Pain is an experience of unpleasant sensations and emotions associated with actual or potential tissue damage. In the global context, billions of people are affected by pain disorders. There are particular challenges in the measurement and assessment of pain, and the commonly used pain measuring tools include traditional subjective scoring methods and biomarker-based measures. The main tools for biomarker-based analysis are electroencephalography (EEG), electrocardiography and functional magnetic resonance. The EEG-based quantitative pain measurements are of immense value in clinical pain management and can provide objective assessments of pain intensity. The assessment of pain is now primarily limited to the identification of the presence or absence of pain, with less research on multilevel pain. High power laser stimulation pain experimental paradigm and five pain level classification methods based on EEG data augmentation are presented. First, the EEG features are extracted using modified S-transform, and the time-frequency information of the features is retained. Based on the pain recognition effect, the 20–40Hz frequency band features are optimized. Afterwards the Wasserstein generative adversarial network with gradient penalty is used for feature data augmentation. It can be inferred from the good classification performance of features in the parietal region of the brain that the sensory function of the parietal lobe region is effectively activated during the occurrence of pain. By comparing the latest data augmentation methods and classification algorithms, the proposed method has significant advantages for the five-level pain dataset. This research provides new ways of thinking and research methods related to pain recognition, which is essential for the study of neural mechanisms and regulatory mechanisms of pain.
This retrospective study investigated the effects of combining manual therapy and acupuncture on the pain and maximal mouth opening (MMO), which were associated with temporomandibular joint dysfunction (TMD). The 49 TMD patients (15 men, 34 women; mean age = 30.47 years, SD = 13.52 years) were treated with a combination of acupuncture and manual therapy two or three times a week at the hospital. The pain and maximal mouth opening were assessed before and after 1 and 4 weeks of treatment. The combination therapy produced significant changes in pain levels (p < 0.001) and mouth opening (p < 0.001). All pairwise non-parametric comparison showed a significant improvement in pain (p < 0.05 for all pairs) and MMO (p < 0.05 for all pairs). These findings suggest that combining manual therapy and acupuncture decreases the pain level and increases the MMO of TMD patients. However, future studies should further investigate the efficacy of combined treatment on TMD with more rigorous randomized clinical trials.
Our previous study has demonstrated that 6 weeks of Tai Chi exercise significantly improves knee pain and stiffness in elderly with knee osteoarthritis. This study also examine the effects of Tai Chi exercise on gait kinematics, physical function, pain, and pain self-efficacy in elderly with knee osteoarthritis. In this prospective, pretest-posttest clinical trial, 40 men and women (64.4 ± 8.3 years) diagnosed with knee osteoarthritis participated in 6 weeks of instructed Tai Chi training, 1 hour/session, 2 sessions/week. The following measures were taken at baseline and the conclusion of the intervention: (a) gait kinematics including stride length, stride frequency, and gait speed quantified using video analysis, (b) physical function, (c) knee pain, and (d) pain self-efficacy. Data were analyzed using repeated MANCOVA, MANOVA, ANOVA and Wilcoxon tests. After 6 weeks of Tai Chi exercise, stride length (p = 0.023; 1.17 ± 0.17 vs. 1.20 ± 0.14 m), stride frequency (p = 0.014; 0.91 ± 0.08 vs. 0.93 ± 0.08 strides/s), and consequently gait speed (p < 0.025; 1.06 ± 0.19 vs. 1.12 ± 0.15 m/s) increased in the participants. Physical function was significantly improved (p < 0.001) and knee pain was significantly decreased (p = 0.002), while no change was observed in pain self-efficacy. In conclusion, these findings support that Tai Chi is beneficial for gait kinematics in elderly with knee osteoarthritis, and a longer term application is needed to substantiate the effect of Tai Chi as an alternative exercise in management of knee osteoarthritis.
The present study was conducted to clarify the role of the anterior cingulate cortex (ACCX) in acupuncture analgesia. Experiments were performed on 35 female Wistar albino rats weighing about 300 g. Single unit recordings were made from ACCX neurons with a tungsten microelectrode. Descending ACCX neurons were identified by antidromic activation from electrical shocks applied to the ventral part of the ipsilateral PAG through a concentric needle electrode. Cathodal electroacupuncture stimulation of Ho-Ku (0.1 ms in duration, 45 Hz) for 15 min was done by inserting stainless steel needles bilaterally. An anodal silver-plate electrode (30 mm × 30 mm) was placed on the center of the abdomen. Naloxone (1.0 mg/kg, i.v.) was used to test whether changes of ACCX activities were induced by the endogenous opioid system. Data were collected from a total of 73 ACCX neurons. Forty-seven neurons had descending projection to the PAG, and the other 26 had no projections to the PAG. A majority of descending ACCX neurons were inhibited by electroacupuncture stimulation. By contrast, non-projection ACCX neurons were mainly unaffected by electroacupuncture. Naloxone did not reverse acupuncture effects on the changes of ACCX neuronal activities. Acupuncture stimulation had predominantly inhibitory effects on the activities of descending ACCX neurons. Since the functional connection between ACCX and PAG is inhibitory, electroacupuncture caused disinhibition of PAG neurons, whose activity is closely related to descending antinociception to the spinal cord. This disinhibitory effect elicited by acupuncture stimulation is thought to play a significant role in acupuncture analgesia.
The efficacy of acupressure in relieving pain has been documented; however, its effectiveness for chronic headache compared to the muscle relaxant medication has not yet been elucidated. To address this, a randomized, controlled clinical trial was conducted in a medical center in Southern Taiwan in 2003. Twenty-eight patients suffering chronic headache were randomly assigned to the acupressure group (n = 14) or the muscle relaxant medication group (n = 14). Outcome measures regarding self-appraised pain scores (measured on a visual analogue scale; VAS) and ratings of how headaches affected life quality were recorded at baseline, 1 month after treatment, and at a 6-month follow-up. Pain areas were recorded in order to establish trigger points. Results showed that mean scores on the VAS at post-treatment assessment were significantly lower in the acupressure group (32.9±26.0) than in the muscle relaxant medication group (55.7±28.7) (p = 0.047). The superiority of acupressure over muscle relaxant medication remained at 6-month follow-up assessments (p = 0.002). The quality of life ratings related to headache showed similar differences between the two groups in the post treatment and at six-month assessments. Trigger points BL2, GV20, GB20, TH21, and GB5 were used most commonly for etiological assessment. In conclusion, our study suggests that 1 month of acupressure treatment is more effective in reducing chronic headache than 1 month of muscle relaxant treatment, and that the effect remains 6 months after treatment. Trigger points help demonstrate the treatment technique recommended if a larger-scale study is conducted in the future.
External qigong as a pharmacotherapy adjunct was investigated in 50 subjects with chronic pain (pain lasting > 3 months with pain score of ≥ 3 on 0–10 numeric analog scale) who presented to a qigong healing center. Participants were randomized to receive either external qigong treatment (EQT) or equivalent attention time (EAT) in weekly 30-min sessions for four consecutive weeks. Outcomes were assessed before and after sessions. The primary outcome measure was intensity of pain by a 10-cm visual analog scale used to rate all pain severity measurements. At 8-week follow-up, participants were contacted by telephone and mailed a questionnaire. Most had experienced pain for > 5 years (66%); the rest, for > 3 to 5 years (8%), 1 to 3 years (10%), or < 1 year but > 3 months (10%). The most frequent concomitant diagnoses were multifactorial (26%), osteoarthritis (18%), and low back pain (12%). Most patients were also receiving other treatments (74%); none previously had EQT. Participants were randomly assigned to EQT (n = 26) or EAT (n = 24). These groups had no significant differences at baseline except for prior awareness of qigong (EQT 31% vs. EAT 63%; p = 0.025). Compared to the EAT group, EQT participants had a significant decrease in pain intensity in the 2nd (p = 0.003), 3rd (p < 0.001), and 4th weeks of treatment (p = 0.003). At week 8, these differences in overall decreased pain intensity persisted but were not statistically significant.
The objective of this study was to assess the evidence for or against the effectiveness of moxibustion as a treatment option for pain. Fourteen electronic databases were searched. Randomized clinical trials (RCTs) testing moxibustion in human patients with pain of any type were considered. Trials using direct or indirect moxibustion were included. Studies comparing moxibustion with other treatments of unproven effectiveness, studies testing moxibustion together with other treatments of unproven efficacy and trials where pain was not a central symptom of the condition were all excluded. The selection of studies, data extraction, and validation were performed independently by two reviewers. Four RCTs met all the inclusion criteria. Others were of poor methodological quality. Two RCTs suggested significant pain reductions for indirect moxibustion in osteoarthritis as compared with drug therapy (n = 200, RR, 1.11; 95% CI of 1.02 to 1.21, p = 0.02, heterogeneity: χ2 = 1.03, p = 0.31, I2 = 3%). The other two RCTs suggested positive effects of indirect or direct moxibustion on pain in scleroma or herpes zoster compared to drug therapy, respectively. We conclude that few RCTs are available that test the effectiveness of moxibustion in the management of pain, and most of the existing trials have a high risk of bias. Therefore, more rigorous studies are required before the effectiveness of moxibustion for the treatment of pain can be determined.
A descending inhibitory mechanism from the periaqueductal gray (PAG) to the spinal cord through the nucleus raphe magnus (NRM) is strongly involved in endogenous analgesic system produced by acupuncture stimulation. In addition to the PAG to NRM system which descends in the medial pathway of the brain stem, the nucleus reticularis lateralis (NRL) situated in the lateral part of the brain stem is reported to play an important role in modulating centrifugal antinociceptive action. In the present study, to clarify the role of NRL in acupuncture analgesia, we investigated the response properties of NRL neurons to acupuncture stimulation. The majority of NRM-projecting NRL neurons were inhibited by electroacupuncture stimulation. This effect was antagonized by ionophoretic application of naloxone, indicating that endogenous opioids act directly onto these NRL neurons. By contrast, about half of spinal projecting NRL neurons were excited by electroacupuncture stimulation, suggesting that part of the NRL neurons may modulate pain transmission directly at the spinal level.
Acupuncture has many beneficial effects during cancer therapy and has proven efficacy in the management of side effects induced by chemotherapy and radiotherapy. In this review, we discussed the benefits of acupuncture on cancer patients. In cancer pain management, acupuncture is effective for head and neck pain, waist pain, abdominal and chest pain. Many studies confirm the excellent efficacy of acupuncture against symptoms of vomiting and nausea, including those induced by chemotherapy and radiotherapy. Head and neck cancer patients receiving radiotherapy may develop xerostomia, which may be relieved by acupuncture. Acupuncture may also cause sedative and hypnotic effects in cancer patients for treating nervousness and insomnia.
The objective of this study was to differentiate the neuronal responses, which was related or unrelated, to pain associated with acupuncture stimulation, and to localize the brain regions with response to stimulation that is unrelated to pain by using Blood Oxygen Level Dependent (BOLD) functional MRI (fMRI). BOLD fMRI was performed in six normal healthy beagle dogs, during placebo and verum acupuncture stimulations, at the right side of BL60 (KunLun) acupoint before and after local anesthesia of the acupoint. The order of the four sessions was placebo; verum acupuncture stimulation; before local anesthesia; and followed by the same stimulation after local anesthesia. One-sample t-test analysis was performed to localize the activated or deactivated areas, during both pre-anesthesia and post-anesthesia. In order to compare the pre-anesthesia to post-anesthetic responses, and placebo to verum acupuncture stimulation, within-subject analysis was performed. The post-anesthetic verum acupuncture stimulation resulted in increased activations in the left somatic afferent area I and II, right visual and auditory association area, and the descending reticular activating system of the brainstem. In addition, differential areas during post-anesthesia compared to that of the pre-anesthesia were in the left olfactory peduncle and descending reticular activating system of the brainstem. These results indicate that the areas of specific neural pathway are considered to be unrelated to the pain response during acupuncture stimulation.
The clinical practice of acupuncture and study of the traditional Chinese medicine literature has led to the observation that if the diaphragm is used as an axis of symmetry, there are many symmetrical points on the upper and lower halves of the body. The symmetrical points share several common properties, including physiological functions, mechanisms of pathogenesis and therapeutic effects. Employing these corresponding points on the upper and lower parts of the body simultaneously can frequently enhance the therapeutic outcome rather substantially. This phenomenon may be called the Principle of Symmetry. Traditional and modern scientific literature already provides evidence that verifies the reliability of this principle. Furthermore, this principle may be viewed as the derivative of the Thalamic Neuron Theory.
This study was designed to evaluate the analgesic effect of wrist-ankle acupuncture (WAA) for patients with primary liver cancer (PLC) after transcatheter arterial chemoembolization (TACE). Sixty PLC patients with post-TACE visual analog pain intensity scores greater than 3 were divided equally into two groups receiving either WAA or oral morphine sulphate (MOR) for post-TACE pain. Pain intensity scores were reassessed at 1, 2, 4, and 6 h after analgesic intervention. Patients were also monitored for adverse reactions to analgesic treatment. Pain scores recorded when the patients first felt pain after TACE showed no statistical difference between the two groups (p > 0.05). WAA and MOR had indistinguishable degrees of pain relief 1, 2, and 4 h after analgesic intervention (p > 0.05). At 6 h after intervention, the WAA group experienced significantly greater pain relief than the MOR group (p < 0.05). Incidence of abdominal distension was lower in the WAA group than in the MOR group (p < 0.05). The results suggest that WAA not only had an analgesic effect equal to or greater than MOR in PLC patients with moderate to severe post-TACE pain, but also reduced the incidence of post-operative abdominal distention.
Complementary and alternative medicine (CAM) has gained acceptance throughout the industrialized world. The present study was performed to provide information about the use of CAM at Mayo Clinic, an academic medical center in Northern Midwest of the US. We retrospectively reviewed the electronic medical records of 2680 patients visiting the CAM program at Mayo Clinic, Rochester, between 1 July 2006 and 31 March 2011. Services provided included acupuncture, massage, integrative medical consultations and executive stress management training. Data including age, gender, race, diagnosis and the number of treatment/consultation sessions were collected to describe the use of CAM in our institute over the last several years. It was found that the mean (standard deviation) age of patient was 52.6 (15.5) years. Of those, 73.1% were female and 26.9% were male. Most patients were white. The number of patients referred to CAM increased significantly from 2007 to 2010. The three most common diagnostic categories were back pain (12.9%), psychological disorders (11.8%), and joint pain (9.6%). Back pain was the most common diagnosis for patients receiving acupuncture, and fibromyalgia was the most common for patients receiving massage therapy. Psychological disorders (i.e., stress) were the major diagnosis referred to both integrative medical consults and executive stress management training. These results suggest that the diseases related to pain and psychological disorders are the main fields of CAM use. It also shows the increasing trend of the use of CAM at an academic medical center in the US.
Traditional Chinese medication (TCM) has analgesic and anti-inflammatory effects in patients with knee osteoarthritis (OA). We conducted the first systematic review of the best quantitative and qualitative evidence currently available in order to evaluate the effectiveness of TCM in relieving pain in knee OA. A comprehensive literature search was conducted using three English and four Chinese biomedical databases from their inception through March 1, 2015. We included randomized controlled trials of TCM for knee OA with intervention durations of at least two weeks. The effects of TCM on pain and other clinical symptoms were measured with the visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The total effectiveness rate, which was used to assess overall pain, physical performance and wellness, was also measured. Two researchers independently extracted data on study design, population characteristics, duration, intervention, outcomes, risk of bias, and primary results. We performed a random-effects meta-analysis when appropriate. We also explored factors that could explain the heterogeneity by conducting subgroup and meta-regression analyses. Twenty-three studies, totaling 2362 subjects, met the eligibility criteria. Treatments were formulated with an average of 8 Chinese herbs and were prescribed based on the traditional Chinese diagnostic method of syndrome differentiation. The mean treatment duration was seven weeks, with oral administration occurring one to three times a day. Compared with non-steroidal anti-inflammatory drugs and intra-articular hyaluronate injections, 18 of the studies showed significantly improved VAS pain scores (Mean Difference [MD] = 0.56; 95% confidence interval [CI], 0.18 to 0.94; p=0.004), six of the studies showed significantly improved WOMAC pain subscale scores (MD = 2.23; 95% CI, 0.56 to 3.91; p=0.009), and 16 of the trials showed significantly improved total effectiveness rates (risk ratio = 1.12; 95% CI, 1.05 to 1.19; p= 0.0003). In addition, TCM showed a lower risk of adverse events than standard western treatments. This evidence suggests that TCM is safe and effective for improving pain, function, and wellness in treatments of knee OA. However, there is inherent clinical heterogeneity (diverse TCM formulations, controls, and treatment regimens) among the included trials. Despite these limitations, the potential analgesic effects of TCM warrant further methodologically rigorous research to determine the clinical implications of TCM on pain management in knee OA.
Tai Chi Chuan (TCC), a traditional Chinese martial art, is well-documented to result in beneficial consequences in physical and mental health. TCC is regarded as a mind-body exercise that is comprised of physical exercise and meditation. Favorable effects of TCC on body balance, gait, bone mineral density, metabolic parameters, anxiety, depression, cognitive function, and sleep have been previously reported. However, the underlying mechanisms explaining the effects of TCC remain largely unclear. Recently, advances in neuroimaging technology have offered new investigative opportunities to reveal the effects of TCC on anatomical morphologies and neurological activities in different regions of the brain. These neuroimaging findings have provided new clues for revealing the mechanisms behind the observed effects of TCC. In this review paper, we discussed the possible effects of TCC-induced modulation of brain morphology, functional homogeneity and connectivity, regional activity and macro-scale network activity on health. Moreover, we identified possible links between the alterations in brain and beneficial effects of TCC, such as improved motor functions, pain perception, metabolic profile, cognitive functions, mental health and sleep quality. This paper aimed to stimulate further mechanistic neuroimaging studies in TCC and its effects on brain morphology, functional homogeneity and connectivity, regional activity and macro-scale network activity, which ultimately lead to a better understanding of the mechanisms responsible for the beneficial effects of TCC on human health.
Acupuncture has been a popular alternative medicine in the United States for several decades. Its therapeutic effects on pain have been validated by both basic and clinical researches, and it is currently emerging as a unique non-pharmaceutical choice for pain against opioid crisis. However, the full spectrum of acupuncture indications remains unexplored. In this study, we conducted a cross-sectional survey among 419 acupuncturists nation-wide to investigate the top 10 and top 99 acupuncture indications in private clinics in the United States. We found the top 10 indications to be: lower back pain, depression, anxiety, headache, arthritis, allergies, general pain, female infertility, insomnia, neck pain and frozen shoulder. Among the top 99 indications, pain represents the largest category; and mental health management, especially for mood disorders, is in greatest demand. The following popular groups are: immune system dysfunctions, gastrointestinal diseases, gynecology and neurology. In addition, specialty index, commonality index, and the potential to become medical specialties were estimated for each indication. Demographic analysis suggests that China trained acupuncturists tend to have broader indication spectrums, but the top conditions treated are primarily decided by local needs. Also, gender, resident states, age and clinical experience all affect indication distributions. Our data for the first time outlines the profile of acupuncture treatable conditions in the US and is valuable for strategic planning in acupuncture training, healthcare administration and public education.
Pain is an unpleasant sensory and emotional experience in many diseases and is often caused by intense or damaging stimuli. Pain negatively affects the quality of life and increases high health expenditures. Drugs with analgesic properties are commonly used to relieve pain, but these Western medications could be overwhelmed by side effects including tolerance and addiction. Herbal medicines may provide alternative measures for pain management. In this review paper, after introduction of Chinese medicine theory and treatment modality, emphasis is placed on the application of Chinese herbs and herbal formulations in pain management. Three of the most commonly used herbs, i.e., Corydalis yanhusuo, Ligusticum chuanxiong, and Aconitum carmichaeli, are reviewed. Subsequently, using this ancient medical remedy, Chinese herbal formulation in treating common medical conditions associated with pain, such as headache/migraine, chest pain, abdominal pain, low back pain, neuropathic pain, osteoarthritis, and cancer pain, is presented. Chinese herbal medicines could be considered as a complementary and integrative approach in the modern armamentarium in combating pain.
Pain is a major public health problem, causing heavy social and economic burdens to patients and society while consuming tremendous medical resources at the same time. Thus, there is a critical need to find low-cost, efficacious, and therapeutic approaches to help manage pain. While acupuncture is increasingly recognized as a promising pain-relieving method, less is known about a specific form of auricular acupuncture known as Battlefield Acupuncture (BFA). The BFA technique involves the sequential placement of semi-permanent, single-use, French ASPⓇ golden needles to five specific acupoints in one or both ears, where they are left in place for 3–4 days or longer [Niemtzow, R.C., Battlefield acupuncture. Med. Acupunct. 19: 225–228, 2007]. The BFA needles (more accurately described as tiny conical darts) pierce the ear in designated locations in a particular order [Levy, C.E., N. Casler and D.B. FitzGerald. Battlefield acupuncture: an emerging method for easing pain. Am. J. Phys. Med. Rehabil. 97: e18–e19, 2018.]. (Figs. 4 and 5) It was developed by Dr. Richard C. Niemtzow in 2001, as a subgroup form of an auricular acupuncture technique based on the somatotopic arrangement of an inverted fetus pattern on the external ear [Romoli, M. Ear acupuncture: historical abstract–differences of ear cartography between the east and the west. Dtsch. Z. Akupunkt. 53: 24–33, 2010.]. Currently, BFA is widely used in the US military, but to our knowledge, there is no review which comprehensively synthesizes the current publications surrounding pain management. This review aims to investigate the effects and safety of BFA in adults with pain. Electronic databases were searched for randomized controlled trials (RCTs) published in English evaluating efficacy and safety of BFA in adults with pain, from database inception to September 6, 2019. The primary outcome was pain intensity change, and the secondary outcome was safety. Nine RCTs were included in this review, and five trials involving 344 participants were analyzed quantitatively. Compared with no intervention, usual care, sham BFA, and delayed BFA interventions, BFA had no significant improvement in the pain intensity felt by adults suffering from pain. Few adverse effects (AEs) were reported with BFA therapy, but they were mild and transitory. BFA is a safe, rapid, and easily learned acupuncture technique, mainly used in acute pain management, but no significant efficacy was found in adult individuals with pain, compared with the control groups. Given the poor methodological quality of the included studies, high-quality RCTs with rigorous evaluation methods are needed in the future.
Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Chinese herbal medicine (CHM) has been used for endometriosis for many years in Asian populations. This is a retrospective study in a territory teaching hospital of the China Academy of Chinese Medical Sciences in Beijing, China to compare the short- and long-term effectiveness and safety of CHM for endometriosis associated pain (EAP) before and after CHM treatment. A total of 338 out of 1143 women confirmed with endometriosis by ultrasonogram or surgery within three months received a CHM decoction twice a day for at least 3 and up to 24 months. All data were collected by a Structured Medical Records of Endometriosis (SMRE) in every clinic visit covering the whole treatment period. Pain score, evaluated by Numeric Rating Scale, was significantly decreased from 3rd to 12th month in women with moderate or severe pain. Frequency and severity rating of menstrual symptoms, evaluated by Cox Menstrual Symptom Scale, were significantly decreased in women with any pain level. Psychological changes rated by Self-rating Anxiety Scale (SAS) were significantly lower in 3, 6, 12, and 24 months of treatment, but those by Self-rating Depression Scale (SDS) was significantly decreased in six months of treatment. There was no severe adverse event but only minor side-effects. In conclusion, our study showed that CHM relieved EAP and related symptoms with minimal side-effects after treatment. A large-scale randomized and placebo-controlled trial could be designed to confirm the efficacy and safety.
Fibromyalgia (FM) is a complicated syndrome characterized by widespread chronic pain, fatigue, sleep disturbances, cognitive dysfunction, and other complications. There is currently no specific treatment available. No comprehensive surveys have been published to summarize the mechanism of acupuncture in FM management. Although several studies have shown that acupuncture can benefit FM patients, their clinical findings are inconsistent. Here, we summarize the operation method of acupuncture for FM. For the first time, we conducted a comprehensive review of the mechanisms of acupuncture for FM, and integrated evidence-based scientific findings with the most comprehensive and updated literature. According to studies conducted using FM patients and animal models, acupuncture may improve symptoms in FM patients by regulating the afferent pain pathway and descending inhibitory pain pathways of various molecules, such as ASIC3, Nav1.7, Nav1.8, and TRPV1, as well as peripheral inflammation and the autonomic nervous system. Furthermore, we discussed the epidemiology, pathophysiology, diagnosis, and management of FM, and reviewed acupuncture-related clinical studies. This review fills a previously unknown gap in knowledge of the mechanism of acupuncture for FM. Although there is growing evidence that acupuncture may be a promising therapy for treating symptoms in FM patients, further investigation is needed.
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