold was measured by the Von Frey test; thermal hyperalgesia was detected by the hot plate test, and depression-like behavior was observed by the tail suspension test. After treatment, peripheral blood was collected from all groups for complete blood biochemical analysis, and the injected feet of the sham, CFA, IBU, YXB, IBU-YXB, and IBU-10-YXB groups were subjected to oxylipin metabolomics analysis. Immunofluorescence double staining was further performed to detect the co-expression of key oxylipin metabolic enzymes(COX2, LTA4H, and 5/12/15-LOX) and macrophage marker CD68 in the sham, CFA, IBU, and YXB-L/M/H groups. Subsequently, confirmatory analysis of positive indicators was conducted in the sham, CFA, IBU, YXB, IBU-YXB, and IBU-10-YXB groups. On D6(acute phase), mechanical pain sensitivity data showed that compared with the CFA group, only the three combination groups(IBU-YXB, IBU-10-YXB, and IBU-1/2-YXB) exhibited significantly increased paw withdrawal thresholds. On D17(chronic phase), only the IBU-10-YXB group showed a mechanical pain threshold significantly higher than all other monotherapy and combination groups. On D17, thermal pain data showed that compared with the CFA group, all groups except IBU-1/2-YXB had significantly prolonged paw withdrawal latency. On D18, tail suspension data showed that compared with the CFA group, the YXB, IBU-YXB, and IBU-10-YXB groups had significantly reduced immobility time. In summary, IBU-10-YXB stably improved the core symptoms of acute and chronic inflammatory pain. Complete blood count data showed that compared with the sham group, the CFA group had significantly increased mean platelet volume(MPV), while compared with the CFA group, the IBU-YXB and IBU-10-YXB groups had significantly reduced MPV. Moreover, the platelet distribution width(PDW) of the IBU-10-YXB group was further reduced compared with the CFA group. These data suggest that the IBU-10-YXB combination regimen has superior effects on inflammation and blood circulation improvement compared with other treatment groups. At the mechanistic level, each treatment group differentially regulated pro-inflammatory and pro-resolving oxylipin(SPM). Specifically, compared with the CFA group, the IBU and IBU-YXB groups significantly inhibited the synthesis of the prostaglandin family downstream of COX2, reducing pro-inflammatory oxylipins PGD2 and 6-keto-PGF1α but inhibiting PGE1 and PGE2, which played positive roles in peripheral circulation, vasodilation, and inflammation resolution. Compared with the CFA group, the YXB group tended to inhibit the pro-inflammatory oxylipin LTB4 downstream of LTA4H and increase SPMs such as LXA4. The IBU-10-YXB group bidirectionally regulated pro-inflammatory oxylipins and SPMs. Compared with IBU, IBU-10-YXB significantly inhibited the pro-inflammatory mediator 5-HETE. Meanwhile, IBU-10-YXB broadly upregulated SPMs, as evidenced by significant upregulation of LXA4 compared with the CFA group, significant upregulation of LXA5 compared with the IBU and IBU-YXB groups, significant upregulation of RvD1 compared with the CFA group and all other treatment groups, and significant upregulation of RvD5 compared with the sham group. Immunofluorescence double staining results were as follows: compared with the CFA group, the IBU group specifically inhibited the oxylipin metabolic enzyme COX2. In the YXB group, COX2, LTA4H, and 5/12-LOX were significantly inhibited. Within the optimal analgesic dose range, YXB's inhibitory effects on COX2 and LTA4H were dose-dependent, while its inhibitory effects on 5/12-LOX were inversely dose-dependent. The two combination groups(IBU-YXB and IBU-10-YXB) inhibited COX2 and LTA4H without significantly affecting 5-LOX, while IBU-10-YXB further significantly inhibited 12-LOX. These results suggest that the IBU-10-YXB combination regimen effectively maintains stable inhibition of COX2, LTA4H, and 12-LOX while enhancing 5-LOX expression. This combinatorial strategy effectively suppresses pro-inflammatory oxylipins and promotes SPM biosynthesis, overcoming IBU's analgesic ceiling effect and its blockade of pain resolution pathways while compensating for YXB's inability to effectively intervene in acute pain and inflammation. Therefore, it achieves more stable anti-inflammatory, analgesic, and antidepressant effects.
Animals
;
Ibuprofen/administration & dosage*
;
Mice
;
Mice, Inbred ICR
;
Drugs, Chinese Herbal/administration & dosage*
;
Male
;
Musculoskeletal Pain/immunology*
;
Tablets
;
Humans
;
Chronic Pain/metabolism*
;
Drug Therapy, Combination
;
Disease Models, Animal
3.Non-pharmacological interventions in chronic prostatitis/chronic pelvic pain syndrome: A network meta-analysis.
Xiao-Hui WEI ; Meng-Yao MA ; Hang SU ; Tong HU ; Yu-Xin ZHAO ; Xing-Chao LIU ; Hong-Yan BI
National Journal of Andrology 2025;31(3):234-245
OBJECTIVE:
To evaluate the efficacy of shockwave therapy, acupuncture, hyperthermia, biofeedback therapy, electrical nerve stimulation, magnetotherapy and ultrasound therapy in the treatment of chronic prostatitis/chronic pelvic pain syndrome(CP/CPPS), and to provide evidence-based support for clinical decision-making.
METHODS:
Two researchers independently searched PubMed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, VIP and Chinese Biomedical Literature databases for randomized controlled trials(RCTs) on the effects of different interventions on CP/CPPS from the establishment of the databases to August 2024. We evaluated the quality of the included literature and extracted the relevant data according to the Cochrane Handbook for Systematic Reviews of Interventions, followed by network meta-analysis using Revman 5.3, R 4.33 and Stata17 software.
RESULTS:
A total of 25 RCTs involving 1 794 cases were included. The results of network meta-analysis showed that electrical nerve stimulation, shockwave therapy, biofeedback therapy, magnetotherapy, ultrasound therapy and acupuncture were significantly superior to conventional medication and placebo in the total NIH-CPSI scores(P< 0.05), and so were electrical nerve stimulation and shockwave therapy to acupuncture and hyperthermia(P< 0.05), magnetic therapy to hyperthermia, and ultrasound therapy to placebo(P< 0.05). Shockwave therapy, biofeedback therapy, electrical nerve stimulation, magnetotherapy and ultrasound therapy achieved remarkably better clinical efficacy than conventional medication and placebo in the treatment of CP/CPPS, and so did shockwave therapy than electrical nerve stimulation, hyperthermia, ultrasonic therapy, magnetotherapy and acupuncture.
CONCLUSION
For the treatment of CP/CPPS, electrical nerve stimulation is advantageous over the other interventions in improving total NIH-CPSI scores, and shockwave therapy is advantageous in relieving pain symptoms and clinical efficacy. This conclusion, however, needs to be further verified by more high-quality clinical studies.
Humans
;
Acupuncture Therapy
;
Biofeedback, Psychology
;
Chronic Disease
;
Electric Stimulation Therapy
;
Extracorporeal Shockwave Therapy
;
Magnetic Field Therapy
;
Pelvic Pain/therapy*
;
Prostatitis/therapy*
;
Randomized Controlled Trials as Topic
;
Ultrasonic Therapy
4.Electroacupuncture for acute exacerbation of chronic obstructive pulmonary disease complicated with gastrointestinal dysfunction: a randomized controlled trial.
Xiang-Yun HU ; Yi-Hao LI ; Hao LI ; Ning LI
Chinese Acupuncture & Moxibustion 2023;43(5):499-503
OBJECTIVE:
To observe the clinical effect of electroacupuncture (EA) for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) complicated with gastrointestinal dysfunction.
METHODS:
A total of 100 patients with AECOPD complicated with gastrointestinal dysfunction were randomly divided into an EA group (50 cases, 2 cases dropped off, 1 case excluded) and a medication group (50 cases). Both groups were treated with symptomatic and supportive treatment such as low flow oxygen, nebulized inhalation of short-acting β2 agonist (SABA) or short-acting muscarinic antagonist (SAMA) combined with inhaled corticosteroid (ICS). The EA group was treated with EA at Zusanli (ST 36), Yinlingquan (SP 9), Zhongwan (CV 12), Shuifen (CV 9), Tianshu (ST 25), Chize (LU 5) and Lieque (LU 7), with discontinuous wave, 2 Hz in frequency, 30 min each time, once a day. In the medication group, oral mosapride citrate tablets were given, 3 times a day, 5 mg each time. Both groups were treated for 5 d. Before and after treatment, the gastrointestinal symptom rating scale (GSRS) score was observe, serum procalcitonin (PCT), C-reactive protein (CRP), and plasma oxygenation index (PaO2/FiO2) were detected, and patient satisfaction degree was evaluated in the two groups.
RESULTS:
Compared with before treatment, except for diarrhea dimension in the medication group, the total scores and each dimension scores of GSRS were decreased (P<0.05), serum PCT and CRP were decreased (P<0.05), plasma PaO2/FiO2 was increased (P<0.05) in the two groups after treatment. After treatment, in the EA group, the total score and abdominal pain, dyspepsia, constipation and diarrhea scores of GSRS were lower than those in the medication group (P<0.05), meanwhile serum PCT and CRP were lower and plasma PaO2/FiO2 was higher than those in the medication group (P<0.05). The improvement of gastrointestinal symptoms, life quality and overall satisfaction degree in the EA group were superior to those in the medication group (P<0.05).
CONCLUSION
EA could improve the symptoms of patients with AECOPD complicated with gastrointestinal dysfunction, reduce inflammatory response, improve oxygenation and patient satisfaction degree.
Humans
;
Electroacupuncture
;
Gastrointestinal Diseases/therapy*
;
Pulmonary Disease, Chronic Obstructive/therapy*
;
Diarrhea
;
Abdominal Pain
;
C-Reactive Protein
5.Effect of pancreatic extracorporeal shock wave lithotripsy on chronic pancreatitis stones.
Wan Xing DUAN ; Wan Zhen WEI ; Xue YANG ; Qi GAO ; Jun CHEN ; Zheng WU ; Zheng WANG
Chinese Journal of Surgery 2023;61(7):590-595
Objective: To analyze the therapeutic effect and safety of pancreatic extracorporeal shock wave lithotripsy(P-ESWL) for patients with chronic pancreatitis complicated by stones of the pancreatic duct and to investigate the influencing factors. Methods: A retrospective analysis was performed on clinical data from 81 patients with chronic pancreatitis complicated by pancreatic duct calculus treated with P-ESWL in the Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi 'an Jiaotong University from July 2019 to May 2022. There were 55 males(67.9%) and 26 females(32.1%). The age was (47±15)years (range: 17 to 77 years). The maximum diameter(M(IQR)) of the stone was 11.64(7.60) mm, and the CT value of the stone was 869 (571) HU. There were 32 patients (39.5%) with a single pancreatic duct stone and 49 patients(60.5%) with multiple pancreatic duct stones. The effectiveness, remission rate of abdominal pain, and complications of P-ESWL were evaluated. Student's t test, Mann Whitney U test, χ2 test, or Fisher's exact test was used to compare the characteristics between the effective and ineffective groups of lithotripsy. The factors influencing the effect of lithotripsy were analyzed by univariate and multivariate logistic regression analysis. Results: Eighty-one patients with chronic pancreatitis were treated with P-ESWL 144 times, with an average of 1.78 (95%CI:1.60 to 1.96) times per person. Among them, 38 patients(46.9%) were treated with endoscopy. There were 64 cases(79.0%) with effective removal of pancreatic duct calculi and 17 cases(21.0%) with ineffective removal. Of the 61 patients with chronic pancreatitis accompanied by abdominal pain, 52 cases(85.2%) had pain relief after lithotripsy. After lithotripsy treatment, 45 patients(55.6%) developed skin ecchymosis, 23 patients(28.4%) had sinus bradycardia, 3 patients(3.7%) had acute pancreatitis, 1 patient(1.2%) had a stone lesion, and 1 patient(1.2%) had a hepatic hematoma. Univariate and multivariate logistic regression analysis showed that the factors affecting the efficacy of lithotripsy included the age of patient(OR=0.92, 95%CI: 0.86 to 0.97), the maximum diameter of the stone(OR=1.12,95%CI:1.02 to 1.24) and the CT value of the stone(OR=1.44, 95%CI: 1.17 to 1.86). Conclusions: P-ESWL is effective in the treatment of patients with chronic pancreatitis complicated by calculi of the main pancreatic duct.Factors affecting the efficacy of lithotripsy include patient's age, maximum stone diameter, and CT value of calculi.
Male
;
Female
;
Humans
;
Retrospective Studies
;
Acute Disease
;
Treatment Outcome
;
Calculi/pathology*
;
Lithotripsy
;
Pancreatitis, Chronic/pathology*
;
Pancreatic Diseases/complications*
;
Pancreatic Ducts
;
Abdominal Pain/therapy*
6.Professor ZHANG Wei-hua's clinical experience in chronic somatic pain treated with zhidong needling techniques.
Jian WANG ; Qing-Xin ZHANG ; Wei-Hua ZHANG
Chinese Acupuncture & Moxibustion 2023;43(3):333-335
The paper summarizes professor ZHANG Wei-hua's clinical experience for the treatment of chronic somatic pain with zhidong needling techniques. In terms of the characteristics of chronic somatic pain, professor ZHANG has integrated zhidong needling with acupuncture kinetic therapy. The satisfactory therapeutic effects are obtained by selecting the painful points and regions as the treatment sites and the specific techniques of zhidong needling depending on the size of affected area, the depth of illness, the size and shape of the cord-like muscle, etc. Five techniques of zhidong needling are used accordingly with twirling, pulling, lifting and thrusting, surrounding needling methods involved, as well as with the manipulation speed, direction and frequency considered.
Humans
;
Vascular Surgical Procedures
;
Chronic Pain
;
Nociceptive Pain
;
Acupuncture Therapy
;
Muscles
7.Chemogenetic and Optogenetic Manipulations of Microglia in Chronic Pain.
Sebastian PARUSEL ; Min-Hee YI ; Christine L HUNT ; Long-Jun WU
Neuroscience Bulletin 2023;39(3):368-378
Chronic pain relief remains an unmet medical need. Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis. Particularly, microglia play a crucial role in the development of chronic pain. To better understand the microglial contribution to chronic pain, specific regional and temporal manipulations of microglia are necessary. Recently, two new approaches have emerged that meet these demands. Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs (DREADDs) specifically in microglia. Similarly, optogenetic tools allow for microglial manipulation via the activation of artificially expressed, light-sensitive proteins. Chemo- and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain. This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.
Humans
;
Optogenetics
;
Brain/physiology*
;
Microglia
;
Chronic Pain/therapy*
;
Neurons/physiology*
8.Factors associated with positive results in English literature of acupuncture for chronic pain.
Ying LIN ; Ji-Ping ZHAO ; Shi-Yan YAN ; Jian-Feng TU ; Li-Qiong WANG ; Jin-Ling LI ; Na ZHANG ; Yu WANG ; Xuan ZOU ; He-Wen LI ; Cun-Zhi LIU
Chinese Acupuncture & Moxibustion 2022;42(5):573-578
OBJECTIVE:
To analyze the main factors affecting the positive results of acupuncture for chronic pain in English literature of randomized controlled trial (RCT), in order to provide reference for the design of acupuncture clinical research.
METHODS:
The RCTs of acupuncture for chronic pain published before March 26, 2020 were searched in PubMed, EMbase and Cochrane Library by computer. A total of 21 factors were analyzed by single-factor analysis, and the factors with statistically significant difference were selected for multivariate Logistic regression analysis.
RESULTS:
A total of 69 RCTs were included, including 47 RCTs (68.12%) with positive results and 22 RCTs (31.88%) with non-positive results. The multivariate Logistic regression analysis was performed with the three screened factors (publication year, treatment frequency and intervention form) selected by single-factor analysis, and the results showed that the positive results were related to the frequency of acupuncture treatment. The positive rate of RCT with frequency≥2 times a week was 3.24 times of that with frequency<2 times a week (OR=3.24, 95%CI =[1.07,9.83], P<0.05).
CONCLUSION
Acupuncture frequency may be the main factor affecting the positive results of RCT in English literature of acupuncture for chronic pain. More researches are needed in the future to explore the influence of acupuncture frequency on the curative effect.
Acupuncture
;
Acupuncture Therapy
;
Chronic Pain/therapy*
;
Humans
;
PubMed
9.Stress reduction via neuro-emotional technique to achieve the simultaneous resolution of chronic low back pain with multiple inflammatory and biobehavioural indicators: A randomized, double-blinded, placebo-controlled trial.
Peter BABLIS ; Henry POLLARD ; Anthony L ROSNER
Journal of Integrative Medicine 2022;20(2):135-144
BACKGROUND:
Beginning with the concepts of stress developed by Selye, an approach to stress and pain management, known as neuro-emotional technique (NET), has been developed. It is a treatment approach based on the principle that the stressor effects of dormant and/or current unresolved issues or trauma are what determine one's bodily responses. These responses are relatively personalized to the conditioned, experiential and emotional reality of the individual.
OBJECTIVE:
To determine the effect of NET on patients with chronic low back pain (CLBP) over time.
DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS:
In a randomized, double-blinded, placebo-controlled study conducted in a single clinic, NET or control treatments were given twice weekly for 4 weeks in a population of 112 patients.
MAIN OUTCOME MEASURES:
Outcome measures, including Oswestry Disability Index, Quadruple Visual Analogue Scale, the psychoneuroimmunology markers of blood serum levels of C-reactive protein, tumour necrosis factor-α, interleukin-1 (IL-1), IL-6, and IL-10, and 10 dimensions of the Short Form Health Survey scale, were assessed at baseline and at 1, 3 and 6 months following the intervention period.
RESULTS:
Compared to placebo, NET produced clinical and statistical significance (P < 0.001) via declines of virtually all physiological, pain and disability markers, accompanied by gains in quality-of-life indicators at 0 (baseline), 1, 3 and 6 months. Reductions of the percentages of patients whose 5 biomarkers lay outside the normative range were achieved at 1, 3 and 6 months by NET but not control interventions.
CONCLUSION:
A randomized, controlled trial of CLBP patients indicated that 8 NET interventions, compared to placebo, produced clinically and statistically significant reductions in pain, disability and inflammatory biomarkers, and improvements in quality-of-life measures.
TRIAL REGISTRATION
The trial was registered with the Australian and New Zealand Clinical Trials Registry (No. ACTRN12608000002381).
Australia
;
Chronic Pain/therapy*
;
Double-Blind Method
;
Humans
;
Low Back Pain/therapy*
;
Pain Measurement
;
Treatment Outcome
10.Efficacy and Safety of Guihuang Formula in Treating Type III Prostatitis Patients with Dampness-Heat and Blood Stasis Syndrome: A Randomized Controlled Trial.
Sheng-Jing LIU ; Ying-Jun DENG ; Yin ZENG ; Ming ZHAO ; Jun GUO ; Qing-He GAO
Chinese journal of integrative medicine 2022;28(10):879-884
OBJECTIVE:
To observe the efficacy and safety of Guihuang Formula (GHF) in treating patients with type III prostatitis and Chinese medicine syndrome of dampness-heat and blood stasis.
METHODS:
Sixty-six patients diagnosed with type III prostatitis with dampness-heat and blood stasis syndrome were randomly divided into the treatment group (GHF) and the control group (tamsulosin) using a random number table, with 33 cases each group. The treatment group received GHF twice a day, and the control group received tamsulosin 0.2 mg once daily before bedtime. Patients in both groups received treatment for 6 weeks and was followed up for 2 weeks. The outcomes included the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score, Chinese Medicine Symptoms Score (CMSS), expressed prostatic secretions (EPS) and adverse events (AEs).
RESULTS:
After treatment, the NIH-CPSI total score and domain scores of pain discomfort, urination and quality of life decreased significantly from the baseline in both groups (P<0.05). The CMSS score decreased in both groups (P<0.05). The WBC count decreased and lecithin body count increased in both groups (P<0.05). GHF showed a more obvious advantage in reducing the pain discomfort and quality of life domain scores of NIH-CPSI, reducing the CMSS score, increasing the improvement rate of the WBC and lecithin body counts, compared with the control group (P<0.05). There were no significant differences in decreasing urination domain score of NIH-CPSI between two groups (P>0.05). In addition, no serious AEs were observed.
CONCLUSION
GHF is effective in treating type III prostatitis patients with dampness-heat and blood stasis syndrome without serious AEs. (Registration No. ChiCTR1900026966).
Chronic Disease
;
Hot Temperature
;
Humans
;
Lecithins
;
Male
;
Pain
;
Prostatitis/drug therapy*
;
Quality of Life
;
Tamsulosin

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