Stereotactic Body Radiotherapy (SBRT) has shown effectiveness in treating bone metastases to alleviate pain. The benefit of SBRT may be further harnessed especially when radiating disease from primary malignancies with low alpha–beta ratios in order to maximize the magnitude and durability of pain relief. However, such an approach has not been studied in a prospective trial. We look to assess single-fraction SBRT for painful non-spinal bone metastases from radioresistant primaries.Forty patients will be enrolled on an open label, phase II single arm trial to receive a single fraction of SBRT (15–20 Gray) to all sites of bone metastases requiring treatment for pain relief. Eligible patients will include those with primary malignancies consisting of prostate cancer, breast cancer, renal cell carcinoma, or melanoma. The primary endpoint is pain response at 3 months post-treatment using the Brief Pain Inventory. Secondary endpoints include pain response at 1 month and 6 months post-treatment, toxicity, patient-reported quality of life, re-irradiation or salvage surgery, and local control.This study will evaluate the efficacy of single-fraction SBRT on painful bone metastases from primary cancers with low alpha–beta ratios. These data will be valuable to promote future randomized trials and support clinical implementation.Trial registration Clinicaltrials.gov, NCT04177056. Date of registration: November 26, 2019. https://clinicaltrials.gov/ct2/show/NCT04177056The online version contains supplementary material available at 10.1186/s13014-021-01897-0. The use of stereotactic body radiotherapy (SBRT) has been a topic of interest in palliative approaches for managing metastatic disease. Advances in radiation planning and delivery allows clinicians to target lesions with higher, ablative doses to tumors, while minimizing dose to organs and tissues at risk. SBRT has been demonstrated to be effective in controlling local metastatic lesions, while delaying distant progression of disease within the context of several retrospective, and small prospective randomized trials , 2.The use of SBRT is appealing in particular for tumors with low alpha–beta ratios such as prostate cancer, breast cancer, renal cell carcinoma (RCC), and melanoma. Such tumors have inherent radioresistance to standard fractionation regimens, and benefit from dose escalation using hypofractionation to yield more potent biological efficacy , 4. TheoA recent phase II randomized trial included patients with bone metastases from all disease sites, and showed that single-fraction SBRT had higher rates of pain response at 2 weeks and 3 months compared to conventional fractionation . HoweverCurrently there is a paucity of prospective data studying the use of SBRT for bone metastases originating from low alpha–beta tumors, with systematic reporting of changes in pain scores and analgesia use over time. Most of the data regarding SBRT for bone lesions focuses on local control and survival, rather than more tangible outcomes in a palliative population including symptom control, durability of response (and need for retreatment), as well as patient reported quality of life; a component that is understudied in this group despite its tremendous value. Furthermore, SBRT for bone metastases has yet to become common practice given the limited evidence for its efficacy, relative complexity as compared to simple single- or multi-fraction palliative approaches, and uncertainty in regards to toxicity.We propose an investigation of the potential benefits of SBRT for symptomatic bone metastases in patients with prostate cancer, breast cancer, RCC, and melanoma. We look to conduct a phase II single arm study (SOLAR-P) to assess pain response using this technique. We will also assess the tolerability of this modality, toxicity rates, and effect on quality of life.This is an open label, phase II single-arm trial. Patients will be accrued from a single tertiary Canadian cancer centre. Eligibility criteria are listed below, and informed consent will be obtained for patients meeting all criteria.Diagnosis of prostate cancer, breast cancer, RCC, or melanomaRadiographic evidence of bone metastases requiring treatment for painBrief Pain Inventory (BPI) score of ≥ 2 at baseline assessmentSpinal lesionsImpending (Mirels’ score ≥ 9) or existing pathological fractureBone metastasis in a previously irradiated siteLife expectancy < 3 monthsAge < 18Karnofsky Performance Status < 50Unable to provide informed consentPregnant or breast-feeding womenComplete or partial pain response at 3 months—Assessed using the BPI (online Appendix A) and converting daily analgesic use to oral morphine equivalent (OME)Complete response defined as BPI pain score of 0 with no increase in OME.Partial response defined as BPI pain score of > 0, and either a reduction of 2 or more with no increase in OME, or no increase in BPI with a reduction in OME or at least 25%.Treatment failure defined as worsening pain on BPI by 2 or more, > 50% increase in OME, re-irradiation for pain/progression, or development of pathologic fracture.Complete or partial pain response at 1 month and 6 months post SBRT—Assessed using the BPI and response as described above.Toxicity—Acute (3 months or less), and late (greater than 3 months) adverse effects from RT will be recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 [CAE) 5.0 .Patient-reported quality of life—Quality of life assessed by European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-Core-15-Palliative (EORTC QLQ-C15-PAL) and EORTC QLQ-Bone Metastasis 22 (EORTC QLQ-BM22), measured at 1 month, 3 month, and 6 months post SBRT [ost SBRT , 19.Re-irradiation or salvage surgery due to symptomatic progression—Patients requiring re-irradiation will not undergo treatment for at least 4 weeks following the study radiation course. Patients requiring salvage surgery for disease progression, instability, or pathologic fractures will be reported.Local control of treated lesions—Defined as time of trial enrollment to date of radiographic progression. Radiographic control evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [IST) 1.1 . To be aPatient eligibility will be determined during the initial assessment which includes a physical examination and review of radiographic evidence of metastases. Fracture risk will be assessed based on Mirels’ Staging System, taking into account the clinical evaluation and imaging available. For patients with high clinical suspicion of impending fracture, further evaluation and assessment may be taken as per standard of care.An initial BPI will be completed prior to treatment during a clinic visit, or over the phone. Use of analgesic medications will be recorded.Enrolled patients will receive the study dose of 15–20 Gy in 1 fraction to all painful bony lesions with SBRT. A dose range is given to facilitate safe treatment to larger lesions and metastases in close proximity to critical structures. If patients are on active systemic therapy, they will be taken off 5 days prior to, and after completion of SBRT. Planning and delivery will be conducted using a volumetric modulated arc therapy (VMAT) approach on the Varian Truebeam platform . Patients will be CT simulated, with custom vacuum-sealed cushions for immobilization, and MRI simulation may be performed. Use of 4DCT will be dependent on the area being treated but is not necessary for every case. The gross tumor volume (GTV) will be defined as the visible abnormality based on CT and MRI simulation imaging. A clinical target volume (CTV) may be contoured based on the characteristics of the target lesion and clinician preference. The planning target volume (PTV) will be an additional 5 mm in all directions. The SBRT prescription will ensure that at least 95% of the PTV will be covered with the prescribed dose, and that at least 99% of the PTV will be covered by 95% of the prescription dose  at 3 months using cRT is approximately 60%. We assume that under the null hypothesis, SBRT will have a similar response rate. We postulate that the pain response at 3 months using SBRT will be 80% . Assuming 80% power, two-sided alpha of 0.05, we will require 40 patients to test this hypothesis using a one sample binomial test.The observed proportion of pain response at 3 months with SBRT will be compared to the null value of 0.6 using a one sample binomial test. The corresponding 95% confidence interval (CI) around the observed proportion will be calculated using the Wilson score method. Toxicity and quality of life will be summarized descriptively at each time point with corresponding CIs. Proportion of patient with who are re-irradiation or have salvage surgery due to symptomatic progression will be described with corresponding 95% CIs. Local control at will be estimated using the Kaplan–Meier method.Conventional radiotherapy has been well established as an effective method in treating painful bone metastases, with 60% overall response rate for both single- and multi-fraction regimens , 14. HowSBRT has demonstrated promising results in the management of bone metastases. It has been shown to improve local control when treating bone lesions from prostate cancer with reductions of in-field failure in comparison to traditional schedules, but it is unclear whether this translates into long term pain relief . Also, tRecently, results were presented for the Canadian Cancer Trials Group SC24 study which was a phase II/III trial examining the use of SBRT for spinal bone metastases for pain relief . PatientFor the present study, we look to answer this question with respect to lesions from low alpha–beta primaries, excluding spinal lesions given the convincing evidence from SC24. A single-fraction regimen was chosen for the protocol to minimize treatment time while potentially giving superior symptomatic control from a radiobiological perspective. This allows for not only improved patient convenience, but also shorter breaks off systemic therapy. Furthermore, single-fraction SBRT may be more appropriate for smaller centers that do not have the resources to provide multi-fraction regimens. In summary, SOLAR-P is assessing the efficacy of single-fraction SBRT in the treatment of non-spinal bone metastases from low alpha–beta tumors for pain relief. The study looks to take advantage of the radiobiological difference in high dose radiotherapy in order to overcome radioresistance, and subsequently maximize symptom control.Additional file 1. Brief Pain Inventory.


The assessment of cervical spine kinematic axial rotation performance is of great importance in the context of the study of neck sensorimotor control. However, studies addressing the influence of the level of provocation of spinal pain and the potential benefit of passive manual therapy mobilizations in patients with acute-subacute non-specific neck pain are lacking.with an intervention design was conducted. We investigated: (1) the test-retest reliability of kinematic variables during a fast axial head rotation task standardized with the DidRen laser test device in 42 Healthy pain-free Control Participants (HCP) (24.3 years ±6.8); (2) the differences in kinematic variables between HCP and 38 patients with Acute-subacute Non-Specific neck Pain (ANSP) assigned to two different groups according to whether their pain was localized in the upper or lower spine (46.2 years ±16.3); and (3) the effect of passive manual therapy mobilizations on kinematic variables of the neck during fast axial head rotation.A non-randomized prospective clinical trial p<0.019). No significant difference was observed between ANSP with upper vs lower spinal pain localization. (3) After the intervention, there was a significant effect on several kinematic variables, e.g., ANSP improved peak speed (p<0.007) and performance of the DidRen laser test (p<0.001), with effect sizes ranging from small to medium.(1) Intra-class correlation coefficients ranged from moderate (0.57 (0.06-0.80)) to excellent (0.96 (0.91-0.98)). (2) Kinematic performance during fast axial rotations of the head was significantly altered in ANSP compared to HCP (age-adjusted) for one variable: the time between peaks of acceleration and deceleration ((1) The DidRen laser test is reliable. (2) A significant reduction in time between acceleration and deceleration peaks was observed in ANSP compared to HCP, but with no significant effect of spinal pain location on kinematic variables was found. (3) We found that neck pain decreased after passive manual therapy mobilizations with improvements of several kinematic variables.NCT 04407637Registration Number: The online version contains supplementary material available at 10.1186/s12891-021-04876-4. Approximately 50% of the population suffers from neck pain at least once in their lifetime, with women being more at risk than men . Neck paMost patients with neck pain are nowadays classified as suffering from “non-specific” neck disorder –6. Since“Non-specific” refers to pain in the neck that occurs without trauma, signs or symptoms of major structural pathology, neurological signs, or specific pathology . DegenerPatients with non-specific neck pain therefore present specific issues for clinicians who must treat the patients’ pain. Classifying patients with neck pain into specific and non-specific categories is certainly a first step in the process of clinical reasoning. But this classification alone does not allow a complete treatment plan to be established. Therefore, a history and a thorough clinical examination are important to guide the clinical reasoning process. The clinical guidelines for the management of patients with neck pain recommended by the Orthopedic Section of the American Physical Therapy Association (APTA) use a classification system based on the International Classification of Function impairments (ICF) for body functions terminology . They reClinicians are showing increasing interest in various tests to better define the clinical picture of patients by focusing on the assessment of sensorimotor control during axial head rotation –19. Calc0 to C2) than from the lower cervical levels (C3 to C7) [Most studies of sensorimotor control have been conducted in patients suffering from chronic neck pain –31. Neve3 to C7) , 31, to Finally, there are a growing number of studies demonstrating the effects of passive spinal manipulations on sensory processing, motor performance, functional performance, sensorimotor integration , 33, and) [Therefore, this study examined sensorimotor performance during the DidRen laser test . We exam) –40.with intervention . Inclusion criteria were acute-subacute (<3months) non-specific neck pain with a Neck Disability Index (NDI) > 8%  and a Nuhttps://www.a-e-c.eu, Brussels, B200-2018-103) and conducted in accordance with the Declaration of Helsinki. The authors confirm that all ongoing and related trials for this drug/intervention are registered .All participants signed an informed consent form, and the study was approved by the Comité Académique de Bioéthique  , the FreThe NDI is a self-rated questionnaire assessing disability due to neck pain, consisting of a series of 10 questions about activities of daily living, all scored on a 6-point scale. Each item is scored at 5 points, resulting in a maximum total score of 50 or a percentage of 100. The NDI score (in %) is interpreted as follows: 0-8 = none; 10-28 = mild; 30-48 = moderate; 50-68 = severe; more than 68 = complete . The NDIThe BQ evaluates several dimensions participants with neck pain, including pain, disability, affective and cognitive aspects of neck pain. Each question (7 items) is scored on an eleven-point (0-10) numeric rating scale. The maximum score for the BQ is 70 points and is the sum of the scores for each of the seven items . The BQ The TSK is a 17-item questionnaire assessing fear of movement or reinjury, in which participants are asked to rate their level of agreement with each item on a scale of 1 (strongly disagree) to 4 (strongly agree). The TSK has been shown to be associated with measures of behavioral avoidance and self-reported disability. A cut-off score of 39 is associated with risk for prolonged pain-related disability . The TSKThe NPRS is commonly used to assess patients with neck pain. It uses an 11-point scale ranging from 0 (no pain) to 10 (worst pain imaginable) . The NPRAfter completing the questionnaires, ANSP were assigned to the examination phases: DidRen laser test and manual examination. The manual examination was used to assign the ANSP to the group with the upper or lower cervical origin. Then, both groups of ANSP underwent passive manual mobilization sessions. After the last session, they were immediately examined for the DidRen laser test, which allowed us to calculate the effect of the intervention on the neck rotation kinematic variables.After completing the questionnaires, the HCP repeated the DidRen laser test a second time. In this way, we were able to calculate the reliability of the neck rotation kinematic variables. After the second test, HCP underwent a manual examination. HCP who were symptomatic on manual examination were removed from the study as they were no longer considered “pain-free healthy controls”. Comparing the results of the DidRen laser test of ANSP and the remaining healthy control participants allowed us to calculate the validity of kinematic neck rotation variables.For blinding, a first examiner supervised the completion of the questionnaires, the DidRen laser test, and the active cervical rotation test (range of motion). A second examiner (RH), who was blinded to the results of the first examiner’s DidRen laser test, performed the cervical manual examination and passive manual mobilization sessions. RH has 20 years of experience as a certified orthopedic manual physical therapist and 15 years of experience as an orthopedic manual therapy instructor.The DidRen laser test was used to homogenize the head-neck complex rotational motion of the participants as described in previous publications –23. BrieDuring the DidRen laser test, axial head rotation was recorded using a validated inertial motion unit sensor, the DYSKIMOT . The DYSAs described in Hage et al. (2019), 14 kinematic parameters were calculated to assess the reliability and validity parts. Thirteen specific kinematic parameters from each angular displacement Fig.  and one To determine the number of test repetitions required to familiarize the patient/healthy control with the test, we conducted a pilot study with 7 healthy subjects. This pilot study showed us that the DidRen Laser test needed to be performed 4 times. Then we recorded the fourth test outcome for the results.The mean value of three active ROM was measured using the DYSKIMOT device : partici0-C2) or lower (C3 to C7) spinal pain group.Based on the manual examination, ANSP were assigned to either the upper  [0-C2 when the examiner assessed stiffness with the axial rotation test C0-C2 and/or the PPIVM’s and PAIVM’s at levels C0-C1-C2. An ANSP patient was classified as “lower spine group” if the patient recognized her/his familiar pain below C2 when the examiner assessed stiffness below C2 with PPIVM’s and PAIVM’s. If the patient reported pain at more than one level of the cervical spine (upper/lower), the examiner selected only the level that reflected the patient’s familiar pain.The manual examination of the spine included the CS (1-10) , 57 whenS (1-10) . An ANSPBecause manual examination of the pain for segmental tenderness is known to have high sensitivity (92%), HCP were excluded if they had pain at one or more cervical spine levels .Once the questionnaires were completed, HCP were assigned to examination part. The reliability of the DidRen laser test and active cervical rotation range of motion was assessed for HCP using the intra-class correlation coefficient (ICC), the standard error of measurements, and the minimum detectable changes.After completing the questionnaires, ANSP were assigned to the spinal region examination part, which included assessment of fast neck rotation with the DidRen laser test, active cervical rotation range of motion, and manual examination. Then the patient was assigned to the intervention phase. Note that the DidRen laser test was assessed by a different examiner to ensure blinding.The intervention for the patient (i.e. physiotherapy treatment) included PAIVM’s mobilizations , 40. As At each session, the patient was assessed and asked to rate whether she/he wanted to continue treatment according to her/his improvement. If the patient was satisfied with the reduction in pain intensity, the treatment was stopped. All patients answered a seven-points “globally perceived effect” questionnaire : “Since Sample size was calculated for DidRen total time only, as this is the only kinematic variable ever studied in a neck pain population  and thisIntraclass Correlation Coefficient (ICC) calculation was performed using IBM SPSS Statistics-25. All other statistical procedures were performed using SigmaPlot 13  with a significance level 0.05.1) and second (T2) DidRen laser tests of the HCP group. T1 and T2 were separated by 20 minutes. Each variable was the result of the average of 5 cycles performed by each healthy control subject during a test.For each kinematic variable, reliability was assessed between the first  [SDγ = standard deviation of γ = average of results of T1 and T2, and Rγ = ICC between T1 and T2. Standard errors of measurement were also calculated in percentage relative to the mean, as follow: MEAN = average of all observations of T1 and T2. The SEM allowed us to calculate the minimum detectable change (MDC) at 95% CI level (MDC95), which was calculated as MEAN = average of all observations of T1 and T2.We used intra-rater reliability with two trials   and with3,2) . ICCs we3,2) . Agreemepost hoc Holm-Sidak method for pairwise multiple comparisons when ANOVA indicated a significant interaction.Because male/female equality between the ANSP and HCP groups was not optimal, we examined the influence of gender (gender x groups) on the kinematic variables. We used a two-way ANOVA with post hoc Holm-Sidak method for pairwise multiple comparisons was conducted when ANOVA indicated significant interaction.To assess the effect of painful cervical level (upper/lower) on the kinematic variables, we used a two-way repeated measure ANOVA with “The ANSP patients’ pre-treatment data were compared with the HCP group using ANCOVA  with post hoc Holm-Sidak method for all pairwise multiple comparisons when ANCOVA indicated a significant interaction.”post hoc Holm-Sidak method for pairwise multiple comparisons when ANOVA indicated a significant interaction. All data were normally distributed, as confirmed by Shapiro’s test or equal variance test.To assess the effect of passive manual therapy interventions, a two-way repeated measure ANOVA was performed with Effect sizes (ES) were calculated to provide a more interpretable quantitative description of effect size .A total of 42 ANSP patients and 54 HCP were screened. Four patients were excluded after the first assessment/treatment because they cancelled their second appointment. Twelve participants were excluded because they were not pain-free .A total of 38 ANSP patients and 42 HCP participated in the study. Table SD Standard Deviation, BMI Body Mass Index, Q1 First Quartile, Q3 Third Quartile, NDI Neck Disability Index, NPRS Numerical Pain Rating Scale, TSK Tampa Scale of KinesiophobiaThe ICC values for the kinematic variables are shown in Table There was no significant difference between the genders of ANSP and HCP (see Supplementary Table p<0.019). This time result was longer than that of SEM (Table Table EM Table .Table 4Rp<0.007), peak acceleration (p<0.038) and deceleration (p<0.005). They were also faster between peak acceleration and deceleration (p<0.002), at stabilizing the laser on target (p<0.033) and at performing the DidRen laser test (p<0.002). All results were smaller than those of the MDC (Table Table ion p<0.08 and decon p<0.00. They weThe average duration of “treatment” was 15 minutes. The mean number of treatment sessions was 4.7 (±2.3) and the mean number of treatment per week was 3.8 (±2.6). The NPRS averaged 5.6 (± 1.7) at baseline and 0.5 (± 0.8) at the end of intervention.For “global perceived effect”, 35 patients were “very much improved” and “much improved”. Three patients were “slightly worse” and averaged 8 treatment sessions”.The results of this study confirm moderate to good reliability of most outcome variables of the DidRen laser test when examined with healthy subjects . This stModerate to excellent intra-individual reliability was observed for all kinematic variables except overshoot, time to peak deceleration, and time to peak acceleration to end of rotation. For average and peak speed, our ICC values in healthy control subjects concur with those of Sarig Bahat (2016), who determined the inter-tester reliability of similar kinematic measurements using a virtual reality system in asymptomatic subjects . In lineThe lower reliability of the results for the overshoot, time to peak deceleration, and time to peak acceleration to end of rotation variables can be explained in part by the fact that these kinematic variables have greater variability among individuals. In the ANSP patient group, we demonstrated before and after the intervention that all significant results were below the MDC. Researchers and clinicians should look for ways to challenge the sensorimotor control system to a greater extent. The DidRen was able to distinguish ANSP patients from HCP, but not enough to be clinically meaningful.Given the observed differences in neck sensorimotor control performance between ANSP patients and HCP, further studies are warranted to investigate the internal and external validity of these findings. Our results confirm previous observations of kinematic behavior in patients with acute and chronic neck pain , 43. Our1-C2 [As for our significant result, we can conclude that pain could be responsible for the observed differences between patients and healthy control subjects. Three hypotheses could explain such observed differences between patients and healthy control subjects including (1) enhanced sensorimotor control of the neck via different sensorimotor channels acting together . During the DidRen laser test, proprioception, vestibular, and visuomotor control simultaneously contribute to the coordination of the head and eye movement control to ensure performance . Thus, a1-C2 . Thus, w1-C2 . The spe1-C2 . This va1-C2  during a1-C2 , 77, 78.1-C2 , 23.0 to C2), as has been observed in patients with traumatic neck pain [n=17) and lower (n=21) cervical spine pain). Nevertheless, with a sample size comparable to ours (upper (n=21) and lower (n=15)), Treleaven et al. showed comparable results with the joint position error test. A second reason could also be that the “axial rotation test” described by Satput et al (2019) [We were unable to confirm our hypothesis that sensorimotor dysfunction would play a greater role in participants with acute-subacute neck pain originating from the upper cervical spinal levels   is not aTo assess pain-related changes in sensorimotor control, we chose passive manual therapy mobilizations, which are known to reduce neck pain . Our resClinicians could gain relevant insights into sensorimotor control by assessing the rotational movements of the head-neck complex as part of their assessment of acute-subacute patients with neck pain. This highlights the interest in the diagnostic process to distinguish patients with acute-subacute non-specific neck pain patients from asymptomatic individuals to determine a cut-off point that may be clinically relevant.In view of our findings, it would be useful to further investigate the various aspects of cervical rotation acceleration and deceleration for rehabilitation of patients with neck pain”.The results of the current study should be viewed in light of several methodological limitations. First, we calculated the reliability only in healthy subjects because, according to the results of Roijezon et al (2010) , we wantSecond, the age did not match between the group of patients and the healthy control group. Twelve control participants were in fact excluded because they reported pain during the clinical examination (PAIVM’s). These were mainly elderly individuals. Indeed, the causal inference of a control group may be affected by various (as yet unknown) clinical biases. Since the prevalence of neck pain increases with age and older patients are likely to have residual effects on neck motor control performance due to previous pain, it is possible that factors other than those studied are responsible for the observed associations . To accoThird, due to the sample size, this study could be considered a pilot trial. Future studies with more diverse ethnic background could be conducted to increase the external validity of the findings. In addition, a relatively large sample could have been more representative. Fourth, recruitment bias cannot be excluded. Namely, the patients were referred to an experienced orthopaedic manual physiotherapist who is known as specialist in neck care. Therefore, a multicenter study with different physiotherapists would have been methodologically more appropriate.Finally, the pain reduction could also be related to the learning effect of the test. However, Bootsma et al.  have shoThe strength of this study is that for the first time, a sensorimotor assessment of patients with acute-subacute non-specific neck pain was performed with a pragmatic intervention and a follow-up test immediately after the completion of the intervention.In order to have a more sophisticated reference measure, we calculated reliability using healthy subjects, without knowing whether these results would have translated for our patients.The moderate to good reliability of the DidRen laser test allowed us to demonstrate the change in a kinematic variable (reduction in time between acceleration and deceleration peaks) in a sample of patients suffering from acute-subacute neck pain compared to healthy participants. Contrary to our original hypothesis, there were no differences in sensorimotor control when we compared patients with upper versus lower cervical spine pain levels. We found that neck pain decreased after passive manual therapy mobilizations, resulting in statistically but not clinically significant effects on several kinematic variables. These results suggest that sensorimotor changes may occur rapidly after pain subsides. The present study is of importance because, to our knowledge, previous studies of sensorimotor control have included mainly chronic non-specific neck pain populations, and this is the first study to examine sensorimotor control of the neck only in acute-subacute non-specific neck pain patients.Additional file 1: Figure S1. Example of C0-C2 axial rotation test to the left (posterior view). The patient was examined in a standardized sitting position with the neck in neutral position. The assessor passively rotated the patient’s head to the left with C2 stabilized and the assessor’s thumb and index fingers to isolate superior cervical levels from below.Additional file 2: Figure S2. Examples of PPIVM’s  in Lateral flexion. Lateral flexion to the left on C1 (A) and C5 (B) with hand placement (“patient” in supine with the “head” beyond the end of the couch). With both hands, the assessor gave support under the occiput. The assessor applied the thumbs directed laterally to the articular pillars from the upper cervical region C1 (A) to the lower region C5 (B) on each side.Additional file 3: Figure S3. Examples of PAIVM’s . Right unilateral on C2 (A) and C6 (B) with hand placement (“patient” in prone with the “head” on the right side of each picture). The assessor applied his thumb directed posterior-anterior force to the articular pillars from the upper cervical region C0-1, C1-2 and C2-3 to the lower region C6-7 on each side.Additional file 4: Supplemental Table 1. Effect of the gender (gender x groups) on the kinematic variables. two-way ANOVA with post hoc Holm-Sidak method for pairwise multiple comparisons when ANOVA indicated significant interaction.Additional file 5: Supplemental Table 2. Results of a two-way repeated measure ANOVA with post hoc Holm-Sidak method for pairwise multiple comparisons was conducted when ANOVA indicated significant interaction to calculate P-Values for kinematic variables during DidRen laser test for all ANSP patients according to the spinal pain location (upper/lower spine levels) and according of the effect of intervention.Additional file 6.Additional file 7.


Temporomandibular disorders (TMD) affect a considerable part of the population . Its mosp < .05. Paired t-tests were used to compare pre- and post-operative pain, MMO and mastication efficiency. Statistical procedures were performed using IBM® SPSS® Statistics – Version 24 and Microsoft® Excel for Mac – Version 16.15.Thirty patients diagnosed with internal derangement of the temporomandibular joint through magnetic resonance imaging were submitted to ALLV, after 6 months of ineffective conservative treatment. A classic, single session, two-needle technique arthrocentesis was performed in all cases, encompassing the injection of 200–300 mL of Ringer lactate solution to the superior joint compartment for lysis and lavage, followed by intra-articular injection of 1 mL of hyaluronic acid for viscossuplementation ,5. PatieDiscussion and conclusions: ALLV is a safe, well tolerated and cost-effective minimally invasive procedure, which proves to reduce pain and functional impairment up to 12 months post-operative, with little or no complications [Twenty-six of the selected patients were women and mean age was 38.86 ± 17.5 years old. In all cases a single side TMJ was treated − 14 left and 16 right. MRI had shown anterior disc displacement (ADD) with complete reduction on opening in 15 patients, without reduction in 9 and with partial reduction in 6. Results show an improvement in pain, both at rest and in function, MMO and mastication efficiency at a statistically significant level, up to 12 months post-operative. The procedure was considered well tolerated (mean Likert: 3.15 ± 1.13) and no adverse events were reported.


Opioids are currently prescribed for chronic non-cancer pain (CNCP), and some patients use opioids continuously for long-term treatment. Stakeholders’ awareness about long-term opioid therapy is essential for improving the safety and effectiveness of pain treatment. The purpose of this study is to explore the perspectives of pain specialists, patients, and family caregivers about long-term opioid use in CNCP management.n = 12), patients (n = 14), and family members (n = 9) were recruited to the study by purposive sampling at the Pain Clinic of Ramathibodi Hospital. Semi-structured interviews were recorded, verbatim transcribed, conceptually coded, and analyzed using Atlas.ti 8.0.This study was a qualitative study and adhered to the COREQ guidelines. Pain specialists  with their physicians. Regular monitoring and evaluation of the risks and benefits, adverse events, and drug-related aberrant behaviors are necessary. Integrated multimodal multidisciplinary therapies and family member collaborations are also important for improving CNCP management.The online version contains supplementary material available at 10.1186/s12871-021-01501-8. Chronic non-cancer pain (CNCP) is defined as pain that persists for at least 3 months beyond tissue healing and is not related to malignant disease. CNCP interferes with patients’ daily activities and physical, emotional, and social functions, and has a severe negative impact on quality of life . The preMany studies have reported that general physicians perceive multiple barriers to prescribing opioids in the long term . Lack ofA qualitative, cross-sectional study was conducted in the form of semi-structured interviews with pain specialists, CNCP patients, and their family members at the Pain Clinic of Ramathibodi Hospital in Bangkok, Thailand and adhered to the COREQ guidelines.The protocol was approved (MURA2019/1198) on 27 November 2019 by the Ethics Committee (Chairman: Assistant Professor Dr. Chusak Okascharoen) of the Faculty of Medicine of Ramathibodi Hospital . Written informed consent was obtained from all participants according to the local regulations and to the principles of Helsinki Declaration. Prior to the interviews being conducted, participants were informed about the aim of the study and provided written informed consent. However, participants were informed that they could withdraw at any time from the study without any negative consequences. All data were confidential. Participants’ data were accessible only to the researchers who involved in the study and all document files were eradicated immediately following data analysis.The study was conducted from November 2019 until April 2020. We used purposive sampling to maximize the likelihood of recruiting participants with sufficient experience associated with long-term opioid therapy. Participants aged 18 and over who were fluent in the Thai language were informed about the study and provided their consent before participation. We recruited patients who 1) had CNCP for at least 3 months before attending the Pain Clinic; 2) had been prescribed with strong opioids  for pain relief for more than 1 year in any dosage form, strength, or method of administration; and 3) came to follow-up. Family members who were caring and living with these CNCP patients for longer than 1 year were also included. In addition, pain specialists who had ever prescribed strong opioids to treat CNCP patients for more than 1 year were eligible to participate in our study.We created open-ended questions based on literature reviews, and a pilot tested them before use in this study. The questions explored the participants’ perspectives about long-term opioid use for the treatment of CNCP in relation to their personal context . However, they stated that drug monitoring and risk evaluation should be carefully assessed. They also mentioned that opioids should be provided for long-term pain control so that patients can perform their usual daily activities; this is considered long-term dosage management. As one specialist described:“There are not many patients who require opioids as a long-term treatment. Most of the patients are well-known cases. Most of them do not worry about reducing opioid dosage and are not willing to stop opioids. I think that the understanding of their pain and how to manage it is necessary. My treatment goals are achieving realistic pain relief and [ensuring patients are] able to participate in work and social activities.”Pain specialists reported that some patients have complex and severe chronic pain that is not responsive to non-opioids, pain intervention, physical therapy, or other alternative treatments. It is crucial to consider initiating and titrating opioids for pain control in these patients. However, pain specialists stated that they restricted opioid prescriptions as necessary, because opioids are not a first-line treatment for CNCP and have severe adverse effects. If the combination of appropriate opioid therapy with non-opioid and non-pharmacological treatments was able to improve both pain and function, then the specialists would initiate opioid therapy with close monitoring. As one specialist reported:“Well, you know, I have some patients who have received morphine for a long time, and they are able to do some more social activities, such as going to the mall or doing a few chores. However, medications may be a supplement to the treatment of pain, more or less. But I also have not given up on other treatments, such as psychotherapy. But not everyone is getting better.”Some pain specialists remarked that the cause of pain was a factor when deciding to initiate and continue prescribing opioids. If opioids were able to reduce pain, the specialists would calculate the total morphine milligram equivalents (MME) per day and convert to methadone if it was not contraindicated. As one specialist stated:“I have a patient who continues to have pain from a spinal cord injury [even] after titrating the maximal dose of anticonvulsants. So I tried to use morphine tablets to control his pain and calculated the total dosage converted to methadone. After he took methadone, he said the pain decreased and he slept better.”All specialists emphasized that, if the benefits did not outweigh the risks, they would talk with the patients to taper opioids and discontinue their use. They recommended additional non-pharmacological and non-opioid treatment options, or considered consulting a multidisciplinary working group if necessary. As three specialists remarked:“If I assessed that morphine did not help, I would advise patients to reduce or stop medication because drugs can't help them to improve. Continuing the medication will have more disadvantages.”“I would advise patients to understand that morphine is not useful for pain control, but that other methods of treatment may be a better solution.”“If morphine is not an appropriate treatment, I would advise patients to participate in treatment with specialists in various fields that can help with other rehabilitation procedures, or psychotherapies such as CBT [cognitive behavioral therapy].”The benefits and effectiveness of long-term opioid therapy for CNCP remain unclear to pain specialists. Some patients required the continued use of the lowest effective dose of opioids to improve functional outcomes and daily activities, combined with non-opioid and non-pharmacological treatments. As one specialist said:“I am concerned about the possibility of opioid tolerance and misuse. I carefully assess [the patient’s] current effective dose, and cut back on their dose if possible.”Some specialists mentioned opioid use disorder. If they suspected this condition, they would offer or convert to methadone if it was not contraindicated. As one specialist said:“If there is any chance of drug addiction during treatment, I will avoid prescribing opioids at 90 MME per day. A small amount of opioids will be prescribed, and opioid rotation to methadone will be considered.”Most of the specialists reported concerns about the adverse effects of opioids. Drug monitoring and continued follow-ups should be scheduled every 2–3 months. As one specialist stated:“My hospital has a policy about prescribing opioids that helps us to easily manage [opioid prescriptions]. For example, it explicitly restricts prescribing more than 2 months.”“I think that if the hospital has regulations that determine which doctor can prescribe morphine to chronic pain patients, we would be able to control the medication properly, and addiction would decrease.”All specialists stated that the implementation of education to healthcare providers and patients about opioid prescribing could help to reduce opioid use disorder. Moreover, they suggested that appropriate knowledge may promote more judicious opioid prescribing and ensure safer prescribing when indicated. As one specialist said:“I think that providing education about the advantages and disadvantages of long-term morphine use to patients and treating physicians was necessary. It decreased adverse events and harm.”Some specialists mentioned that the online national electronic medical record, which alerts opioid prescribing, might reduce patients’ opioid shopping or drug-seeking behaviors. Moreover, the electronic medical record helps to alert physicians about redundant drug prescribing. As some specialists mentioned:“I did not know whether patients had received morphine from other hospitals. Sometimes I felt discomfort about prescribing morphine. If I had known about all of the medications that my patient takes, I might have felt more confident to manage [their medications].”“If I have ordered redundant drugs, the computer software alerts my prescriptions. This made me more confident, and reduced the mistakes made by people.”Specialists reported that hospital policies, regulations, or clinical practice guidelines are necessary to promote the implementation of appropriate prescribing of opioids in CNCP patients. Overall, they believed that this would reduce the occurrence of opioid-related harm and prevent iatrogenic addiction. As some specialists said:CNCP patients mentioned their use of strong opioids for pain management for more than 1 year. The boundaries from the interviews were attitudes about using opioids, benefits and effectiveness, and concerns.“I have very bad pain and that pain really affects my life. I cannot walk, drive, work, or do any activities. I have tried many drugs but none provided good pain control. Morphine helps me for so many hours, more than other drugs”Some patients who disclosed the use of opioids for pain relief considered opioids to be the most effective medications for moderate to severe pain. They stated that their use of opioids was not for pleasure purposes. As one patient said:“I know that morphine is a strong drug, and I don’t worry about continuing opioid therapy because it provides better and fast-acting pain relief. Sure, it can relieve severe pain that other medications cannot. As long as it can ease my pain, I will continue using it. Of course, I don't use it for any purpose other than pain relief.”Some patients discussed tapering and discontinuing opioids if they lacked efficacy or had adverse events. They were ready to follow their pain specialists’ recommendations. As one patient said:“Drugs are prescribed to me depending on my pain level and the doctor’s decision. As the doctor said, if I had no response to pain control or I were harmed [by it], he would discontinue morphine. Whenever the doctor tells me to stop, I will stop.”Most patients rated their pain as the worst and reported disability caused by illness. However, patients accepted opioid therapy and expressed that opioids were useful for pain relief, and were better than previously prescribed non-opioid medications. As one patient said:“Today, I feel better when using morphine for acute pain relief. It allows me to help myself sometimes. Some nights I get pain and cannot sleep, and I use morphine to control my pain. That helps me a lot.”More than half of the patients agreed that opioid management has been much improved over all of pain. Furthermore, opioids were carefully prescribed by specialists under the drug monitoring program. These reasons explained why patients were confident to continue taking opioids. As one patient described:“Although morphine is a narcotic drug, it is prescribed with caution and well-controlled. I think that it has more benefits than risks. I feel no worries using it under the supervision of specialists.”Most of the patients were comfortable to continue opioid therapy because of its effectiveness in pain relief. They also said that opioids encouraged the performance of their usual daily activities. As one patient said:“I have no adverse experiences with morphine. I have no problems with moodiness, no trouble concentrating, no problems getting along with people. My family also agrees with me to continue morphine. They know that uncontrolled pain makes me annoyed, unhappy, and moody.”Some patients were concerned that long-term opioid therapy might be harmful for their organ function when combined with other medications. In this sense, they preferred to continue using opioids for pain control rather than other pain medications. As one patient said:“I worry about the side effects of taking many combined drugs. Do they have any side effects to my liver or my kidney? However, I can take some risks using pain medicines because I am not able to live my life with this pain level.”Patients with a history of alcoholism, smoking, or substance abuse reported slightly higher comfort with regards to continuing opioids without fear of opioid addiction. One patient described that:“Many people warn me to be careful when using morphine because I have a history of meth [amphetamine] addiction. However, in my experience, morphine is very different. I do not feel annoyed, terrible, tired, or drug-seeking when I take it. My mood is better, stable. I do not think that I can be addicted to it.”Alternatively, another patient relayed that:“I think that smoking or alcohol addictions are easier than morphine addiction. If we can stop smoking, we can stop using morphine too.”Overall, patients had no concerns about opioid side effects and did not experience any adverse events, psychosocial problems, or family relationship problems. As one patient mentioned:Family members described their experiences of long-term opioid use in CNCP patients with respect to family relationships, attitudes about using opioids, benefits and effectiveness, and concerns.“I know, whenever he [the patient] suffers severe pain, I let him try using this painkiller. I want his pain to be minimized. I witnessed him after he took it; he felt much better, he could rest, sometimes, he could walk. I think morphine is the key drug that can help him.”All members agreed that long-term opioid prescriptions were dependent on specialists’ decisions. They believed that strict compliance with the doctors’ recommendations would increase the safety and efficacy of treatment. One family member relayed that:“I don’t want him [the patient] to stop morphine. But I am careful not let him take more, and too often. If I notice some adverse events, I will take him to see the doctor.”Alternatively, one member stated that:“I do not interfere with the doctor’s prescription. The decision about a morphine prescription is dependent on the doctor’s opinion. I do not worry about continuing or stopping.”Most of the patients’ family members accepted their continued treatment with opioids because they perceived the severe pain level of the patients. They stated that opioids were able to resolve even the worst pain. They also mentioned that opioids improved daily physical activities and sleep. As one member said:“I used to worry at his [the patient’s] first time using morphine, but I saw that it provided control over his pain. I saw some drowsiness and bit of confusion after use, but that was not much different from normal. He slept better. There are not many side effects so I will keep observing.”Another member mentioned that:“Morphine could provide some relief but he [the patient] still had pain. However, adequate use makes it easier for him to do more activities and sleep. Sometimes, I think that I see some confusion and personality changes, but it is not a big problem. This problem can be reduced and controlled.”Some of the family members mentioned that sleep disruption is a particularly frequent issue for chronic pain patients. As one member described, opioids are a medication that can be used as a sleep aid to take away pain.“Well, you know, every night she [the patient] lies down with pain. She cannot sleep and is agitated. Then she takes a pill, she feels a little bit well and sleeps well. Okay! I just say it helps control her pain.”Most family members approved the use of long-term opioids because of their effectiveness for pain control. They were able to accept the low level of adverse events. However, they noted that adverse events should be continuously monitored. One member expressed that:“When [the patient] started using morphine, I was so worried about addiction, withdrawal symptoms, and also emotional problems, which led to quarrels in my family.”Another described:“I am worried that morphine may cause adverse effects to his [the patient’s] health. He takes a lot of medications to control his underlying disease and he also has a problem with his kidneys.”Most of the family members were concerned about the adverse effects of opioids. The primary concerns were opioid addiction and having psychosocial problems. The secondary concern was physical problems related to the use of opioids. As one family member noted:This study is the first qualitative study to explore the perspectives of pain specialists, patients, and family members about long-term opioid use (for more than 1 year) for CNCP in Thailand. Each group of participants expressed various attitudes toward starting and continuing long-term opioid therapy. The treatment goals of opioid use were different between the groups in our study. Pain specialists mostly prescribed opioids to improve functional outcomes rather than to reduce pain as patients needed, following the CDC guidelines for prescribing opioids for chronic pain . Pain spCNCP patients usually experience irritability caused by pain, and opioids may allow them to relax. Family members regarded opioid use as beneficial to patients’ pain control and for improving family relationships. However, patients mainly asserted that opioids provided them with maximal pain relief and induced sleep. These results are consistent with previous research showing that CNCP patients need opioids for both pain relief and rest. Patients believe that opioids help them to control their pain, and that their pain will be severe if they do not have access to opioids , 21.Another interesting finding was that our patients confirmed that they wished to continue long-term opioid therapy, although its long-term benefits and effectiveness were small. It is possible that chronic pain patients’ belief in opioids is valuable for a variety of pain control, despite their reported ongoing pain. In contrast, pain specialists stated that they would discontinue opioids if the benefits did not outweigh the risks, or would prescribe the lowest effective dosage to improve patients’ physical functions. Our study revealed that pain specialists preferred methadone over other opioids for long-term therapy, if its effectiveness was shown to be the same as that of previous studies –40. MethIn our study, patients were more concerned with the potential achievement of maximal pain relief than with opioid-related harm. Similar to a previous survey of the attitudes and beliefs associated with long-term opioid use prescribed in CNCP, most patients were not very concerned about addiction or side effects . CNCP afIn the present study, pain specialists proposed that the provision of adequate education to healthcare providers, patients, and other stakeholders would help to create a better understanding of opioid use in CNCP. Previous research has noted that good pain education is the key to improving pain management , 41. PatFinally, in the present study we also found that hospital regulations and policies can support the process of care. The pain specialists proposed the use of an online national electronic medical record that provides alerts for opioid prescribing, which they believe would control and prevent redundant opioid dispensing and reduce opioid shopping or drug-seeking behaviors. These results warrant consideration, because a previous report from Tasmania suggested that a real-time prescription monitoring program, DORA (Drugs and Poisons Information System Online Remote Access), is useful for clinical decision-making and reducing doctor shopping, and allows for better control of substances such as opioids , 45.This study has some limitations. First, the study was only performed at a single institution; therefore, our results may not be generalizable to other situations. Second, our patients’ characteristics were not grouped by cause of pain, psychological disorder, pain interfering with daily activities and functions, occupational status, or type of opioid use. Finally, our study was conducted in Thailand and the results may not be generalizable to other races or nationalities because of the influence of sociocultural differences on beliefs and attitudes. Future research should assess opioid use disorder combined with interviewing for the evaluation of evidence.The benefits and effectiveness of long-term strong opioids prescribed for CNCP are limited. Opioids may be appropriate for only a small proportion of the causes of pain. Awareness about balancing the benefits against the possible side effects of long-term opioid use is recommended for its close monitoring in prolonged use. Diverse perspectives about long-term opioid use need to achieve consensus between professionals, patients, and family members, with appropriate education, sharing of information, well-planned and -organized treatment regimes, and acceptable healthcare environments. Concurrently, the treatment of CNCP warrants a multidisciplinary approach, including both pharmacological and non-pharmacological treatments.Additional file 1.


Background and objectives: Many mediators and cytokines are involved in the pathogenesis of osteoarthritis (OA). Some of these cytokines are spontaneously expressed by cultured fibroblast-like synoviocytes. Therefore, using serum samples, the efficacy and the effects of avocado/soy unsaponifiables, ASU, (Arthrocen) on cytokine changes were assessed in patients with knee OA (KOA). Materials and Methods: Experimental procedure: A randomized, double-blind, placebo-controlled clinical trial was conducted on patients with a diagnosis of mild to moderate OA who received either Arthrocen 300 mg/day (n = 61) or placebo (n = 58) for 3 months. Data collection was performed using questionnaires including the Western Ontario and McMaster Universities osteoarthritis index (WOMAC), 20-item short form survey (SF-20), Lequesne index of severity for osteoarthritis of the knee (LISOK), and three visual analog scales (VASs) as pain quality indices. The serum levels of interleukins 2 (IL-2), IL-4, IL-10, IL-17α, and TNF-α were measured using an ELISA reader. Results: Both quality of life indices, pain sensation and scored by specialists (as VASs), respectively, including WOMAC and SF-20, as well as joint dysfunctionality symptoms assessed by physicians were significantly improved (p < 0.05) in OA patients receiving Arthrocen. The serum levels of anti-inflammatory interleukins 4 and 10 were also augmented, while levels of inflammatory IL-17 and TNF-ɑ cytokines were decreased significantly (p < 0.05) compared with the control groups during the 3- and 6-month treatment. Conclusions: Arthrocen consumption may increase the quality of life in OA patients through amelioration of inflammation and improvement of functional activities without any adverse effects in the long term. Human osteoarthritis is a degenerative disorder involving activation of the immune system accompanied by the production of pro-inflammatory cytokines that play a significant role in the destruction of articular cartilage and disease progression . AlthougThe current treatment options for OA vary from non-pharmacological and pharmacological strategies to joint replacement . The parOn the other hand, there is an increasing tendency toward using herbal extracts as a way to treat OA due to their time-tested safety and efficacy . In partIn terms of cellular mechanisms of OA, it is mainly started by sequential inflammation and then local inflammation in the damaged joints that is associated with systemic inflammation markers . It is phttp://www.consort-statement.org/consort-2010 (accessed on 29 January 2018). Initially, the study protocol was evaluated and approved by the Ethics Committee of the Iranian Ministry of Health. The tenets of the Declaration of Helsinki and Nuremberg Protocol were observed in all stages of the study.This study was conducted in Tehran hospitals according to the ethical guidelines of the Iranian Ministry of Health . In our research, we used “Consolidated Standards of Reporting Trials (CONSORT) 2010” that was adapted from A double-blind randomized clinical trial was performed on patients that suffered from OA in hospital clinics of Tehran between March 2018 and December 2019. All patients were individually informed about the study protocol and randomized placebo-Arthrocen prescription, and consent was obtained from each patient before inclusion in the study. The inclusion criteria were as follows: (a) mild to moderate degenerative knee OA, (b) bilateral OA, and (c) age under 65 years. The OA of the knee was diagnosed according to the clinical and radiological findings and self-reports of pain in patients with a mild to moderate active movement index (minimum of 40 mm on a 100-mm of VAS) based on the American College of Rheumatology (ACR) criteria . PatientEligible patients presenting to the clinics were randomly assigned to treatment and control groups. Patients in the treatment group received Arthrocen  capsules containing 300 mg ASU for 6 months, while placebo was used in the control group d. The duration of treatment was three months (once daily) in both groups. Before the clinical trial, a completely randomized sample of patients was used as a basis for the comparison of post-test data.The patients were assessed before and after the experiment in three ways: (a) measuring the serum levels of systemic cytokines, (b) visiting patients by an experienced team of rheumatologists, and (c) using several questionnaires which are described in the below section. A brief diagram of the study procedure related to clinical and preclinical assessments is given in Blood samples were collected from each participant following a standardized protocol and according to clinical practice. Briefly, serums were separated from the whole blood by 2000 rpm centrifugation. Then, the levels of IL-4, IL-10, IL-17α, and TNF-α cytokines were measured in the serum samples using the sandwich Elisa method according to the manufacturer’s instructions .In brief, in this study, the patient was visited by an experienced team of rheumatologists that assessed factors such as internal and lateral joint tenderness, swelling, patella crepitus, crepitus, and flexion contracture. Moreover, questionnaires included the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) , 20-itemp-value thresholds of less than 0.05 and 0.10 were considered as significant and suggestive levels, respectively.All statistical analyses were performed in open-source statistical software R (v 3.4.0), a language and environment for statistical computing . In the p < 0.05)  A,B.By contrast, the results showed a significant increase in the serum levels of anti-inflammatory IL-10 and IL-4 compared to the relative control groups; however, the placebo group was not significantly different from the control group. In brief, the results showed the effect of Arthrocen on anti-inflammatory factors C,D.p < 0.05). However, there was no significant difference between placebo and ASU groups before treatment  and placebo (p < 0.05) groups  after Arthrocen treatment. However, the difference between the two groups was not significant (p > 0.05). Analysis of the results of examinations before and after treatments showed a significant reduction in internal or lateral tenderness in the Arthrocen  groups . The patp < 0.001). The results of the WOMAC and VAS for pain severity showed similar results; however, despite a significant decrease after Arthrocen treatment in both groups , no difference was found between the placebo and Arthrocen groups. The LISOK  did not change significantly after treatments in both groups. Although two VAS indicators for the overall health status of patients reported by patients and physicians showed significant improvements  in patients treated with Arthrocen, these indicators showed no significant difference with the placebo groups . Therefore, the health status improved significantly after the intervention, and Arthrocen had a greater effect on the improvement of the patients compared to placebo. According to The present study was conducted to examine the effect of Arthrocen on the patients’ quality of life, activities of daily living, and pain and their relationship with inflammatory cytokines in patients with knee OA, as these molecules are thought to play a leading role in the pathogenesis of OA. It is worth mentioning that the role of inflammatory and anti-inflammatory cytokines in the pathogenesis of OA is not clear, which warrants further research . Our finBased on the results, Arthrocen significantly improved the quality of life, activities of daily living, and pain from OA; moreover, two important anti-inflammatory cytokines including IL-4 and 10 increased markedly in the serum samples of Arthrocen patients. Although IL-10 increased in the placebo-treated group, this may be more related to the use of NSAIDs, especially diclofenac or acetaminophen codeine during intolerable pain, which was more common in the placebo-treated patients .Cytokines are classified according to their inflammatory or anti-inflammatory role . InteresHuman chondrocytes synthesize IL-10 and express IL-10R on their surface. Since IL-10 inhibits IL-1 and TNF-alpha expression, its upregulation in osteoarthritic chondrocytes may counteract the detrimental effects of these catabolic cytokines. However, the functions of IL-10 in cartilage may go beyond those activities established in the immunological setting. The high levels of IL-10 in fetal cartilage, as an actively growing tissue, suggest that IL-10 may play a role in controlling chondrocyte metabolism under physiological conditions, which is very important for normal function .Previous studies on ASU showed that ASU suppresses TNF-α, IL-1β, COX-2, NOS gene expression, and PGE2 and nitric oxide production in human articular chondrocytes and monocyte/macrophages . In the In this study, placebo had no marked effect on the health status of patients except for the VAS reported by the patient. In contrast, a meta-analysis of 35 randomized placebo-controlled trials by Machado et al. found that, in comparison with placebo, NSAIDs did not provide a clinically important effect on spinal pain . It was tried to collect the maximum possible data through questionnaires, which could reduce the reliability and precision of the data from the questionnaires because a large number of questionnaires and questions may be tedious for patients. Therefore, a clinical evaluation was carried out by experts to ensure the quality of the questionnaire data. Fortunately, except for the SF-20 index, the results of other questionnaires were almost similar to clinical evaluations by experts. The reason for this mismatch can be the complexity of SF-20 questions compared to other scales. In this trial, the results of the questionnaires and clinical evaluations showed a significant difference between the ASU and placebo groups in terms of the health status of patients as well as pain reduction, which were consistent with the anti-inflammatory effect of ASU administration on reducing TNF-α and IL-17 and increasing IL-10, and IL-4 blood levels in comparison with placebo in both early and chronic stages of drug administration.The limitations of our study would be taken into account when interpreting our results. At first, the interference events such as smoking and pollution may involve in the assessment of systemic inflammation or pain within a patient. Secondly, although widely used to assess the intensity of pain in clinical studies, the measurement of pain using a VAS is influenced by a variety of factors associated with the perception of pain ,15. NeveThese findings reasonably advocate the anti-inflammatory properties of Arthrocen that may affect the joint pain and dysfunctionality improvement as well as the quality of life in OA patients. Improving joint function and pain relief can cause patient activity, which is important for public health concerning the recovery of quality in lifestyle. At the clinical level, Arthrocen may prove to be an effective therapeutic agent with minimum side effects that prevents progression of OA symptoms.


The prevalence of diabetes mellitus is growing worldwide, as well as in the aging population, and its comorbidity and mortality rates are higher in aging people than they are in young people. It has been observed that the number of drugs used increases in aging patients, especially in diabetic patients. This study aimed to investigate the relationship between polypharmacy and modified Charlson Comorbidity Index (CCI) and Katz Index of Independence in Activities of Daily Living (Katz ADL) scores in aging diabetic and non-diabetic patients.This prospective study included 184 diabetic and 62 non-diabetic subjects who were ≥65 years old. Comorbidity was determined with CCI, and dependency on daily basic activities was assessed with Katz ADL.P = .001). In all subjects and in the diabetic group, there was a negative correlation between CCI and Katz ADL ; there was a positive correlation between CCI and number of drugs .CCI and the number of drugs were significantly higher in diabetic groups (We found an increase in the number of drugs taken by the aging patients, positively correlated with the CCI score. The increase in the number of drugs used is closely related to the insufficiency in daily life activity and comorbidity, and this predicts 10-year survival. Patients should be directed to special centers or physicians who will be scheduled for multidisciplinary treatment for the prevention of polypharmacy, especially in the aging. It is estimated that by 2050, the aging population will rise from 900 million to 2 billion people, which means that the proportion of the world’s population over 60 years old will nearly double between 2015 and 2050, from 12% to 22%.4Aging patients are more susceptible to issues caused by an increased number of drugs, which is called polypharmacy, than young people. Yet, there has been a considerable increase in polypharmacy in the geriatric population.8In the hope of improving quality of life on newly developed drugs, more and more drugs are given to patients, especially elderly patients. We think that multidrug use may decrease quality of life and negatively affect the survival of aging patients. When we look at the geriatric patient population that we followed in our outpatient clinic, we found that DM was a very comorbid disease because the frequency of diabetes increases with age and we thought that the number of drugs used in these patients may be greater and that diabetic patients may be more exposed to the risk of polypharmacy. In this prospective study, we aimed to investigate the relationship between polypharmacy, the modified Charlson Comorbidity Index (CCI), and the Katz Index of Independence in Activities of Daily Living (Katz ADL) to determine whether polypharmacy affects CCI and/or Katz ADL scores in aging diabetic and non-diabetic patients.This prospective study was conducted from January 2017 to January 2018 after receiving institutional ethical approval from Ethics Committee of Bakirkoy Dr. Sadi Konuk Training and Research Hospital (2018/336). The study included 184 diabetic (group 1) and 62 non-diabetic (group 2) subjects who were 65 years or older and visited our Diabetes or Internal Medicine outpatient clinics. The non-diabetic patient group consisted of patients who had not previously been diagnosed with DM type 2, had a glycolyzed hemoglobin (HbA1c) level below 6.5%, and had a fasting glucose level below 140 mg/dL. Written consent was obtained from all participants. Before obtaining blood samples, data  of the patients enrolled in the study were recorded on standardized forms.CCI, a prognostic assessment tool, is based on comorbid conditions with varying assigned weights, resulting in a composite score; it predicts 10-year survival in patients with multiple comorbidities.t test was used for comparing two independent groups in variables with normal distribution. A P-value < .05 was considered significant.Statistical analyses were conducted with SPSS version 23 . Mean, standard deviation, median, minimum, and maximum values of variables were given for descriptive calculations between groups. Mann-Whitney U test was used in comparison of two independent groups for variables that did not display normal distribution, and Spearman’s rank correlation coefficient was used to determine the relationships between variables. Student’s P = .472). There was a significant difference between the two groups regarding HbA1c, random urine albumin/creatinine ratio, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), dual-energy X-ray absorptiometry, and serum iron, magnesium, hemoglobin, and albumin levels  and group 2 consisted of 62 (46 women) subjects with mean ages of 71.15 ± 5.28 years and 71.58 ± 5.35 years, respectively (P = .001 for both). Katz ADL did not differ between the groups (P = .059)  .r = 0.525, P = .001) and weak positive correlations with HbA1c  and random urine albumin/creatinine ratio . In addition, CCI had weak negative correlations with glomerular filtration rate (GFR) and serum magnesium, iron, and hemoglobin levels. Katz ADL had weak positive correlations with GFR and serum magnesium and iron levels; in addition, it had a weak negative correlation with HDL-C levels. Number of drugs had a weak positive correlation with HbA1c and a weak negative correlation with GFR, LDL-C, and serum magnesium, iron, and hemoglobin levels .In all subjects, CCI had a moderate positive correlation with age ; in addition, there was a positive correlation between CCI and number of drugs ; moreover, there was a positive correlation between CCI and number of drugs . In addition, age of DM diagnosis had positive correlations with CCI and number of drugs . Similar studies conducted in the future may focus on these issues.The increase in the number of drugs taken by aging patients with and without diabetes is positively correlated with CCI score. As we know, this scoring system is being used as a predictor of 10-year survival in patients with multiple comorbidities. Thus, polypharmacy could be a quick determinant of prognosis in such a group of patients. Further detailed studies are needed to verify this.Polypharmacy decreases quality of life and affects the survival of aging patients.The number of drugs taken by the patients had a statistically significant positive association with modified Charlson Comorbidity Index in aging people with and without diabetes mellitus.Patients should be directed to special centers or physicians who will be scheduled for multidisciplinary treatment for the prevention of polypharmacy, especially in the aging.


Paravertebral block (PVB) is the most recognized regional anesthesia technique after thoracic epidural anesthesia for postoperative analgesia in thoracic and breast surgery. Erector spinae plane block (ESPB) is a recently discovered blocking technique, and it has evidenced excellent postoperative analgesia for breast and thoracic surgery with fewer adverse reactions. However, there are controversies about the postoperative analgesic effects of the two analgesic techniques.To assess the analgesic effects of PVB versus ESPB in postoperative thoracic and breast surgery.We systematically searched PubMed, Cochrane Library, EMBASE, Web of Science, and ScienceDirect databases up to April 5, 2021. The primary outcome was postoperative pain scores. Secondary outcomes included: opioid consumption, additional analgesia, postoperative nausea and vomiting (PONV) 24 hours post-operation, and the time required for completing block procedure. This study was registered in PROSPERO, number CRD42021246160.After screening relevant, full-text articles, ten randomized controlled trials (RCTs) that met the inclusion criteria were retrieved for this meta-analysis. Six studies involved thoracic surgery patients, and four included breast surgery patients. Thoracic surgery studies included all of the outcomes involved in this meta-analysis while breast surgery did not report pain scores at movement and additional analgesia in 24 hours post-operation. For thoracic surgery, PVB resulted in significant reduction in the following pain scores: 0–1 hours , 4–6 hours , and 24 hours  at rest; significant reduction in pain scores at 4–6 hours , 8–12 hours , and 24 hours  at movement. Moreover, the opioid consumption at 24 hours post-operation  and the incidence of additional analgesia in 24 hours of the postoperative course  were significantly lower in the PVB group than in the ESPB group for thoracic surgery. However, no significant differences were found in pain scores at rest at various time points postoperatively, and opioid consumption at 24 hours post-operation for breast surgery. The time required for completing block procedure was longer in the PVB group than in the ESPB group for thoracic and breast surgery, and the incidence of PONV between the two groups showed no significant difference.The postoperative analgesic effects of PVB versus ESPB are distinguished by the surgical site. For thoracic surgery, the postoperative analgesic effect of PVB is better than that of ESPB. For breast surgery, the postoperative analgesic effects of PVB and ESPB are similar. Acute postoperative pain is a common complication of most surgeries, especially for thoracic and breast surgeries. And ineffective alleviation of postoperative pain may produce a series of detrimental acute and chronic complications such as: anxiety, hemodynamic disturbances, immunity imbalances, increased myocardial oxygen consumption, myocardial injury, etc –3. For tS1 File.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations  were folS2 File.Two independent researchers (Chang Xiong and Chengpeng Han) conducted the literature search process in PubMed, Cochrane Library, EMBASE, Web of Science, and ScienceDirect databases from the inception of each database to April 5, 2021. The search terms included the following: “paravertebral plane block”, “paravertebral block”, “PVB”, “erector spinae plane block”, “ESP block”, “thoracic surgery”, “thoracoscopic surgery”, “thoracotomy”, “modified radical mastectomy”, “mastectomy” and “breast surgery”. We made appropriate adjustments when searching different databases. The retrieval strategy in PubMed database is shown in The inclusion criteria were as follows: (1) RCTs; (2) Adult patients (over 18 years old) who underwent thoracic or breast surgery; (3) Interventional use of PVB for postoperative analgesia (PVB group); (4) Use of ESPB for postoperative analgesia (ESPB group) in the control group. The exclusion criteria were as follows: (1) Incomplete studies; (2) Unreported relevant outcomes.Relevant data, including author, year of publication, country, number of patients in each group, location of nerve block, local anesthetic dose, surgical approach, duration of surgery and outcomes were extracted independently from eligible articles by two researchers (Chang Xiong and Chengpeng Han). Attempts were made to retrieve raw data for continuous variables from the eligible articles if variables in the full texts were presented as median and range; however, if data could not be extracted, then, the median and range were transformed to the mean ± standard deviation (SD) ,14. WebPThe quality of included RCTs was assessed by two independent researchers (Chang Xiong and Chengpeng Han) using the Cochrane Collaboration Risk of Bias tool and the Jadad Score ,17. Any χ2 test and I² statistic were employed to estimate statistical heterogeneity across studies. The I² statistic was stratified into three levels: low-level (0–49%), moderate-level (50%–74%), and high-level (>75%). The fixed-effects model was used in the event of low-level heterogeneity; otherwise, a random-effect model was applied. For moderate-level and high-level of heterogeneity (I2>50%), sensitivity analysis or subgroup analysis was performed. Sensitivity analysis was performed by omitting one study by turns. Subgroup analysis based on a priori hypothesis that is the analgesic effects of PVB and ESPB are related to surgical site. The Egger’s test, as well as visual examination of the funnel plot were used to assess potential publication bias. RevMan  was used to perform meta-analyses, and STATA 14/MP  was used for conducting Egger’s test (metabias module).Continuous data on outcomes, including postoperative pain scores, opioid consumption at 24 hours post-operation and the time required for completing block procedure were presented as mean difference (MD) at 95% confidence interval (CI). The dichotomous data on outcomes, such as incidence of additional analgesia in 24 postoperative hours and PONV were expressed as the relative risk (RR) at 95% CI. The  The selected studies were published between 2019 and 2020, and they were carried out in different countries, such as China, Turkey, Egypt, USA, and Japan. Six studies Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: PartlyReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't KnowReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: General comments: The overall benefit of PVB vs ESPB is found to be statistically significant but are the observed reduction in pain scores and especially opioid consumption clinically significant?I would describe the nerve block technique in a different word than using puncture, such as time to completion of block or procedure. Puncture implies injuring the nerve or organ causing a wound. Puncture is used throughout the manuscript.Introduction:Line 84 – “high incidence of … respiratory depression…” the article (7) cited here actually concludes that TEA has a low incidence of major complications. Additionally, TEA can have a beneficial effect by reducing pulmonary dysfunction after thoracic or major abdominal surgery.Line 97 – citation 11 is an editorial that does not describe data suggesting reduction in analgesic use or pain scores with ESPB.In the introduction, there is no description of what the ESP block actually is or why does it have significantly reduced block difficulty? Should briefly describe technique and why it is different from PVB or cite from an article that describes ESP technique.Discussion:Line 316: “…high rates of respiratory depression,…” The article cited (28) states that TEA reduces pulmonary dysfunction following thoracic or major abdominal surgery and can be safely used in patient with compromised respiration. Reference 29 states “Good analgesia from an epidural can result in early extubation, better ventilatory mechanics and gas exchange and reduced rates of lung collapse, pneumonia and pain”.Line 322: urine storage – would change to urinary retentionLine 326, 336, 369: would change the word punctureLine 361: Discusses results of this study compared to previous meta-analysis (36) analyzing ESP vs PVB and how there is a discrepancy between results. Is there a reason that this study did not include the trials from cited study? Mona 2020, Yavuz 2020, Nan 2020, Yasuko 2019, Matthew 2020, Hong 2020 which all compare ESP vs PVB for breast or thoracic surgery.Figures:There are no descriptions for any of the figures listedReviewer #2: Xiong’s team performed a nice meta-analysis coming the analgesic effect of PVB and ESPB. The manuscript is nicely structured and easy to follow. I just have a few concerns that I hope the authors could address.Major comments:1. The aggregation of postoperative pain data. The 10 RCTs included in this meta-analysis measure pain scores at different time points or time intervals, and not all reported pain score at rest/at movement. In the write-up of the result section, the authors should clearly state how many studies reported relevant data for each time point assessed and how the data are aggregated.  It might be clearer, if outcomes in Table 1 can be a bit more detailed.2. In the subgroup analysis for pain score comparisons, I-squared still indicated heterogeneity for some of the comparisons – is sensitivity analysis performed to see if any study caused heterogeneity?Minor comments:1. Ln 223-225, line 230-232. When reporting difference at multiple time points, place the results immediately after each time point to make it easier to follow.2. Result section: Why choosing to report pain scores at 0-1h, 4-6h, 8-12h and 24h? Several studies reported pain score at 2 hrs postop, are these data utilized?**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  26 Jul 2021Dear Editors and Reviewers:I am very grateful to you for giving me an opportunity of minor revision, and I also cherish this chance. In view of your questions, my team and I have made a lot of efforts to improve our articles to meet your requirements during the past few days. The following is the reply to your suggestions.Response to Journal Requirements:1.We have tried our best to revise the manuscript to meet PLOS ONE's style requirements, including those for file naming. However, we hope the editor could review it again because we can't guarantee that the revised manuscript will fully meet the requirements of the journal.2.We have uploaded the completed PRISMA checklist as Supporting Information with a file name “PRISMA checklist”.3.According to the problems pointed out by reviewer 1, we have replaced references (7), (11), (28), (29).Response to Reviewers:Reviewer #1: General comments: The overall benefit of PVB vs ESPB is found to be statistically significant but are the observed reduction in pain scores and especially opioid consumption clinically significant?Answer: Generally, pain scores are divided into three levels: 1-3 as mild, 4-6 as moderate, and 7-10 as severe. Most patients can tolerate mild-level pain, which generally does not have a significant impact on the body. Moderate- and severe-level pain often need to be controlled. In our study, additional analgesia was used when the pain scores were ≥4. In fact, current studies rarely report severe pain, thanks to the two effective analgesic techniques PVB and ESPB, as well as various intravenous analgesics. These control the postoperative pain scores of some patients at a mild level, which introduces difficulty in showing the difference between PVB and ESPB in these patients. We believe that the decrease in the pain scores of PVB compared with ESPB in thoracic surgery is closely related to the reduction of the scores of patients with moderate- and sever-level pain. In other words, fewer patients who use PVB analgesia experience moderate- or higher level pain than those who use ESPB, which is confirmed by the incidence of additional analgesia. Similarly, the amount of opioid consumption in the PVB group within 24 hours after surgery decreased by about 2.74 mg, compared with the ESPB group; if corresponds to patients with moderate- and severe-level pain scores, this value may increase. More importantly, we think your question is very constructive, and we are considering designing a larger sample size, more detailed and more targeted trial to verify the above conjecture. I would describe the nerve block technique in a different word than using puncture, such as time to completion of block or procedure. Puncture implies injuring the nerve or organ causing a wound. Puncture is used throughout the manuscript.Answer: After reading the relevant literature, we have accepted your proposal and amended “puncture” to “block procedure” or “block”. And these changes were marked in red throughout the manuscript. Introduction:Line 84 – “high incidence of … respiratory depression…” the article (7) cited here actually concludes that TEA has a low incidence of major complications. Additionally, TEA can have a beneficial effect by reducing pulmonary dysfunction after thoracic or major abdominal surgery.Answer：After careful reading, we replaced Reference (7). Line 97 – citation 11 is an editorial that does not describe data suggesting reduction in analgesic use or pain scores with ESPB.Answer：After careful reading, we also replaced Reference (11). In the introduction, there is no description of what the ESP block actually is or why does it have significantly reduced block difficulty? Should briefly describe technique and why it is different from PVB or cite from an article that describes ESP technique.Answer: Thank you for this suggestion. Accordantly, we have added a brief description of ESPB in the introduction section at lines 94-99.Discussion:Line 316: “…high rates of respiratory depression,…” The article cited (28) states that TEA reduces pulmonary dysfunction following thoracic or major abdominal surgery and can be safely used in patient with compromised respiration. Reference 29 states “Good analgesia from an epidural can result in early extubation, better ventilatory mechanics and gas exchange and reduced rates of lung collapse, pneumonia and pain”.Answer: We also replaced references 28 and 29. Thank you very much for pointing out the errors in the references. Line 322: urine storage – would change to urinary retentionAnswer: We have changed “urine storage” to “urinary retention” in the manuscript.Line 326, 336, 369: would change the word punctureAnswer: We have changed “puncture” to “block procedure” or “block” in the manuscript.Line 361: Discusses results of this study compared to previous meta-analysis (36) analyzing ESP vs PVB and how there is a discrepancy between results. Is there a reason that this study did not include the trials from cited study? Mona 2020, Yavuz 2020, Nan 2020, Yasuko 2019, Matthew 2020, Hong 2020 which all compare ESP vs PVB for breast or thoracic surgery.Answer: The previous meta-analysis showed that the PVB analgesic efficacy was like that of ESPB in pain scores and opioid consumption at 24 hours after surgery. But this study found that the postoperative scores and opioid consumption at 24 hours after surgery were significantly lower in the PVB group than that in ESPB group for thoracic surgery. We have discussed it in the discussion section at lines 362-373.The studies of Mona 2020, Yavuz 2020, Nan 2020, Yasuko 2019, Matthew 2020, Hong 2020 included in the previous meta-analysis (Ref 36) are actually included in this study, but the naming method is different. For example, "Mona 2020", the full name of the first author of this study is "Mona Raafat El Ghamry", and the name given in PUBMED is "El Ghamry MR", therefore, we cite "El Ghamry MR 2020" in this study. Their relationship is as follows：Mona 2020 = El Ghamry MR 2019 (Ref 20) (this study was indeed published in 2019); Yavuz 2020 = Gürkan Y 2020 (Ref 22); Nan 2020 = Chen N 2020 (Ref 18); Yasuko 2019 = Taketa Y 2019 (Ref 25); Matthew 2020 = Swisher MW 2020 (Ref 24); Hong 2020 = Zhao H 2020 (Ref 27).Figures:There are no descriptions for any of the figures listed.Answer: According to the journal requirements, each figure caption was showed directly after the paragraph in which they are first cited.Reviewer #2: Major comments:1. The aggregation of postoperative pain data. The 10 RCTs included in this meta-analysis measure pain scores at different time points or time intervals, and not all reported pain score at rest/at movement. In the write-up of the result section, the authors should clearly state how many studies reported relevant data for each time point assessed and how the data are aggregated.  It might be clearer, if outcomes in Table 1 can be a bit more detailed.Answer: In accordance with the reviewer’s comment, we have added relevant information in the results section at lines 203-207. Moreover, we have also added “Time to assess pain scores” in Table 1.2. In the subgroup analysis for pain score comparisons, I-squared still indicated heterogeneity for some of the comparisons – is sensitivity analysis performed to see if any study caused heterogeneity?Answer: Based on the subgroup analysis, it can be seen that the heterogeneity was significantly decreased in the breast surgery subgroup, while remained in the thoracic surgery subgroup. By conducting a sensitivity analysis omitting one study by turns on the subgroup of thoracic surgery, we found that the significant heterogeneity was still present among the trials. As mentioned in the write-up of the discussion section, there may be many factors that produce heterogeneity, such as differences in experience and proficiency of the doctors who performed the block, large operation time span, differences in types and concentrations of local anesthetics, errors in data conversion, and differences in assessment of pain scores.Minor comments:1. Ln 223-225, line 230-232. When reporting difference at multiple time points, place the results immediately after each time point to make it easier to follow.Answer: We accepted your comments and revised all of them in the manuscript. .2. Result section: Why choosing to report pain scores at 0-1h, 4-6h, 8-12h and 24h? Several studies reported pain score at 2 hrs postop, are these data utilized?Answer: At the beginning, we planned to report pain scores at 0-2 h, 4-6 h, 8-10 h, and 24 h after surgery. We believe that the pain scores within such time intervals will not have much difference, which helps to continuously observe the changes in postoperative pain. Only 4 studies reported the pain scores at 2 h postoperatively. Therefore, we did not use the data, and adjusted the time interval from 0-2 h to 0-1 h after surgery. Meanwhile, we adjusted the time interval from 8-10 h to 8-12 h to include more research data, for which the pain scores of 8-10 h and 10-12 h are relatively close and can be analyzed together.Finally, I would like to extend my sincere wishes to the editor and the reviewer for a healthy life and a smooth career.AttachmentResponse to Reviewers.docSubmitted filename: Click here for additional data file. 11 Aug 2021Postoperative analgesic effects of paravertebral block versus erector spinae plane block for thoracic and breast surgery: a meta-analysisPONE-D-21-14032R1Dear Dr. Zhijian Lan We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Ehab Farag, MD FRCA FASAAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments: 13 Aug 2021PONE-D-21-14032R1 Postoperative analgesic effects of paravertebral block versus erector spinae plane block for thoracic and breast surgery: a meta-analysis Dear Dr. Lan:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofDr. Ehab Farag Academic EditorPLOS ONE