Background: The main purpose of obturation is to achieve a complete three-dimensional sealing of the pulp space to create a tight seal and prevent bacterial movement and its toxins to the periapical tissues. Different approaches and sealants have been developed due to the root canal system's intricacy for ensuring tight adherence. The root canal sealants need to establish a bond between the material and root dentine in order to prevent leakage. Even though the biocompatibility and sealing abilities of the materials are prioritized in modern endodontics, some sealers incorporate therapeutic or antibacterial drugs like corticosteroids or calcium hydroxide. An endodontic sealer's cytotoxicity and antibacterial capabilities must be perfectly balanced. Due to the limited evidence in endodontic literature regarding the relationship between postoperative pain and the sealers that are used in this study, we conducted the research to explore the same.Aim: This study aimed to evaluate and compare pain in responses to polydimethylsiloxane and calcium silicate-based endodontic sealers (CS-BG).Methodology: The participants were divided into two groups, Nanoseal  and Bioceramic  with 20 patients in each group. After caries excavation and access opening, the biomechanical preparations were performed in each tooth. To avoid over-instrumentation, the working length was verified after each instrument use. The standard irrigation protocol was performed. Sealers were mixed according to the manufacturer's instructions followed by obturation. The patients were asked to take medicines only if they had pain. The pain was evaluated using the visual analog scale (VAS) postoperatively at 24 hours, 48 hours, and a week after the root canal obturation.Results: Pain perception using Nanoseal-S™ and CeraSeal™ materials were compared at 24 hrs, 72 hrs, and seven days. Nanoseal showed statistically significant repletion at 24 hrs and seven days.Conclusion: The decreased irritation character of CS-BG for the periapical tissues explains the lesser percentage of pain during and pain immediately after root canal obturation observed in this investigation, which proves CS-BG is highly biocompatible with periapical tissue and further reduces patient anxiety during root canal obturation. Obturating the root canal space which has been prepared properly is one of the essential factors for a successful root canal procedure. Gutta-percha and sealer are helpful means for obturating the canal space . InadequAlthough the biocompatibility and sealing abilities of the materials are prioritized in modern endodontics, some sealers incorporate therapeutic or antibacterial drugs like corticosteroids or calcium hydroxide. The cytotoxicity and antibacterial capabilities of an endodontic sealer should be considered .Root canal sealants can potentially inhibit the repair of periodontal tissues through the root end and lateral canals as well as the periodontium . PostopeThe composition of the sealer, in particular, has a significant impact on the severity of the inflammatory reaction and activates ions of sensory neurons. Also, sealers may cause postoperative pain after the completion of therapy. Sealers used in root canal treatment might activate trigeminal nociceptors; consequently, this activation and the immunologic response might trigger symptoms of pain and may flare up .Bioceramics are biocompatible ceramic or metal oxide materials with improved sealing properties, and antibacterial, and antifungal activity used in dentistry. A root canal sealer incorporates nanosilver in chemical form, NanoSeal-S™  is a flowable polydimethyl siloxane. It has outstanding radioopacity and a great ability to seal. Chemically adding silver serves as a preservative. Due to the limited evidence in endodontic literature regarding the relationship between postoperative pain and the sealers used in this study, we conducted research to explore the same. So we aimed to evaluate and compare, using a VAS scale, the post-operative pain in responses to polydimethylsiloxane and calcium silicate-based endodontic sealers  .This observational study was conducted in the Department of Conservative Dentistry and Endodontics, Sharad Pawar Dental College, Sawangi (Meghe), Wardha, India. The Institutional Ethics Committee of Datta Meghe Institute of Medical Sciences (DMIMS(DU)/IEC/2022/881) approved the study protocol. The patients visiting the Outpatient Department (OPD) participated in the study. All patients were informed thoroughly regarding the procedure and the materials used for the study. Written consent was obtained from them before the treatment.Inclusion CriteriaThe study included participants who were symptomatic and above 18 years old. These patients were referred for endodontic treatment. Also, the patients having more than one tooth indicated for Root Canal Therapy (RCT) were considered multiple samples. For them, however, the treatment was conducted at the interval of 14 days.Exclusion CriteriaThe study excluded the participants with teeth requiring re-treatment, root fracture, a badly mutilated tooth that cannot be isolated with a rubber dam, patients under 18 years of age, teeth responding positively to pulpal sensitivity test, and patients with systemic diseases.MethodologyThe participants were divided randomly into two groups of 20 patients each. A total of 40 patients having preoperative pain and indicated for root canal treatment, two groups of 20 subjects each, For Group I, Nanoseal  was used, whereas for Group II, Bioceramic  was used.The entire procedure was performed under rubber dam isolation. Caries were excavated, and access opening was done using round bur and further, the access opening was refined using safe end bur. The pulp was extirpated with a suitable barbed broach. Then, the working length was established with the apex locater and confirmed using an intraoral periapical radiograph. Path finder files were used to create a glide path. Biomechanical preparation was performed using the ProTaper Gold system  and the X-Smart endodontic system . An X-Smart endodontic motor was used for the endodontic filing, to avoid over-instrumentation and the working length was verified after using each instrument. Two mL of 2% sodium hypochlorite (NaOCl) was flushed after each instrumentation. The master apical file that was used in the study ranged from F1 to F3 according to the dimensions of the apical foramen. Two mL 2% sodium hypochlorite (NaOCl) was ultrasonically activated for 30 seconds. The final rinse used was normal saline. Master cone fit was checked clinically and radiographically. The final irrigation was done using 2% chlorhexidine (CHX). Canals were dried using appropriate absorbent points till they were dry. Sealers that were used were mixed according to the instructions provided by the manufacturer. Then, the obturation was done. Alcohol was used to clean the pulp chamber to ensure the complete removal of the endodontic sealer. Each tooth was then post-endodontically restored with a composite restoration. The final radiograph was then obtained after the removal of the rubber dam. The medications were not prescribed to the patient, until and unless in the event of pain; they were instructed to take only paracetamol and diclofenac sodium. The intensity of evaluation of postoperative pain was registered postoperatively at 24 hours, 48 hours, and a week after the root canal obturation. The patients were provided with a Visual Analogue Scale (VAS) and instructed to record pain intensity based on their pain experience at that particular time. Scores from 1 to 10 were attributed. Any need for analgesics was recorded.Statistical AnalysisThe mean and standard deviation were used to express all parametric particulars. Multivariate analysis of variance in order to juxtapose the postoperative pain scores between groups and to identify changes over time, repeated measurements were used. StatPlus:mac software  was used to statistically analyze the data.Tables The occurrence or cause of the pain cannot be attributed to any certain factor, as root canal treatment (RCT) consists of tedious and multiple steps. RCT involves chemically and mechanically removing the structures infected by bacterial toxins and obturation of root canals. After clinical affirmation obturation of the prepared root canal space was completed in the same appointment, as the root canal was clean and had relatively less pathogenic load eventually as a result of the bio-mechanical preparation . The occGender differences have been emphasized by differences in the pain reaction to the stimulus. But, the current study showed gender and the type of tooth may not affect the occurrence of pain during and immediately after root canal obturation . Most ofFurthermore, there was a significant difference in statistics of the incidence of PD depending on the endodontic treatment method . The speOther cases of “Discomfort” and “Pain” levels immediately after root canal obturation had no symptoms within a week. In an earlier study, it was emphasized that eugenol has a caustic effect and that resin during the early curing phase depicts similar effects. Rest other states that, due to its rather unstable physical characteristics, the bioceramic-based sealer exhibits significant cytotoxicity in its freshly combined condition. The physicochemical stability and biocompatibility of CS-BG are thought to be responsible for the low proportion of pain experienced during root canal obturation and pain experienced right away after root canal obturation that was seen in this study. The beginning of postoperative pain, however, is said to be unaffected by these sealers in any other way. The findings of this study agree with those of the earlier ones. It would be useful to compare and contrast the occurrence of postoperative discomfort following root canal obturation with CS-BG and all the other sealers in the longer-term plan .The study participants reported only 1% and 0.5% of "Discomfort" and "Pain" in their CS-BG-obturated teeth, respectively. The decreased irritation character of CS-BG for the tissues, present periapically may explain the lesser percentage of pain during and pain immediately after root canal obturation as observed in this investigation. These clinical findings demonstrate that CS-BG is highly biocompatible with periapical tissue thus reducing patient anxiety during root canal obturation. A clinical trial would eventually offer a most relevant clinical study, which would cater to a relatively increased level of proof for evaluating the CS-BG when compared to the other sealers being used.


Animal assisted intervention is an increasingly accepted tool to improve human well-being. The present study was performed to assess whether dog assisted education has a positive effect on children suffering from rheumatic disorders with pain and adolescents with chronic pain syndrome. Two groups of juvenile patients were recruited: 7-17-year-old children in children with rheumatic diseases and adolescents with chronic pain syndromes. Overall, n=26 participated in the intervention, and n=29 in the control group.  The intervention group met once a month, 12 times overall, for working with man trailing dogs in various locations. TM Scoring Algorithm), pain intensity, perception, coping (Paediatric Pain Coping Inventory-Revised), and state anxiety (State Trait Anxiety Inventory) was assessed.The influence of dog assisted education on quality of life  might lead to an increase of the quality of life, (2) leads to decreased state anxiety from pre to post intervention and (3) does not influence pain perception, frequency and intensity.  Animals accompany children and adults in different conditions, with the intention of improving distress in a structured manner with a specific goal . AAI was lacking . It is important to distinguish dog-ownership, companion-animals, animals assisting patients, and animal assisted interventions, specifically trained animals and trainers with specifically designed treatment with animals in order to enlarge the empirical basis for AAT, AAE, AAI and AAA. For example, AAI has proven effective for patients with chronic pain , yet comA plethora of animals have been used in AAI, including dogs, horses, dolphins, cats, cows, rabbits, ferrets, guinea pigs and birds . AAI resDogs are an attractive animal of choice for AAI, since they are a common companion animals that react on emotions of humans and show friendly, caring behaviour . In addiFor patients with chronic pain complementary therapy dog visits in a waiting room, temporarily reduced distress but did not lower pain in most patients . In hospPatients with lasting and chronic pain have an increased sensitivity towards pain and disturbed rewarding stimuli induced by impaired operant learning . Pain rewhether children and adolescents with chronic pain would profit from DAE in a qualified setting. Our research question is We hypothesized thatDAE increases quality of life of children and adolescents with chronic pain, DAE improves pain coping over the time course of the intervention andDAE reduces anxiety from before to after the intervention.The study was a prospective non-randomized, controlled study, conducted between May 2013 and November 2016 in an outpatient setting. Two age-groups of patients  with chronic inflammatory disorder and/or pain syndrome were included in the study (see participants). We chose two age groups because of different interaction styles with the animals. Children interact with the animals and the parents, the adolescents interact with the animals without any parental support. Both age-groups consisted of an intervention group and a control group. Demographic data are given in table 1 Locations and goals of the interventions were set up during concept meetings by experts for experience-based learning , dog trainers  and a paediatrician (AJ) before beginning the study. Both self-reported and parental assessment questionnaires were used. The different questionnaires and investigated time-points are summarized in table 2 Approval of the studies was obtained from the LMU ethics committee .The twelve interventions were performed in monthly intervals and were conducted by eight to ten certified dog trainers and their approved man trailing dogs from the K-9 Suchhundezentrum . The dogs were variable in size and character, from e.g. dachshunds (≈5kg) to bloodhounds (≈40kg). Participants could choose the dog they wanted to work with. Interventions took place during the week in the afternoon and lasted about three hours. Parents accompanied children of the younger age group but did not take part in the intervention itself. For details of the intervention see attachment 1 .included in the study. Chronic inflammation happens when the response of the body to fight against infections, injuries etc. and causes abdominal pain, chest main, rashes, fever, fatigue. Chronic pain refers to pain that continues long (<3-6 months) after the cause is gone. Participants were excluded if current medication was modified in the last three months or change of medication was planned during the study. Participants were diagnosed the Department of Rheumatology & Immunology, Dr. von Hauner Childrens Hospital, Munich, and were patients from practices and hospitals in and around Munich. For the study 130 service users were approached. Parents of eligible patients were contacted by phone. Parents and children were informed and gave written consent. Some participants were dog owners or with other pets and animals . Pet ownership is shown in table 1 Participants with chronic inflammatory disorders  and chronic pain syndrome (adolescents) were Questionnaires were chosen according to the main outcomes to quantify quality of life, pain coping and state anxiety. The German version of the questionnaires were used.The total scale score of the PedsQL was used to verify the hypothesis that DAE increases quality of life of children and adolescents with chronic pain. The sum of all items related to the number of items answered creates the total scale score .The PedsQL was filled out by both parents  and children/adolescents (self-assessment) before and at 7 time-points during the intervention  at twelve and six time-points in children and adolescents, respectively. Additional questionnaires, their background and explanation, are listed in attachment 1 , supplement 2.Statistical analyses were performed using IBM SPSS Statistics 24.0. Frequencies of main scores were calculated, Normal distribution was checked. Repeated measures analysis was implemented for all questionnaires. Primary outcome was the main parameter of the questionnaire with group as between-participants effect. Missing values are replaced by means of the remaining participants. Follow-up Bonferroni tests were performed for pairwise comparisons. Statistical analysis of the correlations were carried out using Pearson’s correlation test (PedsQL). Paired Student’s T-Tests were used for comparing pre-post conditions (STAI-S). Demographic data for both children and adolescents and overall are listed in table 1 Data are presented in table 3 2=.49). The intervention group did not show overall increased scores than the control group =1.09, p=35, n.s.). A repeated measures ANOVA showed that the main effect for point of measured was significant. The total scale scores increased with time in the intervention and the control group =38.00, p<.001; eta2=.34). The interaction of time and group was significant =2.082;p=0.02; eta2=.05). The post-hoc tests revealed that the significance is driven by two differences where once the control group had significantly lower values, at one time point significantly higher values than the intervention group. The significant differences are marked with an asterisk int 3. The total scale scores increased with time in the intervention and the control group =38.48; p<.001; eta2=.02). The post-hoc tests revealed that the significance is driven by one significantly higher value of the self-assessment than the parental assessment at the fourth intervention. There was some consensus of self-assessment and external assessment of the total health summary scales at assessments with a significant mean correlation of R=.17. A repeated measures ANOVA revealed that the self-assessed quality of life was rated significantly higher than the parental assessment =6.77; p=.01 eta2=.68). Data are shown in table 4 The PPCI was implemented to verify the hypothesis that DAE improves pain coping over the time course of the study. The PPCI was not different comparing intervention and control groups =.15; p=.69; n.s.). Repeated measures ANOVA did reveal changes of pain coping over time for both, the intervention and the control group =109.83; p<.001; eta2=.14). A post-hoc comparison showed that the decline of state anxiety from pre-post intervention was significant for the first six interventions and ranged between 18% and 30% =31.20; p<.001; etawhether children and adolescents with chronic pain would profit from DAE in a qualified setting. We will separately present the results for pain and quality of life and anxiety.Our research question was DAE did not result in robust changes of pain perception, frequency, intensity. In other studies 15-minute therapy sessions with a dog led to lower pain levels of children that underwent total knee or hip arthroplasty . The difIn the present study we observed a decrease of state anxiety from before to after all interventions. This is in concordance with other studies, that also noted a pre-post effect of AAI but before the next session, STAI-S values were back to pre-intervention scores . InteresIt is well accepted, that chronic pain is associated with increased anxiety . PatientTo our knowledge, there are no validated standards concerning character qualifications and health examinations of dogs or other animals. It is known however, that the effectiveness is associated with the species and personality of the animals . SubsequFurther studies in an outpatient setting could easily reduce complexity and costs. Our suggestions would be to expand the design to a multi-center study in order to include more patients. The inclusion of patients with more diverse diagnoses with chronic pain could help increase patient numbers to advance knowledge on how the intervention works. We chose the three week rhythm of the interventions in order to be feasible for patients, parents and cooperation partners. It would be interesting to see how beneficial weekly interventions or even daily interventions could change the effects. In our study our idea was to maximize transfer of the effects to the home of the patients a longer follow-up to the study could therefore be beneficial in shorter intervention studies.More research is needed to verify our effects and in our experience with a few changes concerning the setting it might be possible to expand our design to a multi-center study. Due to organisational reasons the study could not be randomized or blinded, the number of available participants for intervention and control group was rather small. Participants of the intervention group had to be willing to work with dogs. Therefore, the results may not transfer to people with an aversive attitude towards dogs. Participants of the control group were matched with regards to sex, age and diagnoses and part of the control group to due travel distance. A randomized control group was thus not part of the study and control group participants could vary in other covarying factors due to travel distance. As well, we cannot rule out that covarying factors like physical activity or enriched social contact and communication with other patients with relatable symptoms might have positively influenced or even caused our results. Furthermore, due to a lack of studies with comparable interventions and outcome parameters no a priori sample size could be calculated as the effects could not be estimated. The quantitative approach we took was meant to get an insight into how large the effects of the DAE could be. However, a qualitative approach i.e. systematic interviews with the adolescents, children and parents might have complemented the present study to verify what DAE really meant to the patients. DAE leads to decreased state anxiety from pre to post intervention in children with rheumatic diseases and adolescents with chronic pain syndromes. Further, despite having a very small sample, our results indicate that it might lead to an increase of the quality of life. Pain perception, frequency and intensity are not influenced. We consider DAE a valuable alternative treatment method to lower anxiety that might have a positive influence on the lives of children and adolescents with chronic diseases. Data for this article are available from Open Data LMU . FurtherThe author Nadja Herbach deceased in 2020.First of all, we want to thank our generous sponsor Edith-Haberland-Wagner-Stiftung, Munich. Without their continuous support we wouldn’t have been able to perform this study.Furthermore, we would like to thank: Verein Kinder-Rheumahilfe München e.V., for organizing and managing the interventionsChildren, adolescents, their parents and families for participating in the study The K-9 dog trainers and experts for taking care of the participants and involving them in the interventions: Daniela Rottenwaller, Ina Rebel, Gusti Kittlinger, Karin Haeringer, Mareike Haase, Eduard Bichler, Eva Fuhrmann, Andrea Roehricht, Sonja Zietlow, Carmen Schäffler, Robert Jansson, Matthias Lang, Christiane Wildhirt, Anja Lehmann, Leila Badry.The Specialists for Pediatric and Adolescent Rheumatology for recruiting participants: Rainer Berendes, Landshut; Philipp Schoof, München; Gerd Ganser, Sendenhorst; Gert Reutter-Simon, Nürnberg; Susanna Späthling-Mestekemper, München.The authors declare that they have no competing interests. The translation of the title into German has been corrected.


We aimed to evaluate the efficacy of electroacupuncture in relieving acute pain after total knee arthroplasty (TKA) and related mechanism.n = 20) and sham‐acupuncture group (n = 20) from November 2020 to October 2021. All patients received electroacupuncture or sham‐acupuncture for 5 days after TKA. Their brain regions were scanned with resting‐state functional magnetic resonance imaging before and after intervention. Pain was scaled. Another 40 matched healthy controls underwent scanning once. The amplitude of low‐frequency fluctuation (ALFF) values was compared. Pearson's correlation analysis was utilized to explore the correlation of ALFF with clinical variables in patients after intervention.In this randomized, single‐blind, and sham‐acupuncture controlled study. Forty patients with postoperative acute pain were recruited and randomly divided electroacupuncture group (p < .05). Patients had higher ALFF value in bilateral precuneus, right cuneus, right angular gyrus, bilateral middle occipital gyrus, and left middle temporal gyrus after electroacupuncture (AlphaSim corrected p < .01). Correlation analysis revealed that the change (postoperative day 7 to postoperative day 3) of ALFF in bilateral precuneus were negatively correlated with the change of NRS scores  in EA group.Compared with the HCs, patients with acute pain following TKA had significantly decreased ALFF value in right middle frontal gyrus, right supplementary motor area, bilateral precuneus, right calcarine fissure and surrounding cortex, and left triangular part of inferior frontal gyrus (false discovery rate corrected The functional activities of related brain regions decreased in patients with acute pain after TKA. The enhancement of the functional activity of precuneus may be the neurobiological mechanism of electroacupuncture in treating pain following TKA. Acute postoperative pain after TKA prolongs rehabilitation duration, weakens the therapeutic effect, and thereby decreases the patient's quality of life. Intense postoperative pain is associated with chronic pain, and it may also prolong rehabilitation duration, weaken the therapeutic effect of TKA, and thereby decrease the patient's quality of life , which gauges fluctuations in the blood oxygen level‐dependent signal, is widely used to explore the neural mechanisms, assess the efficacy of acupuncture treatment, and it is also commonly used for pain research. The amplitude of low‐frequency fluctuation (ALFF), which depicts the intensity of regional spontaneous neuronal activities, strikes a good balance between test‐retest reliability and replicability  the ALFF patterns in patients with acute postoperative pain might be abnormal, and (2) EA could treat acute pain after TKA by regulating the functional activities of specific brain regions.22.1https://www.chictr.org.cn/edit.aspx?pid=54096&htm=4). All study protocols were approved by the Ethics Committee of Shanghai Guanghua Hospital of Integrated Traditional Chinese Medicine and Western Medicine (2020‐K‐44), and all participants provided written informed consent in accordance with the Declaration of Helsinki.The study took place at Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine from November 1, 2020 to October 31, 2021. The study protocol was preregistered with ClinicalTrials.gov  aged 60–80 years; (2) right‐handed; (3) a pain intensity score of 5 or higher on a 0–10 Numerical Rating Scale (NRS); (4) a score > 24 on the Minimum Mental State Examination. The excluded criteria included (1) a history of neurological and psychiatric disorders, or head trauma with loss of consciousness; (2) serious renal, cardiovascular, respiratory or other organic diseases; (3) any contraindications to rs‐fMRI scanning ; (4) unwillingness to sign the consent form; (5) having received acupuncture/EA in the past three months.The sex‐ and age‐matched healthy controls (HCs) without any illness‐induced pain sensation or psychological diseases were also recruited.2.3n = 20 each) for rs‐fMRI scanning.A participant‐blinded, randomized and sham‐acupuncture (SA) controlled clinical trial was applied. Previous studies have shown that 15 participants should be included in each group to ensure stable statistical effect for brain fMRI analysis  3 to POD 7. Patients were instructed to completed postoperative pain diary by documenting the onset time, pain intensity (measure by NRS score), rescue medication use, and rs‐fMRI scanning, which collected at POD 3 and POD 7.2.4The group allocation information was sealed an envelope and given to the acupuncturist. The surgeons, principal investigators, study staff, data analysts, and the participants were blinded to grouping. Using the sham electroacupuncture design in the previous literature at POD 3 (preintervention) and POD 7 (postintervention) were analyzed. The primary outcome was mean reduction in pain intensity represented by the NRS score of patients. To obtain the NRS score, the patients were asked to circle a number ranging from 0 (no pain) to 10 (the most intense pain imaginable) that best fit their current level of pain. The reduction in Zung Self‐Rating Depression Scale (SDS) score was calculated as the secondary outcome. SDS was used to evaluate the subjectively reported depression by the patients. The scale consisted of 20 items and each item was divided into 4 levels according the frequency of symptoms, which is suitable for adults with depression. For the SDS score, patients scored on the scale according to their emotional state.2.62; acquired matrix, 64 × 64 matrices; 43 slices with a thickness of 3.5 mm; voxel size, 3.52 × 3.52 × 3.52 mm3; bandwidth, 2250 Hz/pixel. The scanning duration was 12 min and 13 s. In response to a questionnaire after the scan, all participants stated that they had not fallen asleep.The rs‐fMRI data were acquired using a Clinical 1.5 Tesla whole body MR imager . Although our previous clinical trial  was presented for continuous variables; while frequency was used for categorical data with corresponding p and t/F values. A two‐side test was applied, with a confidence interval of 95% and p < .05 indicating statistically significant.Clinical outcomes were analyzed using a statistical package for windows version 25 . A single‐factor ANOVA/two‐sample 2.7.2http://www.fil.ion.ucl.ac.uk/spm/software/spm12/) and run using MATLAB R2014. Before analysis, we performed left and right head flip in patients underwent left TKA, thereby lateralizing the reflection area to the same hemisphere in all patients. The processing included  based on Statistical Parametric Mapping 12  at each voxel. The averaged square root was used as the ALFF, which was transformed by Fisher's p < .05, cluster‐p < .05). For patient group‐level analyses, we used AlphaSim correction for multiple comparison . The ALFF was analyzed by two‐sample t‐test and paired t‐test using SPM 12 software.To investigate the alternations in HCs and patients in POD 3, we used false discovery rates (FDR) correction for multiple comparison (voxel‐2.7.3p < .05 was considered as a significant difference.The EA‐stimulation difference (EA_ POD 7 vs. POD 3) and group difference (HCs vs. patients at POD 3) were chosen as the regions of interest (ROI). The mean values in the ROI between the two groups were analyzed using the receiver operating characteristic curves. Pearson's correlation coefficients were calculated to indicate the relationship between the mean ALFF values in ROI in patients, where 33.1Totally, 38 patients  completed the two rs‐fMRI scans (baseline and after 5‐day treatment). Forty HCs completed one rs‐fMRI scan. Due to excessive head movement (>3 mm) in scan, 7 patients and 8 HCs were excluded  and emotional state .Table 3.3Compared with HCs, all patients at POD 3 had significantly lower ALFF in the right middle frontal gyrus (MFG), right supplementary motor area (SMA), bilateral precuneus, right calcarine fissure and surrounding cortex (CAL), and left triangular part of inferior frontal gyrus (IFGtriang) Table .In EA group, the patients showed significantly higher ALFF at POD 7 in bilateral precuneus, right cuneus, right angular gyrus, bilateral middle occipital gyrus (MOG), and left middle temporal gyrus (MTG), compared with those at POD 3  and not significantly correlated with the change of SDS score  in EA group. There was no significant difference between the changed (POD7–POD3) ALFF values of bilateral precuneus correlated with the change of NRS  and SDS , respectively  and group difference (HCs vs. patients at POD 3) as shown by ALFF overlapped in bilateral precuneus, which was chosen as the ROI. Correlation analysis revealed that the change (POD 7–POD 3) in ALFF of bilateral precuneus were negatively correlated with the change of NRS scores , compared with HCs without any pain symptoms. MFG and IFGtriang in the prefrontal cortex can modulate pain perception  and group (HC vs. POD 3) difference as shown by ALFF overlapped in precuneus. The nucleus cuneiformist is an inhibitory region in the descending pathway, and the hypoactivity in this region indicates reduced inhibition of the pain response in patients, which produces a higher pain score  in brain regions related to pain regulation were found on rs‐fMRI in SA group. The different changes of brain regions in the two groups indicated the central mechanisms of EA and SA were different. Part of the therapeutic effect of SA may be produced by the physiological effects on the skin during the stimulation. It should be noted that the AlphaSim correction was applied to explore the mechanism of EA analgesia in our study. Although the precuneus functional activities in EA group were closer to those HCs, the finding did not survive the more stringent FDR correction methods, and the AlphaSim correction method is relatively loose; therefore, further studies are needed.Taken together, we propose that EA relieves acute pain after TKA by increasing right cuneus, right angular gyrus, bilateral MOG, left MTG, and precuneus functional activity. The increased ALFF in pain‐related brain regions may exert beneficial impacts on pain‐regulating functions in patients after TKA. Besides, the EA‐stimulation and group difference overlapped in precuneus, suggesting that precuneus functional activities increase with the decreased pain intensity, which is pivotal to pain processing and regulation. Our research confirms the abnormal decrease of the precuneus functional activity can be reversed by EA, but the results need further validation.Our study has several limitations. (1) The small sample size of the study may increase the likelihood of a false positive error. Ours are preliminary findings, which lack prior power calculations, and thus should to be verified by studies with larger sample sizes. (2) This study only verifies the EA effect at the group level, and the specificity of EA analgesia is not fully explained. Future studies are needed to confirm the immediate effect of EA and validate our findings. (3) Due to excessive head movements, quite a few participants were excluded; but it should be emphasized that the exclusion of the images exerts no impact on treatment response. (4) Due to some practical difficulties and the limitations of experimental conditions, we failed to enroll an untreated group to investigate the effect of elapsed time on pain management after TKA. Hopefully, we will overcome the disadvantages in the subsequent work.5In conclusion, the functional activities in the right MFG, right SMA, bilateral precuneus, right CAL, and left IFGtriang in patients with acute pain after TKA decreased. EA on four acupoints  can increase the functional activities of right cuneus, right angular gyrus, MOG, left MTG, and precuneus. The functional activity of the precuneus is a biomarker of pain after TKA. Enhancement of functional activity of precuneus may be the neurobiological mechanism of EA in treating acute pain following TKA.BXK, CZ, and JM conceived the study; BXK drafted the study; HQW, XLG, HX, SZ, CXG, and XRX recruited the participants. XYA and JX collected clinical data. MMD and CZ were responsible for statistical analyses and tables. LBX and JS have primary responsibility for the final content. All authors contributed to writing and revising the paper and agreed to submission.The authors declare that they have no conflict of interest.This study was approved by the Ethics Committee of Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine and was in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent to participate was obtained from all of the individual participants included in the study.The trial was registered in Chinese Clinical Trial Registry (ChiCTR2000033778).https://publons.com/publon/10.1002/brb3.2913.The peer review history for this article is available at


Prompt and appropriate treatment of chronic low back pain (cLBP) is of the utmost importance for preventing relevant disability, high burden of disease, and increasing costs for the healthcare system. Recently, the concept of functional impairment has been associated with any type of chronic pain, and mounting attention has been paid to extending the aims of treatment beyond mere pain remission, including restoration of working capacity, everyday functioning, mobility, and quality of life. Nevertheless, a shared definition of functionality is still lacking. Notably, different specialists involved in the treatment of cLBP such as general practitioners, orthopedists, pain therapists, and physiatrists, and patients themselves have different opinions on what “functional impairment” actually means. On these premises, a qualitative interview study was performed to investigate how the concept of “functionality” is interpreted by different specialists involved in the management of cLBP, and by patients. Overall, all different specialists agreed that functionality should be assessed in clinical practice. However, in spite of several instruments available for evaluating functionality, no homogeneity of behavior is observable. Chronic low back pain (cLBP) is a common and persistent health problem that affects a significant portion of the population worldwide . The conRecently, there has been an increasing focus on expanding the goals of cLBP treatment beyond just alleviating pain. This includes improving working capacity, daily functionality, mobility, and overall HR-QoL ,9,10,11.In particular, the International Classification of Diseases (ICD)-11 underlined the concept of functional impairment associated with any type of chronic pain, including cLBP . Indeed,Several strategies can be used to study this problem and provide answers that can be useful for improving outcomes. For this aim, qualitative research can be a valid opportunity . Well-deOn these bases, we conducted qualitative research to investigate how the concept of “functionality” is interpreted by different specialists involved in the management of cLBP, and by patients themselves.The study comprised two different surveys; the former was directed to physicians handling chronic low back pain (cLBP) in their practice, and the latter involved patients with cLBP. The investigation was performed in compliance with the EphMRA code of conduct. Every participant, including clinicians and patients, provided voluntary and informed consent for data collection and usage, based on a comprehensive comprehension of the study’s objectives and data collection purposes.Physicians with a broad experience in cLBP management who work in different Italian geographical areas of Italy were involved. These clinicians work in the community and in different settings, including general hospitals, specialized hospitals, and research hospitals, either from the national health system or the private healthcare network. Therefore, they included GPs, orthopedists, pain therapists, and physiatrists. Each participant was asked to write two short papers, one on chronic pain issues in cLBP patients and the other on functional recovery of cLBP. Each participant was then interviewed by an expert in qualitative research in a face-to-face meeting, with the aim to clarify opinions and issues mentioned in the papers and to explore how functionality recovery is addressed in clinical practice. Interviews were personalized based on the content of the short papers and lasted approximately 1 h.The second survey was directed to patients with cLBP. Enrolled patients belonged to different age groups  and were stratified according to their level of instruction, duration of disease , disease severity, and specialist they are followed by.(a)Diagnosis of cLBP. The pool of eligible patients was provided by the clinicians who participated in the survey. Clinical data were independently evaluated by two expert researchers (A.C. and F.M.).(b)Able to understand the information describing the research study.(c)Signed informed consent prior to filling in the survey.The eligibility criteria for participation were the following: (a)Uncertain diagnosis of pain.(b)Any cognitive impairment.(c)Refusal to participate in research.The exclusion criteria fort participation were the following:Each enrolled patient was interviewed by an expert of qualitative research in a face-to-face meeting lasting about 75 min, with the aim of narrating their “patient journey” with cLBP. The interview focused on the difficulties encountered along the journey.All texts and transcripts of interviews were analyzed using the T-Lab software  to extract different word patterns or subject patterns; more frequently used words were extracted, and relationships of words related to function recovery were explored. In the first phase of the text analysis, words were converted into a standardized pattern . The second phase of the analysis provided the frequencies of words in the texts, connections among words (which words were most often used in connection with words of interest for the study), and narrative semantic cluster analysis. For this survey, approval by Ethics Committee was not required. According to the current Italian legislation for noninterventional or observational studies , it is necessary to submit a survey for approval by an Ethics Committee only if “the study focused on problems or pathologies within which medicinal products are prescribed in the usual way in accordance with the conditions set out in the marketing authorization. The inclusion of the patient in a specific therapeutic strategy is not decided in advance by the trial protocol but is part of normal clinical practice and the decision to prescribe the medicine is completely independent of that of including the patient in the study” ,20.The first survey enrolled 52 participants: 16 general practitioners (GPs)  and 36 specialists . All physicians were working in different Italian areas . A total of 10–15% of subjects with chronic low back pain (cLBP) managed by GPs and orthopedists had moderate to severe pain. The proportion was higher for patients treated by pain therapists (40–50%) and highest for those attended by physiatrists (70–80%). Word analysis was carried out on 1458 words, occurring at least once, from the texts about chronic pain or functionality written by the participating physicians . OverallSentences used in texts about functional recovery were dealing with five main areas: (1) definition; (2) treatments; (3) aims ; (4) physical dimension (features of disability and treatment opportunities); and (5) assessment . The frequency of semantic clusters was different for participants pertaining to different specialties . The definition of function recovery was a marginal topic for participants of all specialties (10–16% of texts) . OrthopeA deeper focus on each specialty is provided below, in a narrative way.This group of physicians used words related to many different themes. They wrote about pain, the psychological impact of cLBP, physical impairment, and psychosocial impairment. The impairment of functionality is described as a reduced ability to attend to everyday activities. It is caused by pain and consists of physical disorders preventing motility and consequently normal activity. In this perspective, function recovery means physical recovery. Control of pain was considered a preliminary aim, necessary to pursue a functional recovery. GPs are concerned with the choice of the best drug for pain control and feel confident in the effectiveness of the pharmacological treatment of cLBP, but they do not use drugs for direct action on functionality. They leave the patient to manage functionality by her/himself, and they generally do not refer patients to other specialists for guided physical exercise. Therapies and the physical dimension of disability were the most frequent subjects mentioned by orthopedists in texts about function recovery in patients with cLBP. Indeed, functional recovery was interpreted as secondary, following pain control. It consisted of recovery of mobility, and the ability to attend everyday activities with as little pain as possible. Therapy was the tool they described as useful to obtain function improvement. Therefore, in their opinion, pain control was the first necessary step toward functional recovery. Therapies mentioned in texts were mainly NSAIDs and myorelaxants.Texts about function recovery written by pain therapists were mainly interested in the physical dimension of health and in quality of life. The aim of the interventions was to enable the patient to work and recover her/his social dimension. In the opinion of these specialists, functional recovery is related to autonomy, social life, and psychological and physical wellbeing. According to most pain therapists, functional recovery corresponds to “mobility” and “everyday activities”, while according to a minority of them, it corresponds to the HR-QoL. It is mainly intended as mobility in the absence of pain; thus, the absence of pain means functional recovery.The analgesic pharmacologic treatment is considered a useful tool for functional recovery. Some pain therapists stated that drugs are part of a complex strategy and must be used in association with physical activity, under the supervision of a physiatrist; in their opinion, drugs would not directly induce a functional recovery but enable the patient to follow a rehabilitation plan.The main interest of physiatrists was the measurement of function. Recovery can be pursued only by starting with an attentive and objective evaluation of the patient, using assessment scales and scores for function and pain. The use of validated scales is considered mandatory. Function recovery means physical autonomy, and physical autonomy is identified as a satisfactory quality of life, according to this group of participants.The term “functional recovery” was interpreted as recovered muscular strength and joint flexibility. These texts suggested that a patient with good motility may face everyday activity and possibly sports. The main therapeutical strategies are physical exercise and drugs, which cannot be used independently and act on two sides. In particular, drugs act on pain and physically guided activity works on functionality.Twenty-four patients (12 men), all living in large city areas  answered the second survey. Time from diagnosis was 1–5 years for 12 subjects, 5–10 years for six patients, and >10 years for six subjects. Nine patients were 45–60 years old, nine were 61–74 years old, and nine were ≥75 years. Although the patient’s journey may have great variability, all patients with LBP first sought the advice of GPs. At the time of the survey, six patients were followed by their GP, six by an orthopedist, six by a pain therapist, and six by a physiatrist. Patients with acute cLBP or first exacerbation were followed by GPs or orthopedists, and those with exacerbations of cLBP were referred to pain therapists and physiatrists.The analysis of interviews showed that patients shared some basic opinions about cLBP. Patients believe that it is not possible to detect a cause of LBP, and therefore to identify a cure. They feel that pain may occur suddenly, and that the disease heavily impacts their HR-QoL. They think that skills and approaches to cLBP, including pharmacological treatments, are very similar across all specialties. Therefore, patients report relying more on the personal relationship than on the scientific background of the physician. Although pharmacologic therapy is not curative in patients’ opinion, it may control pain, avoid flares, and indirectly protect from functionality deterioration. Patients never aim at functionality recovery as a primary objective; they believe that it may occur secondarily to pain improvement.Although there is a widespread fear of disease flares, patients feel they lack physician’s support for the management of everyday life; they usually conceive and actively implement strategies, also pharmacological treatment with over-the-counter remedies, directed to reduce the impact of pain. This approach usually limits personal activities and social life, with a strong sense of discomfort and inadequacy. This further reduces the HR-QoL, generating a vicious circle.In this qualitative study, the area of functionality in chronic low back pain (cLBP) as perceived by physicians and patients was investigated. Overall, pain was reported to be a common goal of management, and pharmacological treatment was considered mandatory. Functional impairment was rarely seen as a primary objective of patients’ management and appears to be associated with the use of dedicated scales. Furthermore, patients often come to these specialists when all the others have exhausted their therapeutic capacities, thus finding themselves at the bottom of a supply chain in which not only has pain become chronic, but also highly disabling.At this point, the problem is cultural, as it is not possible to untie the concept of pain from that of functional recovery. This is true not only in terms of social life and relationships but also of social cost. The worrying fact is that not only some specialists do not consider functional recovery a primary goal, but also patients. These data must be interpreted in the light that there is no correct information on the fearful consequences of pain.The term “functionality” is used with different meanings by specialists, in relation to the specific aims of their activity. The different specialists involved in the study agreed on the importance of evaluating functionality in clinical practice, but also on the lack of tools able to assess this parameter. In more detail, functionality is described as physical autonomy and mobility by general practitioners (GPs) and orthopedists who usually deal with the early phases of the disease and with exacerbations. Physiatrists and pain therapists interpret functionality as a more comprehensive sphere, corresponding to physical, social, and psychological wellbeing. These specialists are usually in charge of patients with a long history of cLBP, who seek to slow the deterioration of their working and social abilities. They provide interventions that aim at the wellbeing of the patient, and not only at the direct resolution of pain. The most recent clinical practice guidelines in Europe have identified a broad spectrum of primarily nonpharmacological treatment alternatives . NeverthOpioids must be carefully prescribed and are useful in very selected cases ,23,24. CPatients seem to lack more than physicians the perception of the importance of functional recovery and the hope to obtain to a complete health condition. They also remarked on the impact of pain on their HR-QoL, also limiting social and working activities, and the fear of sudden relapses. This suggests that physicians may fail in communicating the hope for a cure, or a durable improvement of the condition. In addition, they do not seem to support enough patients in their efforts to organize their everyday life. Indeed, patients do not rely on their physicians when deciding how to modify their lifestyle.While quantitative research provides a valuable tool for exploring research questions and hypotheses, it has important limitations . SimilarThe sample size can represent a serious gap. Nevertheless, in qualitative research, what is relevant is how participants are selected. In particular, they must represent their category in terms of beliefs and opinions . In our Finally, there is an important lack of depth as this quantitative research may not provide a deep understanding of the individual experiences of participants on the investigated cLBP issues. Therefore, we recognize that truly appreciating functionality moves beyond mere words; it requires the inclusion of context to convey its inherent worth. By incorporating patient–specialist pairs, there is potential to uncover shared aspects or disparities in assessing functionality in cases of chronic low back pain. It is important to note that these functional criteria can be subjective when they are tied to the individual patient and evaluated by the specialist based on specific assessment criteria.Chronic low back pain (cLBP) is not only a health problem, but a social concern . NotablyNevertheless, cLBP can be assumed as a paradigm of chronic pain, a model on which a change can and must begin . ProbablThe next phase involves recognizing that the objective of pain therapy is not solely pain reduction, as measured quantitatively, but also the alleviation of its adverse effects on quality of life . In partOn the other hand, investment entails not only training but also the allocation of economic and human resources . TraininThe aim of pain therapy training should be to develop a curriculum that enables accurate diagnoses and appropriate referrals to the most suitable specialists. To achieve this truly ambitious aim, specialists must also be trained from a managerial point of view. However, investing in training alone is insufficient if there is no commitment to establish a well-functioning network between pain therapy centers and general practitioners (GPs), utilizing technological tools such as telemedicine ,40,41,42Nevertheless, this network will be futile unless accompanied by investment in human resources . Time isLooking ahead, addressing cLBP requires substantial investments in cultural, economic, and human aspects. Nonetheless, considering the potential returns, including economic benefits, these investments seem relatively small. Additionally, the development of standardized and collaborative guidelines is crucial to ensure equal and consistent care for all cLBP patients .While attention to pain control is now widely recognized, functional recovery is still only a secondary objective for patients with chronic low back pain (cLBP). In order to promote a global approach to cLBP leading the patient from pain control to the improvement of HR-QoL and reestablishment of a healthy condition, some actions could be proposed. These processes should encompass (1) a cultural effort which is necessary to raise attention to the risk of disability for patients with cLBP; (2) a better understanding of the correct use of pharmacological and nonpharmacological strategies among physician; (3) careful pain management for increasing the effectiveness of guided exercises and physiatrist interventions; (4) a strategy aimed at implementing the search of new tools useful in different settings ; (5) definitions and approaches shared among specialties for better management of patients with cLBP, following the right timing.


Microstructural alterations have been reported in patients with urologic chronic pelvic pain syndrome (UCPPS). However, it isn’t clear whether these alterations are reproducible within 6 months or whether long-term symptom improvement is associated with specific microstructural changes. Using data from the MAPP-II Research Network, the current study performed population-based voxel-wise DTI and probabilistic tractography in a large sample of participants from the multicenter cohort with UCPPS (N = 364) and healthy controls  over 36 months. While fractional anisotropy (FA) differences between UCPPS patients and HCs were observed to be unique at baseline and 6-month follow-up visits, consistent aberrations in mean diffusivity (MD) were observed between UCPPS and HCs at baseline and repeated at 6 months. Additionally, compared to HCs, UCPPS patients showed stronger structural connectivity (SC) between the left postcentral gyrus and the left precuneus, and weaker SC from the left cuneus to the left lateral occipital cortex and the isthmus of the left cingulate cortex at baseline and 6-month. By 36 months, reduced FA and MD aberrations in these same regions were associated with symptom improvement in UCPPS. Together, results suggest changes in white matter microstructure may play a role in the persistent pain symptoms in UCPPS. Additionally, group differences in cerebral DTI measures were positively correlated with pain and symptom severity scores, including segments of the right corticospinal tract, the right anterior thalamic radiation, as well as within regions of the sensorimotor network and cingulate cortical areas. However, the extent to which these differences are reproducible in a separate, independent cohort of patients using multiple measurements, as well as how any fluctuations in imaging measurements might reflect UCPPS symptom progression, remains largely unknown.The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network was created in part to identify brain imaging biomarkers that are sensitive to diagnosis or early progression of UCPPS and to evaluate treatment effectiveness.32 we hypothesize DTI differences between UCPPS and HCs inherent to the disease could be identified and reproduced when looking at measurements over a short period of . Additionally, we studied DTI changes in UCPPS occurring within these distinct areas shown to be uniquely altered in UCPPS patients during long-term  changes in UCPPS clinical symptoms. To test these hypotheses, differences in white matter integrity between UCPPS patients and HCs were evaluated twice, 6 months apart, to determine “disease-associated” fractional anisotropy (FA), mean diffusivity (MD), and microstructural connectivity (SC) measured using probabilistic tractography. We theorize that, despite any transient fluctuations in symptoms, white matter microstructural reorganization is not likely to occur within a short 6-month interval. Then, we examined long-term, 36-month fluctuations in symptom severity and quantified FA, MD, and microstructural connectivity changes that correlate with these fluctuations, then determined whether these areas overlap spatially in the brain with “disease-associated” patterns observed when comparing UCPPS and HCs. In this case, we theorize white matter reorganization, if it does occur, would manifest over a longer period of time (~3 years).Since UCPPS has been characterized as a chronic disease with no significant changes in overall disease severity,29: 1) UCPPS symptoms present for a majority of the time during most recent 3 months, 2) age 18 years and above, and 3) response 1 or greater on the bladder/prostate or pelvic pain/pressure/discomfort scale 35 during past 2 weeks. Exclusion criteria include symptomatic urethral stricture, neurological disease or disorder affecting the bladder, bladder fistula, a history of cystitis caused by tuberculosis, radiation therapy or chemotherapy, prior augmentation cystoplasty or cystectomy, active autoimmune or infectious disorder, history of pelvic cancer, current major psychiatric disorder, severe cardiac, pulmonary, renal, or hepatic disease, unilateral orchalgia (without pelvic symptoms), and prior prostate procedures . Participants from the HC cohort were excluded if they reported any pain in the pelvic or bladder region. For more specific inclusion and exclusion criteria, please see Clemens et al.7 All subjects provided informed written consent to participate in the current study. All consenting procedures and protocols were approved by the institutional review board at each of the participating sites, which included the University of California, Los Angeles (UCLA), Northwestern University (NWU), University of Michigan (UM), University of Iowa (UI), University of Washington (UW), and Washington University in St. Louis (WUSTL). Detailed demographic for all participants and for participants of each site were summarized in A total of 364 UCPPS participants  and 61 heathy controls  were prospectively enrolled in the current study (MAPP-II) that included observational multimodal MRI and evaluation of UCPPS symptoms. Inclusion criteria for UCPPS participants consisted of29 Multiple urologic symptom measures previously included in the MAPP I symptom patterns study protocol29 were retained in the current longitudinal observation. After organizing all UCPPS outcomes based on pain and urinary symptoms, an exploratory factor analyses within the MAPP research network19 identified 2 unique dimensions to UCPPS based on pain  and urinary  severity. This group then assigned composite pain and urinary symptom scores based on combinations of these symptom measures  as outlined in Griffith et al.19 Note the focus of the current study was to explore the impact of composite measures of pain severity on changes in white matter integrity only, so urinary symptom severity was not explicitly examined. Detailed clinical data for all participants and for participants of each site were summarized in Neuroimaging was conducted during multiple visits that took place within 4 weeks of the baseline visit, 6-month follow-up, and 36-month follow-up .29 MultiPAINrepository.org.MRI scanning was performed at multiple sites using different scanner technology (3T Siemens Prisma (UCLA and UI), 3T GE Discovery (UM), 3T Philips Achieva (UW), and 3T Siemens Trio (NWU and WUSTL)). Neuroimaging data were collected, quality controlled, and archived according to multi-site imaging procedures developed collaboratively between the MAPP Research Network, the UCLA PAIN repository, and the UCLA Laboratory of Neuroimaging. Detailed procedures and descriptions of the repository are available at b-value of 1000 s/mm2. Additionally, a single reference b=0 s/mm2 image was used as a reference and a 1 mm 3D isotropic MPRAGE T1-weighted image was acquired for alignment. The acquisition parameters for T1-weighted images at different scanning sites are also summarized in The acquisition parameters for DTI at different scanning sites were summarized in MRtrix3 software package .6 Then FMRIB’s Diffusion Toolbox (FDT) (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FDT) was used to correct for eddy currents (which cause stretches and shears in images) and head motion, and images were affinely registered to reference b = 0 s/mm2 images for each participant. Following skull extraction using the Brain Extraction Tool (BET), fractional anisotropy (FA) and mean diffusivity (MD) values at the voxel level were calculated for DTI, using mask consisting of the disjunction between the white matter and deep gray matter masks of interest  as defined previously.13 To identify and anatomically localize group differences between UCPPS and HCs in FA and MD, all FA and MD images were linear and nonlinearly registered to the Johns Hopkins University DTI atlas (ICBM-DTI-81 1mm FA atlas) using the FLIRT and FNIRT commands, respectively, in FSL (https://fsl.fmrib.ox.ac.uk/fsl).All DTI data were quality controlled according to multi-site imaging procedures developed within the MAPP Research Network. Image processing and analyses of the DTI data were conducted at the UCLA Center for Computer Vision and Imaging Biomarkers. All diffusion-weighted images were first denoised using the http://www.fmrib.ox.ac.uk/fsl/fdt/). After DTI data for each patient was eddy current corrected, Markov Chain Monte Carlo sampling was used to build the diffusion orientation distribution functions (ODFs) for each voxel using Bedpostx  to model a total of 2 fibers per voxel and a total of 1,000 iterations. After the distributions for each diffusion parameter were generated for each patient, seed and target ROIs were placed on anatomical landmarks defined in the Desikan-Killiany cortical atlas to quantify the connectivity between these structures.10 A total of 5,000 individual pathways were generated from the seed points using a step length of 0.5mm and a maximum of 2,000 steps. A cosine curvature threshold of 0.2 (approximately 80 degrees) was used to limit how sharply pathways can deflect during tract generation. Additionally, a waypoint mask using common clusters showing differences in either FA or MD at both baseline and 6-month follow-up was used to prune and isolate results to streamlines that pass through the areas in the brain commonly altered in UCPPS relative to HCs. Lastly, ROI-to-ROI SC networks were computed between all brain regions defined in MNI, where the number of streamlines that pass through the waypoint mask represent the weight of the specific regions in the network. Abbreviations for ROIs can be referred to Probabilistic DTI tractography was performed using the FMRIB Diffusion Toolbox  to decide if statistical correction for site effect will be included when investigating reproducible microstructural changes associated with UCPPS. It is also important to note that because 1) no significant site differences were observed within HC cohorts, and 2) unlike MAPP-I, the DTI acquisition parameters and sampling scheme were standardized for MAPP-II, we decided to not include the site effect as a covariate in all statistical analyses.https://afni.nimh.nih.gov/) to 1) evaluate common inter-group differences between UCPPS patients and HCs, at both baseline and 6-month follow-up, and 2) explore the correlation (by Pearson’s correlation coefficient) between changes in DTI measurements and reducing pain symptom severity over longitudinal observation.To test whether significant differences occurred between baseline and 6 month follow up, repeated measures two-way ANOVAs were performed. A general linear model (GLM), with age and sex included as covariates, was implemented through AFNI  correction approach at the cluster level through command 3dClustSim in AFNI. The cluster-extent threshold corresponded to the statistical probability  of identifying a random noise cluster at a predefined voxel-wise threshold of P < .05 (uncorrected). This process was performed individually for both baseline and 6-month follow-up comparisons. After exporting cluster masks at both time points, the masks were superimposed to identify overlapping clusters with common differences in FA and MD. For SC network comparisons, we performed ROI-to-ROI analyses using a GLM with age and sex included as covariates. The level of significance for all statistical analyses was set at p < 0.05.To identify inter-group differences in FA and MD between UCPPS patients and HCs, a voxel-wise GLM was utilized through AFNI 3dcalc command). Then a voxel-wise GLM was utilized through AFNI 3dttest++ command to identify the correlation between changes in FA and MD, and reduce pain severity, with age included as covariates. For permutation testing used to estimate the proper cluster threshold, we implemented a family-wise error (FWE) correction approach at the cluster level through command 3dClustSim in AFNI. The cluster-extent threshold corresponded to the statistical probability  of identifying a random noise cluster at a predefined voxel-wise threshold of P < .05 (uncorrected). We further superimposed the cluster map on the Johns Hopkins University DTI atlas to identify clusters’ anatomical localization, and the overlapping volume of each cluster with specific pre-defined white matter pathway in the standard space. To explore the correlation between SC network changes and reduced pain severity, we performed ROI-to-ROI analyses with age included as a covariate. The level of significance was set at P < .05.For the correlation analysis using FA and MD measurements, we firstly calculated brain maps representing the changes in FA and MD for each individual participant (through AFNI P = .2473) or sex (P = .1511). When evaluating UCPPS patients pain severity at baseline, 6-month follow-up and 36-month follow-up, respectively, we found a continuous and significant decrease in pain at each clinical visit that was 6 months , and 36 months  apart from baseline , suggesting no common “disease-associated” FA alterations in UCPPS, several brain regions showed consistently higher MD in UCPPS patients, suggesting these areas might represent reproducible, “disease-associated” brain alterations in UCPPS. Specifically, UCPPS patients exhibited higher FA along the left superior longitudinal fasciculus, the left anterior and superior corona radiata at baseline visit  and the left superior corona radiata , which both demonstrated an increased FA and decreased MD associated with reduced pain symptom severity. Additionally, the posterior limb  and external capsule, the left corona radiata (superior and posterior sections), and several association fibers in the left hemisphere known to connect the cingulate, temporal lobes, parietal lobes, sensorimotor areas, and specific frontal/prefrontal regions in UCPPS compared with HCs at both time points. This “disease associated” pattern of altered MD was not only consistently observed in other visceral pain syndrome, eg, irritable bowel syndrome (IBS),18 and the postcentral gyrus, which is the primary sensory region and a main component of the pain matrix. Therefore, a stronger SC between precuneus and the postcentral gyrus might be indicative of alterations in pain perception in chronic stages of disease. Although the lateral occipital cortex was not traditionally associated with brain response to pain, studies have shown that painful stimuli can decrease functional connectivity within the posterior cingulate gyrus (default mode network) and the lateral occipital cortex,25 supporting potential hypoconnectivity between the occipital lobe and the isthmus of cingulate cortex in the current study. It should also be noted that altered functional connectivity (FC) among those regions has been reported to be associated with UCPPS patients (MAPP-I research network). Specifically, the posterior medial cortex, including precuneus and the posterior cingulate gyrus, showed decreased FC to default mode network in female UCPPS when comparing to female HCs,30 and altered frequency distributions  were observed in sensorimotor cortices of UCPPS patients.24 The consistency between SC and FC findings suggest that those regions might be potential imaging biomarkers for UCPPS. Together with previous identified “disease-associated” MD differences identified for UCPPS patients with respect to HCs, the current results confirm previous findings of localized alterations in the brain of UCPPS patients,36 and supports the hypothesis that UCPPS is at least partially associated with neuroplastic changes in specific brain areas involved in the processing and integration of sensory inputs and pain modulation, making it potentially amenable for clinical interventions that target synaptic and/or neuronal reorganization .In addition to the aforementioned observations in MD, current study identified reproducible “disease-associated” pattern in SC alterations in UCPPS patients, where stronger SC was observed between the left postcentral gyrus and the left precuneus, and weaker SC from the left cuneus to the left lateral occipital cortex and the isthmus of the left cingulate cortex at both baseline and 6-month follow-up. The precuneus is known to be involved in affective responses to pain,13 where lower FA was observed in sensory/motor association/integration regions, but higher FA was observed in frontal lobe regions and the corpus callosum. It is worth noting that since previous study on the separate cohort of UCPPS patients (MAPP-I research network) has suggested that FA changes within these regions might be a consequence of reinforced viscerosensory input to the brain from constant painful stimuli,36 implicating an imbalanced altered cortico-basal ganglia-thalamus-cortical loop in pain modulation,21 these alterations did not appear to be “disease-associated,” or commonly altered in all UCPPS patients, as they were not repeatable at the various different time points tested. While these changes do not appear to be commonly altered in all UCPPS patients at all time points evaluated, Pain, 2022), which demonstrated a significantly higher FA within the basal ganglia in men with IBS, as well as an increase in FA proportional to increased symptom severity. Together, this suggests the potentially altered basal ganglia microstructure observed commonly in chronic pain syndromes may in fact be limited to males with chronic pain disorders. Future studies are necessary in order to validate and identify possible mechanisms for these observations.Differences in FA between UCPPS patients and HCs did not co-localize to the same anatomic regions when comparing scans from baseline and 6 month follow-up. Nevertheless, at both time points, clusters showing significant FA differences were located along similar fiber tracts connecting or projecting to prefrontal/frontal regions and somatosensory processing areas near known pelvic representation. Similar FA alterations have also been reported on the IBS patients,36Results from the current study appear to demonstrate that long-term (36 month) DTI changes within “disease-associated” areas are associated with pain symptom improvement. Besides decreased MD values observed along certain white matter pathways such as the external capsule, the superior corona radiata, the uncinate and superior longitudinal fasciculi, which were found to be common “disease-associated” areas altered in UCPPS, multiple additional regions were identified as having changed with UCPPS symptom severity over 36 months of observation, consistent with previous studies.4 and dynamic changes between the frontal lobe and striatum might suggest how the possible functional connectivity pattern in fully chronic phase supports pain control and modulation.27 Taken together, results from the current study may reflect such ongoing structural reorganization associated with an adaptation to chronic pain. Questions remain, however, as to the clinical implications of this adaptation and whether it is potentially reversible with more targeted therapeutic interventions.It is worth nothing that the thalamus showed both increasing MD and slightly increasing FA associated with reduction in long-term (36 month) UCPPS pain severity. As the relay center of motor and sensory signals, structural and functional alterations have been consistently reported and discussed within thalamus. Studies have found that changes in fronto-striatal connections may be associated with aversive learning in chronic painregression of the mean effects as described by Whitney and Von Korff,34 or effects that show symptom improvement subsequent to entering treatment or a clinical trial at least partially due to the patients having high symptom severity when they initially seek treatment, we contest this did not influence our results. First, the MAPP-II trial explicitly addressed potential effects of initial improvement in UCPPS patients through an extended run-in period prior to imaging evaluation.33 Second, our assumption that DTI measurements are likely stable over a 6-month period is also supported by the fact that microstructural adaptation occurs over longer periods of time compared with functional alterations, and resting-state fMRI has been used to accurately predict changes in pain symptom severity in the short term, after 3 months, but was not able to predict 6- or 12-month symptom trends.27 In line with those findings, associations observed in the current study appeared to suggest that distinct time scales for functional and structural neuroplasticity may occur in UCPPS, with changes in function occurring relatively quickly and changes in structure occurring over longer periods of time. Importantly, the current study defined “disease-associated” DTI signatures based on common differences between UCPPS and healthy controls at the 2 time points and not merely based on symptom severity, so differences in brain microstructure identified in the current study are those that occur even in the presence of slight changes in pain severity. Lastly, regression of the mean effect.Several limitations merit mentioning. The current study assumed that short-term, 6-month interval changes in DTI are not likely to occur despite slight improvement in symptom severity , allowin7 as the purpose of MAPP-II was to perform a long-term (36 month) highly integrated and comprehensive cross-modality assessment of clinical, biological, brain imaging, and pain sensitivity measures within a large cohort of UCPPS patients. Furthermore, while the DTI acquisition parameters and sampling scheme were highly standardized and we didn’t identify significant site differences within HCs, it is possible a more robust method for site correction could have been performed like those proposed by Fortin et al.16 Moreover, the influence of comorbidities and potential medication on brain plasticity or microstructural alterations in patients with UCPPS were not explicitly considered; however, the influence of medications are likely to be minimal based on lack of brain functional differences between treated and untreated patients.27 Also, the HC cohort excluded potential participants if they reported any pain in the pelvic or bladder region or chronic pain in more than one non-urologic body region. Future studies with a better eligibility criterion of healthy controls, analyses accounting for/comparing with other major comorbid conditions  are necessary in determining the imaging biomarker are representative and unique to UCPPS. Lastly, it is possible we could have introduced some error in registration between subjects because we aligned all data to the Johns Hopkins University DTI and Desikan-Killiany cortical atlases and did not use a study population-based template for image registration.Additionally, the number of UCPPS patient was greater than the number of participants in the HC cohort. A larger sample size of HCs would not only improve the statistical power to detect reproducible microstructural differences between the UCPPS and HCs but also help validate that the observed microstructural differences in sex were specific to the UCPPS. Ultimately, the unbalanced nature of MAPP-II consortia study was by design,To summarize, the current longitudinal study identified distinctive FA differences between UCPPS patients and HCs at baseline and 6-month follow-up visits, but reproducible “disease-associated” patterns in altered MD and abnormal microstructural connectivity in UCPPS patients when compared to HCs. These differences were found in regions associated with sensory perception, integration of sensory information and pain modulation. Over longer periods of time, improvement in white matter abnormalities within those regions were associated with improvement in pain symptom severity.Supplemental Tables


No differences in pain reduction and functional improvement were seen between genders. The impact of post-operative rehabilitation and vitamin D supplementation on clinical outcomes was found to be statistically nonsignificant. The results obtained in this study clearly confirm the effectiveness of osteochondral reconstruction using hyaluronate-based scaffolds. The outcomes were equally favorable, regardless of postoperative rehabilitation and vitamin D supplementation.Articular cartilage lesions negatively affect patients’ well-being, causing severe pain and significantly limiting functioning. The purpose of this study was to evaluate the effectiveness of a one-stage reconstruction, performed arthroscopically using a hyaluronate-based scaffold. Pain reduction and functional improvement were assessed. The study also evaluated if postoperative vitamin D supplementation and rehabilitation protocol impact obtained outcomes. A group of 29 patients was included in a retrospective study. All the participants underwent arthroscopic reconstruction of osteochondral lesions using hyaluronate-based scaffolds. The study group used standard questionnaires to self-assess their condition before surgery and at the time of completion. Despite the aforementioned, all the participants fulfilled two original questionnaires on postoperative rehabilitation and vitamin D supplementation. Significant pain reduction (mean NRS 1.83 vs. 7.21,  Articular cartilage lesions are a complex problem which clinicians are increasingly faced with. The lesions remain asymptomatic for a long time, and in a significant number of cases are found as concomitant pathologies during the diagnostic process after a joint trauma.Hyaline cartilage is a tissue that allows joints to glide painlessly. It is composed of specialized cells (chondrocytes) and an extracellular matrix (ECM), which, aside from water , is largely formed by collagens, the most important and common of which is type II. Fluctuations in the composition of articular cartilage can be pathological , but they can also occur as a result of joint dysfunction  .Chondral and osteochondral lesions are an important clinical problem, as they impair joint function, cause pain, and significantly accelerate osteoarthritis. Due to the lack of innervation of the articular cartilage (which enables its function), lesions of intermediate thickness often remain asymptomatic for a long time, while only irritation of the richly innervated subchondral tissue (lesions of grade III and IV according to the ICRS and Outerbridge classification) cause symptoms. Lack of vascularization determines almost no possibility of spontaneous healing of cartilage damage. The quality of articular cartilage can be regarded as an indicator of joint well-being, while any damage to it will be a factor significantly accelerating degenerative changes .Therapeutic methods for suffering from joint surface damage can be divided into conservative  and a variety of surgical procedures . The goa®, Anika Therapeutics, Inc., Bedford, MS, USA). Of note, this is a method that does not require tissue harvesting from the initially uninjured site (as is done during mosaicplasty). The purpose of the microfractures is to stimulate the subchondral layer to deliver mesenchymal cells of the bone marrow to the area being treated, while the role of the scaffold is to secure the produced superclot in place and provide favorable conditions for formation of the regenerate [Several methods designed to reconstruct cartilage have been developed, which vary in surgical technique—some of them can be carried out using a minimally invasive arthroscopic method. It is important in the patient’s recovery process whether the procedure can be performed in a single operation or has to be divided into several stages . The aim of this study was to evaluate the outcome of a one-stage reconstruction procedure that combines the microfracture technique with the use of a hyaluronate-based scaffold  and a complex functional evaluation . The mean evaluation time was 23.9 months after surgery . Participants were also asked about voluntary vitamin D supplementation (this was not included in the post-operative recommendations) and the course of postoperative rehabilitation.p < 0.0001)  versus 1.83  postoperatively ( 0.0001) .p < 0.0001 in both). Before the surgery, the mean score in the OKS questionnaire was 23.1 . Postoperatively, OKS improved to 40.2   .Statistically significant functional improvement was confirmed using the Lysholm Knee Scoring Scale as well. Before the surgery, the mean total score was 40.38 , when postoperatively it improved to 82.38  .A researcher-made original questionnaire assessed postoperative voluntary vitamin D supplementation. Although not specifically recommended by the clinician, most of the study group did supplement with vitamin D .p = 0.474) or function .However, no influence of supplementation in the U Mann–Whitney test was shown, either on postoperative pain (The course of postoperative rehabilitation was self-assessed by participants of the study group .p = 0.474) or function  in the U Mann–Whitney test were found.Similarly, no statistically significant differences in postoperative pain reduction (p = 0.349) or after surgery (p = 0.584). Similarly, no statistically significant differences in OKS and Lysholm scores between gender were observed either before operation  or postoperatively .Moreover, this study shows no gender-dependent differences, neither in preoperative nor in postoperative pain and functional scores. Pain severity, expressed by the NRS, was not gender-related, either before surgery  group of patients that underwent diagnostic and therapeutic arthroscopy of the knee joint  showed the presence of cartilage lesions in 60% of cases. A majority of them (65%) were low grade lesions (Outerbridge grade I and II) that were not accounted for as a main reason for complaints [Cartilage lesions are frequently found as concomitant comorbidities in the diagnostics after an injury, for example, in joint sprains. A retrospective study on a representative  showed a significantly higher incidence of full-thickness damage compared to the general population. Interestingly, MRIs of half of the asymptomatic athletes showed full thickness chondral damage .An Australian cohort study of patients with symptomatic OA proved that untreated cartilage lesions tend to progress and are associated with worsening of ailment severity over a 2-year period . MoreoveResults obtained in this original study illustrate and prove that damage to the articular cartilage of the knee is a significant and disabling problem. Patients suffer from severe pain, their functioning is markedly limited, they are unable to participate in sport activities, and the frequent activities of daily living are significantly impaired. This research demonstrates that cartilage reconstruction with hyaluronan scaffolding is an effective therapeutic method. It is a one-stage procedure, which reduces the risk of complications and the inconvenience of multi-stage surgeries. In the vast majority of cases, it is performed arthroscopically, without the need for arthrotomy. Reduced tissue traumatization enables a faster and more effective recovery.The use of a standardized pain assessment tool enabled us to grade patients’ pain. Subgrouping, dependent on the results of pain intensity scales, has been functioning for a long time in the treatment of oncologic patients. It is established that on an 11-point scale (0–10), scores of 0–4 correspond to mild pain, 5–6 to moderate pain, and 7–10 to severe pain . The litThe difference in pre/postoperative pain, achieved with the described method, means a two-grade severity reduction (from severe pain to mild pain). A significant reduction in the severity of pain enables the use of drugs from the lower levels of the analgesic ladder. This means that patients can reduce or completely abandon opioid drugs. Aside from improving quality of life, minimizing the use of pain medications will significantly reduce the risk of side effects. By reducing the symptoms, appropriately selected physiotherapy may be sufficient as pain relief treatment.Postoperative rehabilitation is an important factor in improving and refining the function of the musculoskeletal system. Interestingly, despite significant differences in either duration, frequency, and form of rehabilitation, no statistical significance was found. The improvement in function, as reported by patients, was significant. The data obtained do not diminish the relevance of postoperative rehabilitation, but prompt further research. Postoperative rehabilitation is a critical component of the therapeutic process; hence, it should be carried out according to a well thought out plan. This is particularly important for patients with high demands, such as professional athletes. The aim of treatment is to restore joint function and decelerate the progression of osteoarthritis. The pace of rehabilitation varies depending on the patient and his general and local condition. Hence, the rehabilitation protocol should not be standardized, but rather drawn up individually . This stDue to the existing literature reports indicating an association between vitamin D and articular cartilage, we retrospectively evaluated the effect of postoperative supplementation on outcomes. We evaluated spontaneous postoperative supplementation that was not recommended by the supervising physician.Studies on rats have shown that vitamin D supplementation has a positive effect on articular cartilage thickness, glycosaminoglycan levels, and collagen fiber density, while a vitamin D-deficient diet has a detrimental effect on knee cartilage composition, causing a significant decrease in proteoglycan content ,22. VitaIn our assessment we found no statistically significant association between vitamin D supplementation and clinical improvement, as the effects were equally favorable in both subgroups of patients.Nonetheless, these results must be interpreted with caution and a number of limitations should be considered in the light of some limitations. First, the study group was not numerous. Despite proving strong relationships, a larger sample would reduce the risk of bias. The second limitation is the fact that, as it was a retrospective assessment, all of the obtained data were self-report. Data may be biased due to the non-remembrance of study participants. The third limitation is the varying time from surgery to data collection (patients were operated on between 2017 and 2022). The average evaluation time for the group was 23.9 months, varying for the patients operated on earliest and latest—7 months (3 patients) and 18 months (2 patients), respectively. All the other patients were evaluated 24 months after surgery. The mean evaluation time for the whole study group was 23.9 months after surgery .This research is also limited by the lack of data on vitamin D serum levels, hence, it cannot be determined whether it was sufficient or not, both pre- and postoperatively. Additionally, patients supplemented various vitamin D products, such that variability could bias the results. Taking the aforementioned limitations into account, it is necessary to conduct further research with a control and a study group that supplement defined doses of vitamin D homogeneously regarding health conditions affecting its absorption. It may be possible that a prospective study will result in different findings.The results obtained in this study clearly support the effectiveness of osteochondral reconstruction using hyaluronate-based scaffolds. The achieved functional improvement and substantial pain reduction are crucial for patients’ well-being. From a long-term point of view, the treatment of cartilage injuries significantly delays development of osteoarthritis. Considering the single-stage and minimally invasive nature of this procedure, the authors suggest it to be more widely used.In a qualitative descriptive study, we retrospectively assessed the functional outcome and pain reduction among the patients that underwent arthroscopic surgery due to osteochondral lesion of the knee. All of them were operated on in the Clinic of Orthopedics and Traumatology, University Clinical Hospital in Wroclaw, between 2017–2022.2 . The average time of surgery was 110.16 min . Patients stayed at the hospital for minimum 1 and maximum 5 days .A total of 32 patients were eligible to take part in the study; finally, 29 of them consented and were included. One person was excluded because they underwent two surgeries on the same knee and the other two refused to participate. Finally, the study group counted 13 females and 16 males. At the time of the surgery study, the group age was, on average, 40.9677 years old  and had a BMI of 26.8227 kg/mEvaluation of the patients was performed between 2020 and 2023. Patients were evaluated after a time of at least 18 months, while the patients operated earliest were evaluated at 27 months after surgery and those operated latest were assessed at 18 months after surgery. All the other patients were evaluated 24 months after surgery. The mean evaluation time was 23.9 months after surgery .®, Anika Therapeutics, Inc., Bedford, MS, USA) fixed with a tissue glue. All of the surgeries were performed arthroscopically and none of them required arthrotomy. Each surgery was performed by one of three orthopedic surgeons highly experienced in knee arthroscopy.The procedure consisted of lesion debridement, microfractures, and cartilage reconstruction using a hyaluronate-based membrane as a scaffold  was performed using the wet-arthroscopy technique, whereas implantation and fixation of the scaffold were performed using the dry-arthroscopy technique .The study group self-assessment was based on widely used questionnaires: the Numerous Rating Scale (NRS), Oxford Knee Score (OKS), and Lysholm Knee Scoring Scale. In addition to these scales, all the participants fulfilled two questionnaires compiled specifically for this study. Those questionnaires were based on self-assessment on postoperative rehabilitation and voluntary postoperative vitamin D intake. The questionnaires were completed by the researcher during teleconsultation or a face-to-face post-operative follow-up.Patients were asked to fulfill the NRS, OKS, and Lysholm Knee Scoring Scales twice, regarding their condition before surgery and currently.All the medical data from the day the patients were admitted to the hospital were obtained.p < 0.05.Statistical analyses were performed using TIBCO Software Inc. (2017). Statistica , version 13.3 PL. All analyses were performed on the total population. Descriptive analyses were used to describe the baseline characteristics. All data were analyzed for Gaussian distribution using the Shapiro–Wilk and Kolmogorov–Smirnov normality tests. The U Mann–Whitney test for two independent samples was used because values were not normally distributed. To calculate the difference between sets of pairs and analyze these differences to establish if they are statistically significantly different from one another, the Wilcoxon test was used. For correlation analyses, the Spearman’s Rho correlation test was used. In all calculations the statistical significance was considered at