Background: This study investigated how diffuse idiopathic skeletal hyperostosis (DISH) influences clinical characteristics in patients with cervical ossification of the posterior longitudinal ligament (OPLL). Although DISH is considered unlikely to promote neurologic dysfunction, this relationship remains unclear. Methods: Patient data were prospectively collected from 16 Japanese institutions. In total, 239 patients with cervical OPLL were enrolled who had whole-spine computed tomography images available. The primary outcomes were visual analog scale pain scores and the results of other self-reported clinical questionnaires. Correlations were sought between clinical symptoms and DISH using the following grading system: 1, DISH at T3-T10; 2, DISH at both T3–10 and C6–T2 and/or T11–L2; and 3, DISH beyond the C5 and/or L3 levels. Results: DISH was absent in 132 cases, grade 1 in 23, grade 2 in 65, and grade 3 in 19. There were no significant correlations between DISH grade and clinical scores. However, there was a significant difference in the prevalence of neck pain (but not in back pain or low back pain) among the three grades. Interestingly, DISH localized in the thoracic spine (grade 1) may create overload at the cervical spine and lead to neck pain in patients with cervical OPLL. Conclusion: This study is the first prospective multicenter cross-sectional comparison of subjective outcomes in patients with cervical OPLL according to the presence or absence of DISH. The severity of DISH was partially associated with the prevalence of neck pain. Ossification of the spinal ligaments impairs spinal mobility and occasionally leads to a spinal disorder ,2. OssifThis multicenter prospective cross-sectional study used data from 16 member institutions of the JOSL established by the Japan Ministry of Health, Labour, and Welfare. The inclusion criteria were as follows: age ≥20 years; diagnosis of cervical OPLL based on radiographic findings; symptoms such as neck pain and upper and/or lower extremity numbness regardless of whether surgery was required, clumsiness, and gait disturbance; a visit made to a participating institution for symptoms between September 2015 and December 2017; and whole-spine CT scans available to determine the location of ossified lesions in the spine. The only exclusion criterion was a history of cervical spine surgery for OPLL. The study was approved by the institutional review board of each participating institution and conducted in accordance with the relevant guidelines and regulations.Basic demographic and clinical data of patients were collected, including age, sex, diabetes mellitus (DM) status, body mass index (BMI), and presence of neck pain, back pain, and/or low back pain (LBP). Clinical status was evaluated using the following measures: cervical Japanese Orthopaedic Association (JOA) score , which iCT images of the whole spine were collected for each patient. The images included the cervical, thoracic, and lumbosacral segments, spanning the occipital bone to the sacrum. The incidence of OPLL in the cervical spine from the clivus to C7 and in other spinal regions from T1 to S1 was evaluated on mid-sagittal CT images. Blinded to clinical outcomes, six senior spine surgeons  independently evaluated the images, as described previously . OPLL wan = 107) and the group without DISH (n = 132). The demographic and clinical characteristics of the patients are shown according to DISH status in Patient demographics are shown according to DISH grade in The score for each item in the JOA-CMEQ and JOA-BPEQ was evaluated to assess whether the severity of DISH in terms of cervical myelopathy and lumbar spine function affects the ability to perform activities of daily living. There were no significant correlations among the four groups for JOA-CMEQ scores a–e. SimiThe prevalence of neck pain was significantly correlated with degree of DISH, but back pain and LBP were not . FurtherVAS scores from the JOA-CMEQ and JOA-BPEQ were investigated to clarify the relationship between degree of DISH and pain associated with cervical myelopathy. However, no significant difference was found in the VAS scores among the three DISH grades .DISH is a systemic condition characterized by ossification of ligaments and entheses throughout the body. Considered to be mostly an asymptomatic condition, DISH was largely ignored by clinicians and researchers until the 1990s. However, it is now known that DISH can sometimes result in specific symptoms, including back pain , stiffnePatients with cervical OPLL often have ossification of other spinal ligaments, including the ligamentum flavum, anterior longitudinal ligament, and the interspinous and supraspinous ligaments. In earlier studies ,20,21,22DISH has been recognized to be not only a structural abnormality in the human thoracic spine but also a result of metabolic syndrome. Okada et al.  comparedThis prospective multicenter study is the first to investigate subjective outcomes in patients with cervical OPLL according to DISH status. Although we collected patient-reported outcomes for activities of daily living, we found no DISH-related differences in patients with cervical OPLL. These findings are consistent with the opinion of some clinicians that DISH should be considered a state rather than a disease . DISH maSeveral studies have investigated the association between presence of DISH and physical pain. Mata et al.  comparedThis study has several limitations. First, it was a cross-sectional cohort study of a specific disease and not population-based. Second, the study was not longitudinal and thus cannot reach conclusions on causality. Third, the presence of DISH was evaluated only on reconstructed sagittal CT images with no review of bony bridges at the lateral portion of the intervertebral segments. Fourth, we could not determine whether mobility of the segment adjacent to DISH affects neck pain or LBP. Fifth, the JOA-CMEQ could not evaluate pain states in detail. Further studies are required in the general population to clarify these clinical questions and eliminate confounding factors in terms of each spinal ligament. However, despite these limitations, we believe that our findings provide important information on the clinical features of DISH in patients with cervical OPLL.This study is the first prospective multicenter cross-sectional comparison of subjective outcomes in patients with cervical OPLL according to the presence or absence of DISH. There were no significant correlations between DISH grade and clinical scores. However, there was a significant difference in the prevalence of neck pain among the three grades, albeit not in the prevalence of back pain or LBP. Interestingly, DISH localized in the thoracic spine (grade 1) could create overload at the cervical spine and lead to neck pain in patients with cervical OPLL.


While the Patient-Reported Outcomes Measurement Information System (PROMIS) is mainly designed for computer adaptive testing, its static short forms (SF) are used when a paper-pencil format is preferred or item banks are not yet translated into the target language. This study examined the measurement properties of the German PROMIS-SF for pain intensity (PAIN), pain interference (PI) and physical function (PF) in total hip arthroplasty (THA) patients.SF were collected before and 12 months post-surgery. Higher scores indicate more PAIN, higher PI and better PF. Oxford Hip Score (OHS) was the main reference measure. Six months post-surgery, a subsample completed the SF twice within 14 days to test reliability.Of 172 eligible patients, 147 consented to participate and received questionnaires; 132  returned baseline questionnaires (mean age 65.8 ± 10.2 years) and 116, 12-month questionnaires. Forty-five patients provided test-retest data.Correlations of all SF with OHS were large . Cronbach’s alpha values were: PAIN, 0.86; PI, 0.93; PF, 0.91. Intraclass correlation coefficients were: PAIN, 0.77; PI, 0.81; PF, 0.69. Standard errors of measurement were: PAIN, 3.8; PI, 2.8; PF, 3.6. Smallest detectable change thresholds were: PAIN, 8.8; PI, 6.6; PF, 8.4. Follow-up data showed a ceiling effect (best score) for PAIN (66%), PI (76%), and PF (66%). SF change scores showed large correlations with OHS change scores (│r│ > 0.6).Our results provide some evidence of construct validity, and acceptable reliability and responsiveness of PROMIS-SF for pain and function in THA patients. These SF can thus be considered acceptable for use, although patients’ improvement in physical function might be underestimated due to the large follow-up PF score ceiling effects. Measurement qualities of PROMIS instruments are mainly assessed for computer adaptive testing but not for non-adaptive short questionnaires. As these questionnaires are in use, their measurement properties must also be evaluated. Results from computer adaptive testing cannot simply be transferred.We studied the measurement qualities of the German PROMIS short questionnaires for pain intensity, pain interference and physical function in patients undergoing hip replacement. We wanted to see how these questionnaires perform when compared to the Oxford Hip Score, a standard questionnaire commonly used to test hip-related disability in these patients.The three questionnaires can be considered acceptable for use in hip replacement patients, but some limitations do exist. Patient improvement in physical function might be underestimated because many patients reach the highest possible score and further improvements cannot be measured. Also, any small but important improvement in physical function cannot be distinguished from measurement error in individual patients. The Patient Reported Outcomes Measurement Information System (PROMIS®) aims to provide a common health metric for many medical conditions . It is pGerman language CAT item banks for pain and function were under development by the German PROMIS group at the time of this study. In future, these PROMIS CAT instruments will be offered by this group for third party use via REDCap . Furthermore, not all patients actually prefer electronic over paper forms , and this can influence response rate and adherence. The SF can be easily implemented in clinical registries , while connecting CAT platforms to active registries might initially require additional resources. We decided to use the shortest available SF, which were most feasible for our purposes and minimized respondent and administrative burden . Therefore, the aim of the study was to examine the psychometric properties of German PROMIS-SF for pain intensity (PAIN), pain interference (PI) and physical function (PF) in THA patients. Valid SF would allow the use of PROMIS metrics when CAT cannot be implemented or when SF are deemed more feasible.This prospective study included consecutive patients of our THA registry from November and December 2016 , PI and PF (each with 4 items) provided by the PROMIS Germany research group. Answers are given on 5-point verbal rating scales. For PAIN, we used the form 3a (v2.0) that assesses pain over a 7-day recall period and current pain . Form 4aWe used the reference Oxford Hip Score (OHS), a condition-specific instrument that assesses constructs encompassing the selected PROMIS domains and 2 single-item questions rating surgical success.Specifically, we used the cross-culturally adapted and validated German OHS , 12. ThiHow much did the operation help your hip problem?” on a 5-point Likert scale ranging from “helped a lot” to “made things worse” [If you had to spend the rest of your life with the symptoms you have right now, how would you feel about it?” on a 5-point Likert scale ranging from “very satisfied” to “very dissatisfied” [At 12 months, patients rated their global treatment outcome (GTO): “s worse” . They altisfied” .Construct validity was assessed using scale-specific hypothesis testing and considered good if at least 75% of the hypotheses were confirmed. We tested correlations with OHS total score and OHS pain and function subscales at baseline and 12 months, and SSWB at 12 months. All correlations were expected to be large , and specific correlations were expected to be negative for PAIN and PI with OHS and for PF with SSWB and positive for PAIN and PI with SSWB and PF with OHS.agr = √). The effect size based on SEMagr was calculated from the mean change score. The smallest detectable change (SDC) for individuals that can be considered above the measurement error with a 90% confidence level was calculated as SDC90 = 1.65 * √2 * SEMagr [Internal consistency was calculated using Cronbach’s alpha with values between 0.70 and 0.95 indicating appropriate internal consistency . Test-re* SEMagr .d ≥ 1.5 for the decrease in PI and increase in PF based on other studies [Responsiveness defines the ability of a questionnaire to detect clinically important changes over time. Longitudinal validity can be considered a measure of responsiveness and is examined by inspecting the correlation between change scores of the instrument under validation and the reference instrument. We expected negative correlations between change scores of PAIN, PI and OHS, and positive correlations between change scores of PF and OHS, each in the order of |r|  ≥ 0.5. The smallest effect size of interest was defined as a Cohen’s  studies , 18. ResFloor and ceiling effects were considered acceptable if percentages were below 15%. To determine the individual-level minimal important change (MIC), we used linear regression with the OHS change scores and reported MIC for OHS in THA patients .Analyses were performed using Stata Statistical Software Release 15 .Table Scale-specific hypothesis testing for validity resulted in 100% confirmed hypotheses for PAIN, 89% for PI and 78% for PF Table .Table 2agr and SDC90, whereas PI had the lowest. The effect size based on SEMagr was smallest for PF, and smaller than OHS for all three SF.Cronbach’s alpha ranged between 0.7 and 0.95. ICC confidence intervals were ≥ 0.7 for PAIN and PI, but not for PF Table . PAIN shd  values were: PAIN, − 2.9 (− 3.3 to − 2.5); PI, − 3.0 (− 3.4 to − 2.6); PF, 2.7 (2.4 to 3.1).Hypothesis testing for responsiveness resulted in confirmation of all hypotheses about correlations between SF and OHS change scores; SF change score scatter plots are shown in Fig. We found ceiling effects (best score) for PAIN (66%), PI (76%), and PF (66%) after surgery. MICs were: PAIN, − 10; PI, − 8.8; PF, 7.2 (T-score change).Our results suggest that the construct validity of PROMIS-SF is acceptable in THA patients. The SF have good internal consistency, test-retest reliability and responsiveness. For PAIN and PI, MICs were larger than the corresponding SDC90 values. Some measurement property limitations were nevertheless detected.agr, which means that the joint-specific OHS allows more detailed grading of patient recovery than the PROMIS-SF scales.For PF, MIC was smaller than SDC90 meaning that clinically relevant change could not be distinguished from measurement error on the individual level. Compared to OHS, all SF show 40% to 60% smaller effect sizes based on SEMThe high proportion of patients with best possible scores of PI and PAIN after surgery may be not critical. These scales represent unipolar constructs where the complete absence of pain or pain interference makes it difficult (yet likely less relevant) to differentiate them any further. Nevertheless, researchers should be careful in interpreting PF after surgery because of ceiling effects. This problem may be resolved by using PF CAT without substantially increasing respondent burden , 21. AltTHA is typically associated with very high patient satisfaction. Consequently, we did not have patients in the “poor outcome” category upon dichotomisation of the GTO, and MIC could not be calculated with an anchor-based standard method using the receiver operating characteristics curve. For this reason, we adopted an alternative indirect approach using linear regression from the OHS MIC calculated in a much larger study with 82,415 THA patients .Only 77% of eligible patients responded at baseline and 67% at follow-up. From our internal registry quality-control procedures, we know that “lack of time” is the most common reason for not responding. From follow-up non-responders, less than 3% refused to cooperate because they were dissatisfied with their treatment, which suggests that there was no major selection bias.Unidimensionality of the SF scale structure was not assessed, due to existing reports and guidelines of the development of PROMIS item banks , 22, 23.Our results provide some evidence of construct validity, and acceptable reliability and responsiveness of PROMIS-SF for pain and function in THA patients. The SF can thus be considered as acceptable as another common static instrument (i.e. OHS) for use in these patients, although improvement in PF might be underestimated due to the large follow-up PF score ceiling effects.


False assumptions regarding the generalizability of patients' expectations and preferences across different demographic groups may contribute in part to the increased prevalence of negative peripartum outcomes seen among women of color. The intention of this study was to determine preferences and concerns regarding anesthesia care during cesarean delivery in a largely African-American population and to compare them to those obtained in a prior study conducted in a demographically distinct population.  Women presenting for scheduled cesarean delivery or induction of labor completed a preoperative survey requesting demographic information and the opportunity to rank ten common potential anesthetic outcomes in relation to each other from most to least desirable. Participants were also asked about their biggest fear concerning their anesthetic and their preferences and expectations regarding degree of wakefulness, pain, and other adverse events. Those who underwent cesarean delivery were administered a briefer postoperative survey. We tabulated preference rankings and then compared demographic and outcome data to that obtained in a previous study with a demographically dissimilar population.  A total of 73 women completed the preoperative survey, and 64 took the postoperative survey. Pain during and after cesarean delivery was ranked as least desirable outcomes and fear of paralysis was respondents' principal concern with neuraxial anesthesia. Postoperative concerns were similar to preoperative concerns and did not correlate with the frequency with which specific adverse outcomes occurred. These results were consistent with those from the previous study despite the women in this study being more likely to be younger, unmarried, African-American, and less educated than those in the previous investigation.  Patient preference rankings and concerns were remarkably similar to those previously demonstrated despite a number of demographic differences between the two populations, suggesting generalizability of these preferences to a broader obstetric population. Medical care in the United States has evolved from emphasizing physician paternalism to stressing patient autonomy. Although surgical patients' anesthetic expectations and outcome preferences have been documented , less isResearchers at Stanford University developed and administered a standardized survey to study patient preferences for anesthetic outcomes after cesarean delivery . The surIn this study, we closely followed the previous survey methodology utilized by the Stanford group  and applThis study was approved by the University of Chicago Institutional Review Board . We approached pregnant women presenting for either scheduled cesarean delivery or scheduled induction of labor at The University of Chicago Medicine (UCM) Hospital from July 2017 to June 2019 to participate in this study. Written informed consent was obtained by a study investigator immediately following the routine preanesthesia interview on the day of admission. Women presenting in painful labor, defined as a pain score ≥3/10, were excluded from participation.Consenting subjects were then administered a survey adapted from the one developed by the Stanford group  In additPerioperative expectations and preferences were assessed by 1) asking survey respondents to rank ten common potential anesthetic and related side effect outcomes in relation to each other from the most desirable  asking s and (2) Participants were asked about their preferred degree of wakefulness during surgery, their expectations of pain, how much pain  they would tolerate rather than expose their baby to medication, and their biggest fear of neuraxial anesthesia . Women also completed a “trade-off” table forcing them to make choices between pain relief and several common opioid treatment-related adverse effects . This “trade-off” table allowed investigators to determine how women balance potential benefits and side effects of postoperative analgesia.All patients who delivered via cesarean delivery (both those patients who had scheduled cesarean delivery and those patients admitted for induction of labor who underwent unplanned cesarean delivery) were asked to fill out a briefer survey on postoperative day 1 during the routine postanesthesia visit. The postdelivery survey included the same priority ranking, money distribution exercise (later eliminated), and “trade-off” table as the predelivery survey.n = 82) [The primary outcome variable of interest was the priority ranking for potential anesthesia and related side effect outcomes in the study cohort. A secondary outcome variable was to compare preoperative to postoperative priority rankings. We also compared preferences in the current survey conducted at the UCM to the Stanford study conducted at Lucile Packard Children's Hospital (LPCH). We obtained the raw data from the Stanford group in order to allow for the between-institution comparisons. Since the primary outcome was descriptive in nature, we did not perform a sample size or power analysis but rather chose a convenience sample similar to that used by the Stanford group (n = 82) .t-test or Mann–Whitney U test as appropriate. In order to compare preoperative to postoperative ranking, we first dichotomized ranks as low-rank (rank ≤5) and high-rank (rank >5). Then low versus high rank between pre- and postoperative anesthetic and related side effect outcome preferences per category was analyzed using McNemar's test. The between-institution priority ranking analysis was simplified to identify and compare those patients who indicated pain either during or after surgery as the least desirable outcome. We also identified and compared those patients whose biggest fear was paralysis. A two-sided P < 0.05 was required to reject the null hypothesis. We used STATA version 15.1 for all analyses.Data are presented as mean ± standard deviation, median (interquartile range), and number . Categorical data were compared between groups with Chi-squared or Fisher's exact test as appropriate, and continuous data were compared between groups with Student's We administered 74 preoperative surveys, one of which was incomplete and excluded from analysis, leaving a total of 73 preoperative surveys. A total of 70 of these 73 subjects underwent cesarean delivery, and 64 of them completed a postoperative survey (5 declined to participate and 2 were discharged before completing it).P < 0.0001). There was no difference in representation of healthcare workers or women with a history of previous (noncesarean delivery) surgery requiring anesthesia.Demographic information of the study population is listed in Pre- and postdelivery priority ranking of potential anesthetic outcomes are outlined in Predelilvery survey responses regarding preferences and expectations of anesthesia for cesarean delivery are listed in Patient preferences and concerns regarding potential anesthesia outcomes and related side effects in the current patient population were remarkably similar to those demonstrated in the previous Stanford study cohort . These sWomen ranked pain during and after surgery as their leading concerns, and ahead of potential anesthesia-related side effects including vomiting, nausea, cramping, itching, and shivering. Undergoing cesarean delivery did not significantly influence concerns regarding anesthesia and side effect outcomes; preferences reported in the postoperative survey were nearly identical to those in the preoperative survey. The priority ranking for potential anesthesia and associated side effect outcomes postdelivery was unchanged despite variation in the frequency of outcomes actually experienced. For instance, 18% of patients reported experiencing pain after surgery, and nearly half reported nausea and vomiting; however, the overall ranking still found pain ranked higher than nausea.Several investigators have identified pain as the least desirable outcome among nonobstetric general surgery patients –10. OtheUnique considerations among obstetric patients such as exposing the fetus to medication and being able to breastfeed and care for a newborn shortly after surgery are reflected in preferences for analgesia dose and the degree of pain one would tolerate before requesting analgesia. We found, consistent with the Stanford study, that women believed they would tolerate moderate pain rather than expose their baby to medication. These results highlight that anesthesia providers should elicit patients' understanding of the degree of opioid transmission both transplacentally and via breastfeeding during the preoperative assessment, and should educate patients regarding the safety of postoperative analgesics, as this potential exposure appears to be a concern for women. Future studies investigating patients' understanding of analgesic transmissibility to newborns would help inform discussions about risks and benefits.When offered a hypothetical “trade-off” between pain relief and side effects, the majority of patients would rather have a “moderate dose” of pain medication to offset potential side effects. These findings were similar to those reported in the Stanford cohort . Women'sAlthough the incidence of neuraxial anesthetic-related paralysis in obstetric patients is exceedingly low –14, paraThis study has several strengths. Our high postoperative survey completion rate allowed us to compare preoperative perceptions of side effect outcomes with the actual frequency of outcomes experienced. Also, we were able to demonstrate several demographic differences between subjects in our population versus the Stanford cohort , allowinThe study also has potential limitations. Despite having a research team member present and available for questions during survey administration, many patients had difficulty understanding and accurately responding to certain questions. The dollar allocation section in particular caused significant confusion for many patients and was ultimately excluded from analysis. Interestingly, the Stanford group did not encounter similar issues despite using identical questions. In the present investigation, surveys were administered in the preoperative area shortly before patients anticipated having surgery, whereas the Stanford investigators conducted the survey at expecting parent class weeks before the delivery. Perhaps administering the survey in a more comfortable setting where patients have more time to respond leads to better comprehension of survey questions. Also, the Stanford group asked subjects to mail in responses whereas we conducted interviews in person. Furthermore, the Stanford study was conducted several years ago in 2002–2004. Any of these differences could have impacted between-institution comparisons, but the fact that both groups ranked outcomes in precisely the same preference order lends credibility to our finding that there were no differences in outcome variables between the two groups. Lastly, the multiple-choice format of the question “What is your biggest fear regarding spinal/epidural anesthesia?” most likely led many patients to select the most frightening option, “paralysis.” A free response format might prove more informative of patients' preexisting fears and knowledge of potential adverse outcomes. Furthermore, including risk quantification that appropriately identified paralysis as rare might have allayed patients' concerns about this outcome.Results of this study add to our limited knowledge of obstetric patients' preferences and concerns regarding anesthesia outcomes and related side effects for cesarean delivery. They suggest that obstetric patients' preferences and concerns are fairly uniform and not influenced by racial, ethnic, and socioeconomic differences. Our results highlight the importance of adequate discussion of risks and benefits between providers and patients of all demographic backgrounds and the importance of eliciting individual patient's concerns and considering them when designing anesthetic plans.


Fibromyalgia is a chronic multidimensional pain disease with no curative treatment currently available. Its management relies on a multimodal approach involving pharmacologic and non-pharmacologic elements. Because a suggested factor in its etiology is a central sensitization phenomenon involving the N-methyl-D-aspartate receptor (NMDAR), NMDAR antagonists have been proposed as a treatment target. Ketamine and its levogyre form, S-ketamine, have been used to treat chronic pain for many years without consensus about their therapeutic efficiency. We aim to assess the efficacy of S-ketamine as a co-treatment for fibromyalgia.This prospective, randomized, single-center, double-blind, parallel-group, dose-escalation trial will compare a co-treatment with S-ketamine (intervention) to a control treatment without S-ketamine (control). It will consist of two successive cohorts with 2:1 randomization ratio (S-ketamine at two different doses: control) with 105 participants in each cohort. The protocol follow-up time will be 12 weeks, including 3 visits for the treatment  and 3 visits for follow-up . Our primary outcome, pain relief and/or better patient function, will be assessed with the Brief Pain Inventory questionnaire. The statistical analysis will be performed on an intention-to-treat basis. If the primary outcome is reached at the end of follow-up in the first cohort with low-dose S-ketamine (0.2 mg/kg), the trial will end. If not, the trial will continue with the second cohort and high-dose S-ketamine (0.4 mg/kg).The challenge of our trial is the inclusion of a large number of participants in comparison to other trials involving ketamine or S-ketamine infusions for chronic pain management. The originality of our protocol is to include functionality in addition to pain relief as a primary outcome because these two endpoints are not linked in a linear way. For some patients, functional status is more important than pain relief.ClinicalTrials.gov: NCT04436250, first posted June 18, 2020; last updated July 21, 2020. Protocol version 2.2 issued on September 30, 2020, after a revision by the ethics committee. https://clinicaltrials.gov/ct2/show/NCT04436250EudraCT reference: 2020-000473-25, The online version contains supplementary material available at 10.1186/s13063-021-05814-4. Chronic pain is a multidimensional syndrome affecting 17–44% of the population of western countries . FibromyA central sensitization phenomenon has been proposed as one of the etiological mechanisms in fibromyalgia , 9. ThisKetamine has been hypothesized to provoke a “reset of the central nervous system,” reversing the deleterious effects of central sensitization. This drug thus has been proposed as a co-treatment for chronic pain involving central sensitization phenomena, such as fibromyalgia . KetaminKetamine has been used in chronic pain treatment for as long as 20 years with various dosage and administration modalities, and consensus guidelines for its use have been established . HoweverOur hypothesis is that S-ketamine, through its NMDAR antagonist properties, would improve the quality of life  of patients diagnosed with a fibromyalgia syndrome according to the ACR 2016 criteria and who exhibit the characteristics of a central sensitization phenomenon  > 40) , 16. If Our primary objective is to evaluate whether S-ketamine used as a co-treatment in chronic pain management will result in better pain control and/or in improvement of functionality in patients with fibromyalgia. We specifically target this double objective because pain relief and improved function are only partially linked: better pain relief does not always lead to improved functionality, and some patients prioritize a gain in function despite maintaining the same level of pain. In fact, studies have not been able to demonstrate a linear relationship between pain relief and gain of function , 18.Our secondary objectives are to assess how S-ketamine used as a co-treatment affects quality of life, satisfaction, and emotional status, all of which are important in chronic pain syndromes.The trial respects the Guidelines ICH E6 for Good Clinical Practice (01/07/2002), the principles of the Helsinki declaration, the ICH E2A Guidelines , the European Union Clinical Trial Directive (2001/20/EC), and all Belgian legislation to maximize participant safety and protection.Relative to the May 7, 2004, Belgian legislation concerning experimentation on human subjects, a no-fault insurance has been subscribed in the name of the Grand Hôpital de Charleroi, Belgium (GHdC).This is a prospective, randomized, monocentric, double-blind, parallel-group, dose-escalation superiority study comparing an analgesic treatment including S-ketamine (intervention) to the same analgesic treatment without S-ketamine (control) Fig. . The stuThis clinical trial is reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)  under a laminar flow hood into syringes of 2 ml containing 25 mg/ml of S-ketamine. Each syringe will have identical packaging with a recognition number linked to the randomization. These syringes will be sent to the pain clinic, where the responsible physician will prepare the right dosage of S-ketamine according to the patient’s weight and dilute it in physiological saline (0.9% NaCl) to obtain a volume of 45 ml. The product will be administered intravenously over 3 h (15 ml/h) with an electronic syringe pump.The placebo, physiological saline (0.9% NaCl), also will be prepared by the GHdC pharmacy, conditioned in syringes of 2 ml with identical packaging to those containing S-ketamine. Each syringe will have a recognition number linked to the randomization. These syringes will be sent to the pain clinic, where the responsible physician will prepare the placebo as if it were S-ketamine, diluting it in physiological saline (0.9% NaCl) to obtain a volume of 45 ml. This solution will be administered intravenously over 3 hours (15 ml/h) with an electronic syringe pump.All participants will receive a control treatment of magnesium sulfate 40 mg/kg, for antinociceptive effects , 25, andPain clinic staff will prepare the control treatment according to the usual procedure. Magnesium sulfate 40 mg/kg (from 3 g/10 ml ampoules) and clonidine 1 μg/kg (from 150 μg/ml ampoules) will be administered together, diluted in physiological saline (NaCl 0.9%) to obtain a volume of 45 ml. The product will be administered intravenously over 3 h (15 ml/h) with an electronic syringe pump.Each patient will simultaneously receive an infusion of the control treatment and an infusion of the test drug (S-ketamine) or placebo, given via two different electric syringe pumps over the 3-h time period. Each participant will receive the treatment three times at 2-week intervals, which is consistent with our current practice and findings in the literature .The trial’s follow-up time is 12 weeks and involves three visits for the treatment  and three visits for follow-up   associated with fibromyalgia as defined by the ACR 2016 criteria , with a Pregnant or breastfeeding women (based on patient questioning and urine pregnancy test for women of childbearing age) will be excluded. A pregnancy discovered during the study will be reported to the ethics committee. Women of childbearing age not using an approved contraceptive method with a safety rate > 99% (< 1% on the Pearl index) also will be excluded. Other exclusion criteria include a history of psychiatric disorders , an inability to give informed consent (including because of a linguistic barrier), allergy or contraindication to any of the products used in the trial, and any medical condition or medication inconsistent with the study, based on the judgment of the clinical investigator.These outcomes have been chosen according to the IMMPACT  recommendations , 18, 28.Our primary outcome is improvement in pain and/or functional status. Improvement will be defined as clinically significant as follows: for pain relief, a 2-point decrease in the Brief Pain Inventory (BPI) pain severity score , and forOur secondary outcomes are a 50% pain decrease on a numerical rating scale, impact on quality of life as evaluated using the EQ5D-5 L questionnaire, impact on emotional status using the Hospital Anxiety and Depression Scale questionnaire, and the incidence of adverse events solicited and spontaneously reported to the pain clinic staff. We also will assess patient global satisfaction with the treatment, as evaluated using the Patient Global Impression of Change questionnaire.All questionnaires will be completed before drug administration, and during the follow-up visits together with secondary outcomes assessments Table .This is a double-blind trial, so the packaging of the placebo  and the investigational drug (S-ketamine) will be identical and provided by the pharmacy. The staff of the pain clinic, independent from the protocol, will prepare and give the treatment, as well as monitor the patient. They will also hand each patient the questionnaires to complete and fill the adverse events questionnaire.Each patient will be assigned a code, and data will be collected according to this code, so that investigators are unaware of each patient’s allocation. The investigator will collect anonymous data. The person performing the statistical analysis (JF) is independent of the study protocol.Because of its dysphoric effects, ketamine could be recognized by the patient. We therefore chose to add clonidine for all patients, because it both has analgesic properties and can alleviate these dysphoric effects .Unblinding will be allowed in case of a suspected unattended serious adverse event, if needed to guarantee its resolution and patient care.All participants will be equipped with standard, non-invasive hemodynamic monitoring including heart rate, blood pressure, and oxygen saturation. The pain clinic staff, including a physician, will be present during the treatment administration. All adverse events will be monitored continuously and until resolution. If any expected adverse event occurs, it will be treated based on the incident management protocol  can be pursued during the study participation and adapted if necessary. The patient’s baseline treatment should remain the same from the beginning to the end of the protocol, as far as possible. The attending physician will evaluate the need to adapt the treatment if necessary for the patient’s wellbeing. All changes in baseline medication, if required, will be monitored and reported in the case report form.All patients are free to discontinue the protocol at any time (which is part of the informed consent). Other criteria for study discontinuation for a participant will be lack of adherence to the protocol (for example not coming for the treatment) or serious adverse events.Participants who do not present for one of the three treatment appointments or one of the three follow-up appointments will be excluded from the study and considered as lost to follow-up. To minimize missing data, pain clinic staff will supervise questionnaires’ completion, ensuring they are adequately filled.In cases of missing data, we will analyze the cause, according to Rubin , and wilPatient identity will remain strictly confidential  by means of pseudonymization. All data will be identified by a patient code, keeping it anonymous. Only the investigators’ team will have access to the identity code keys.Participants will fill out paper questionnaires that will be entered into an electronic case report form (password-secured Excel table) held on the GHdC server. The paper case report forms and electronic database will be stored in the anesthesiology department of the GHdC. The locked database will be transferred to the statistician (JF) for analysis.All original study records and the database will be kept at the GHdC for 20 years or for a longer period when required by national rules. When the EU clinical trials regulation 536/2014 is applicable, a period of 25 years after the end of the study will be required.Apart from possible external audit, no internal audit has been scheduled.On the day of the usual medical consult, inclusion and exclusion criteria will be verified and a written informed consent obtained by the physician. Once the patient is included in the trial, the information will be given to the GHdC pharmacy to enter the patient on the randomization list. The pharmacist of the GHdC will create the randomization list using a computer-generated allocation sequence and will be the only source of access to the randomization key. Patients will be randomized in a 2:1 ratio (S-ketamine: control) in blocs of 15 (S-ketamine 10: control 5). The same randomization method will be used for the two studied cohorts.Only the person responsible for the randomization, independent from the study protocol, will have the randomization key. The randomization list and a copy will be edited, placed in a sealed envelope, and kept at the GHdC pharmacy.n = 7) met the pain relief objective and 56% (n = 14) met the functionality objective. Few data were found concerning a placebo effect, which we assessed at 10% under the conditions of our trial , magnesium sulfate, and clonidine for whom we compared data before and 2 weeks after treatment. Applying our primary outcomes, we found that 28% .p value (0.05) by this number of comparisons to arrive at a p value that allows for rejection of the null hypothesis of no difference observed between the groups. With a minimum clinically relevant difference of 5%, an expected rate of 10% improvement for the usual care+placebo group, and an expected rate of 25% improvement for the usual care+S-ketamine group, 55 patients per group are needed. Considering a drop-out rate of 20%, 70 patients per group will be needed to ensure that data for 55 per group will be available at the end of follow-up.The selected size of the study population was calculated based on 0.8 (80%) power at an alpha of 0.0125. The alpha is set to 0.0125 because we will compare two primary outcomes twice, at most: the first comparison will be between the usual care+placebo treatment and usual care+low-dose S-ketamine treatment. If this comparison shows non-significant difference between the two groups, the second comparison will be between the usual care+placebo treatment and the usual care+high-dose S-ketamine treatment. Thus, for the primary outcome, a total of four comparisons will be made, so we divided the targeted This number of patients for inclusion is ambitious, but the pain center treats more than 100 patients with fibromyalgia per year. The duration of recruitment is expected to be one year for the first dose cohort and one more year if a second cohort of patients is needed.All patients will be recruited by the physicians of the pain clinic during their medical consult, according to the described eligibility criteria Fig. .Fig. 3Rp value) threshold for both cohorts is set to p < 0.0125.An independent and blinded statistician (JF) will perform the statistical analysis. The groups will be compared for the primary and secondary outcomes as well as for group homogeneity. As noted, the statistical significance . The protocol also covers the investigator’s responsibility to inform the committee of trial progress (at least once a year), any amendment or modification to the protocol, any serious adverse events, and the end of the trial. In addition to the ethics committee, any serious adverse event will be reported to the AFMPS  in the Development Safety Update Report every year. All important protocol modifications will be communicated by the principal investigators to the study coordinator (AG) who will contact relevant parties.This is a single center academic study for which our ethical committee did not request data monitoring and other committees.Written informed consent based on voluntary participation has to be obtained before inclusion of each participant, who will be informed of the aims, procedures, and risks related to the trial. At any time during the trial, the participant will have the right to withdraw participation freely without any penalty (Additional file Fibromyalgia is a primary chronic pain disease that results in progressive deterioration of quality of life, as well as a reduction in relational and functional capacity. Several brain imaging and psychophysical studies support the hypothesis that a central sensitization phenomenon is involved in the etiology of the disease , 38. In Central sensitization is a condition in which neural “dysregulation” and hyperexcitability lead to a hypersensitivity to nociceptive as well as non-nociceptive stimuli . NMDAR, We designed our trial according to the guidelines for clinical trials in chronic pain, based on the recommendations of the IMMPACT group and the Cochrane Collaboration , 28, 43.We plan to use S-ketamine because this pure dextrorotatory enantiomer of ketamine is about two to four times more potent than the racemic mixture, enabling lower dosage for equianalgesic effects . It alsoBased on our ethical considerations, our protocol provides pain treatment for all patients, with clonidine and magnesium sulfate. Clonidine has well-known analgesic properties in patients with chronic pain , and NMDThe most important strength of our protocol is the inclusion of function as a primary outcome. Pain relief and functional improvement are not linked in a linear way, and some patients will react to a treatment by pain reduction, whereas others will react with a gain of function. For many patients, gain of function can be more important, on a personal as well as a societal level. We tried to build a protocol that reflects our multimodal perception of pain .Protocol version: 2.2 issued on September 30, 2020Recruitment is expected to start early 2021 and to be completed in about 2 years.Additional file 1. SPIRIT checklist.Additional file 2. Incident management protocol.Additional file 3. WHO trial registration data set.Additional file 4. Informed consent form.


Musculo-skeletal complaints in a patient suffering from systemic lupus, with co-existing chronic renal failure, undergoing immunosuppressive treatment after kidney transplantation, can have a varied etiology. The aim of this work was to present a case based review of differential diagnosis of knee pain in such a patient. A literature search was carried out using MEDLINE/PubMed, Google Scholar and EBSCO, with no time limit. We undertook a systematic review of the literature published in English, limited to full-text publications of original articles, letters to the editor, and case reports in peer-reviewed journals, for a discussion and analysis of studies reporting arthralgia in patients with lupus after kidney transplantation. We present a case report of a 45-year-old woman with lupus nephritis, after kidney transplantation, who started to complain of increasing pain in the knees, most pronounced at night and after physical activity approximately 2 years after transplantation. Extensive causal diagnostics were carried out, which revealed bilateral extensive regions of bone infarction in the femur and tibia, chondropathy, degenerative changes of medial meniscuses in the body and posterior horn as well as chondromalacia of the patella. Establishing the right diagnosis is crucial for implementing appropriate treatment. Musculo-skeletal complaints in a systemic lupus erythematosus (SLE) patient after kidney transplantation can have a varied etiology and pose a diagnostic dilemma. Musculoskeletal complaints have been noted in up to 30% of patients receiving kidney transplants. In some patients, symptoms already occur before organ transplantation, and after this procedure, some of these problems persist, others improve, and new joint disorders may also develop .Osteonecrosis is a common bone complication of SLE, which is reported in 4–15% lupus patients. The most common site of osteonecrosis is femoral head. Isolated symptomatic knee osteonecrosis in patients with SLE is a relatively rare complication which mimics the symptoms of lupus-associated non-erosive arthritis. In the differential diagnosis of knee pain, many other causes should also be considered, such as calcium–phosphate imbalance, osteomalacia, osteoporosis, osteoarthritis, or gout. Calcineurin inhibitor pain syndrome (CIPS) also known as immunosuppression-related bone marrow edema syndrome or post-transplant bone marrow edema syndrome is another potential cause of severe bone pain in patient treated with calcineurin inhibitor. The possible causes are numerous and usually multiple factors are present in each patient. Establishing the right diagnosis is crucial for implementing appropriate treatment. Elements of anamnesis such as character of pain (acute or chronic), aggravating and alleviating circumstances (whether pain is worse when first moving a joint or after prolonged use), time from the onset, time frame (new-onset or recurrent), morning predilection, together with laboratory findings and imaging examinations must be analyzed simultaneously to create a coherent picture of specific disorder.Based on the case report of a 45-year old SLE patient with lupus nephritis after renal transplantation presenting chronic knee pain, we review the literature on the potential causes and differential diagnosis of knee pain and prevalence of knee avascular necrosis in this group of patients.A literature search for patients with lupus nephritis after renal transplantation suffering from chronic knee pain as well as the incidence of avascular necrosis of the knee joint in lupus patients was carried out using MEDLINE/PubMed, Google Scholar and EBSCO, with no time limit. The search was conducted using the following key words: “arthralgia knee” OR “knee pain” AND/OR “lupus” AND/OR “kidney transplantation” AND/OR “osteonecrosis”. Using a combination of these search terms, we undertook a systematic review of the literature published in English, limited to full-text publications of original articles, letters to the editor, and case reports in peer-reviewed journals, for a discussion and analysis of studies reporting causes of knee pain in patients with lupus after kidney transplantation  was admitted to the hospital with symptoms of active autoimmune disease. On admission she presented skin lesions of subacute lupus, pericardial effusion, autoimmune hemolytic anemia, leucopenia, low complement components’ levels, high concentration of dsDNA antibodies and active renal disease with daily proteinuria of 4,6 g/24 h, hematuria, creatinine 5,3 mg/dl, eGFR 9 ml/min, metabolic acidosis, hyperuricemia, hypocalcemia, hyperphosphatemia, deep vitamin D deficiency. Antiphospholipid antibodies were negative. CT scan of abdomen revealed nephrocalcinosis and abdominal lymphadenopathy. Due to active SLE with advanced renal insufficiency immunosuppressive treatment has been implemented (EUROLUPUS scheme), but renal function did not improve. Renal replacement therapy in the form of peritoneal dialysis was started. After one year the patient received a deceased donor renal transplant and underwent therapy with tacrolimus, mycophenolate mofetil and steroids. The graft was functioning well, and immunosuppressive medication concentrations were stable  and have diverse causes. End-stage renal insufficiency and chronic dialysis have been reported to contribute to a wide range of musculoskeletal and articular complications, but most of the symptoms improved after KT as a result of corticosteroid therapy. Our literature review revealed only two original publications focused directly on causes of joint pain in patients after kidney transplantation and one study based on MRI findings in kidney recipients with hip and knee pain Table . None ofJoint involvement is one of the most common symptoms of active SLE. Based on the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus, it is defined as either synovitis involving two or more joints, characterized by swelling or effusion, or tenderness in two or more joints and at least 30 min of morning stiffness . RecurreA spectrum of abnormalities related to chronic renal failure such as hyperphosphatemia, hypocalcemia, hyperparathyroidism, osteomalacia, osteopenia, and osteoporosis influence bone structure and trigger bone pain. During the first months after kidney transplant, there is a rapid bone loss mainly due to steroid treatment, but also due to deficiencies of vitamin D, continued secondary hyperparathyroidism, and impaired physical activity . After tClassical X-ray of our patients’ knee did not show any abnormalities, but MRI revealed the true causes of her complaints. Osteoarthritis (OA), chondromalacia and degenerative changes of meniscuses are one of the major causes of musculoskeletal pain , 9. TendAvascular necrosis (AVN) of bone is a well-known complication of SLE even without renal involvement, that occurs in about 4–15% of patients , 12, eveMany theories regarding the pathophysiology of blood interruption have been proposed and include increased bone marrow pressure and intravascular occlusion of subchondral vessels by coagulation, fat emboli or thrombi .Additionally corticosteroid-associated osteonecrosis has been observed in various diseases including systemic lupus, rheumatoid arthritis, asthma, inflammatory bowel diseases and organ transplantation. Steroid therapy, regardless of the original indication, presents a risk of development of multifocal osteonecrosis . Of the Several risk factors refer to the general population , others are specific for the post-transplant population  was another potential cause of severe bone pain in reported patient. It was first mentioned in the early 1990s but finally recognized as a distinct post-transplant pain syndrome in 2001 by Grotz, et al. . Since tIn case of bone and joint pain establishing the right diagnosis is crucial for implementation of successful management. When dealing with an SLE patient after renal transplantation numerous potential causes need to be taken into consideration. However, it must always be considered that, as in the present case, there may be more than one cause of joint pain. Although avascular necrosis is a fairly common complication of chronic steroid therapy, it should be borne in mind that it is not only the hip joint that may be affected. Elements of anamnesis such as character of pain, aggravating and alleviating circumstances, time from the onset, together with laboratory findings and imaging examinations must be analyzed simultaneously to create a coherent picture of specific disorder.


Modern-Type Depression (MTD) is a category of depression that has been studied mainly in Japan; however, no study has attempted to determine its relation to chronic pain.To determine possible associations between psychological traits related to MTD and the chronic pain of patients at psychiatric clinics.Two hundred and twenty-one first time patients who visited the psychiatric clinic at a Japanese university medical center or an associated clinic were enrolled. The Hamilton Depression Rating Scale was used to measure depressive symptoms. The 22-item Tarumi's Modern-Type Depression Trait Scale (TACS-22), Achievement Motive, and 20-item Toronto Alexithymia Scale were used to assess psychological traits related to depression and chronic pain. The clinical diagnosis of each patient was confirmed by use of the Structured Clinical Interview for DSM-IV Axis I Disorders, administered by experienced specialists. The medians of the psychological traits identified were compared between patients with or without chronic pain. Analysis was also done of patients with Major Depressive Disorder (MDD).Of the 221 patients, 139 had chronic pain. Patients with chronic pain had more severe depressive symptoms, Alexithymia, and high scores for the complaint trait of MTD. Seventy-three of the 221 patients met the criteria for MDD (53 had chronic pain). Patients with MDD comorbid with chronic pain had a higher competitive achievement score, severe depression, and difficulty identifying feelings.Complaint and competitive traits were shown to be related to chronic pain in psychiatric settings. Further study will allow us to design multidimensional approach for patients suffering from depression. The global prevalence of depression is estimated at 3.76%, and the prevalence in Japan was reported to be 2.66% in 2019 , 5, and Alexithymia has been reported to be associated with both depression and chronic pain. In a recent meta-analysis, the degree of alexithymia was correlated with pain intensity, physical interference, depressive symptoms, and anxiety in a group of chronic pain patients . EconomiModern-type depression (MTD), an independent type of depression that is different from the conventional depression based on a melancholy temperament, has been widely reported in Japan –13. ThisAchievement motive (AM) is another instrument used in Japan to assess psychological traits related to depressive symptoms. It consists of two aspects of motivation: competitive and self-fulfillment. Those whose competitive achievement motive is high have been reported to have difficulty accepting social support and to have a tendency toward stronger depressive symptoms .Studies have related the personality traits of MTD and AM to depressive symptoms, but their relation to chronic pain is unknown. Thus, to clarify which traits are related to chronic pain, we used the above inventories to investigate the interaction between depression and personality traits of patients with or without chronic pain. The patients were recruited from psychiatric clinics because we expected many of them to suffer from depression. The level of depression and confirmation of the diagnosis of the patient's base disease were assessed by semi-structured interviews done by experienced psychiatrists or psychologists.Patients who first visited the Mood Disorder/Hikikomori Clinic in the Department of Neuropsychiatry at Kyushu University Hospital or affiliated psychiatric institutes between July 2018 and February 2021 and who gave written consent were enrolled. Patients referred from other psychiatric medical institutions due to refractory symptoms and suspected of having a mood disorder were included. Patients who could not complete a face-to-face semi-structured interview and patients for whom detailed information about their pain was not available were excluded, leaving the data of 221 patients available for analysis.This study was approved by the ethics committee of Kyushu University, Fukuoka, Japan. Participants agreed to join in the study after being informed that their anonymity would be maintained and that participation was voluntary.The study was cross-sectional and done through the use of self-reporting questionnaires and a structured interview of all participants to examine psychological factors related to their depression and pain. The questionnaires were used to assess specific patient psychological traits, factors related to their disease, and clinical data including age, gender, location and duration of pain, socioeconomic status . Pain lasting more than 3 months was considered chronic. The following evaluations were done.The SCID (Japanese version) is a semi-structured psychiatric interview with established reliability that assesses if the patient has reached a diagnostic threshold according to the DSM-IV . All of The Hamilton Depression Rating Scale (HDRS) is a structured interview that assesses the severity of depression . AnswersThe PHQ-9, this screening questionnaire is based on the diagnostic criteria of DSM-IV and consists of nine questions on depression in the preceding 2 weeks. It was used for assessment of depression severity . AnswersTACS-22 is a self-reporting questionnaire that assesses the premorbid personality traits of MTD . The queTAS-20 is a 20 item self-reporting questionnaire that assesses Alexithymia-related personality traits . It consAM is a self-reporting questionnaire that evaluates the strength of motivation to achieve a goal. It consists of 23 questions  and asseP-values of < 0.05 were considered to be statistically significant, and P-values of < 0.1 were considered as marginally significant.For the analysis, patients with pain lasting more than 3 months were placed in a chronic pain group (CP). All met the diagnostic criteria for major depression, and this group is referred to as MCP. Patients without pain (NP) were placed in a control group. All met the diagnostic criteria for major depression, and the group is referred to as MNP. The median values of each psychological scale measured were compared by Wilcoxon-Mann-Whitney test. Statistical analysis was done with R version 4.1.1. The frequencies of the patients' primary disease for which the diagnostic threshold of the structured interview (SCID) was exceeded are summarized in n = 139) and NP (n = 82) is shown in p = 0.00002, HDRS: 14 (CP) vs. 9 (NP), p = 0.0000001). The median TAS-20 score was also marginally higher in the CP group but was without significance [49 (CP) vs. 47 (NP)/p = 0.0532]. The median values were significantly high for Complaint of TACS-22 and DIF of TAS-20 . Although the median values for Low Self-esteem of TACS-22 were the same for CP and NP, the mean value was higher in CP .A comparison of the median values of each psychological scale for CP (n = 53) than in the MNP group (n = 20) [HDRS: 19 (MCP) vs. 15 (MNP)/p = 0.0111]. The median TAS-20 score was also marginally higher in the MCP group, although it did not reach the level of significance [52 (MCP) vs. 48.5 (MNP)/p = 0.0678]. The median value of the MCP group was higher for the DIF of TAS-20 [19 (MCP) vs. 14 (MNP)/p = 0.00211]. In addition, the competitive achievement motive of the AM inventory was higher in the MCP group [45 (MCP) vs. 40 (MNP)/p = 0.0163].The median values of each psychological scale were compared for the patients of each group who reached the diagnostic threshold for major depression . DepressIn our study to clarify the psychological characteristics of psychiatric outpatients with or without pain, patients with pain lasting more than 3 months showed more depressive symptoms and a tendency toward Alexithymia. This tendency was also observed in patients who met the diagnostic criteria for major depression. For all patients analyzed, personality traits related to MTD were stronger in the group with chronic pain, but there was no significant difference when only patients with major depression were included. The competitive achievement motive “aiming to beat or overcome others to be appreciated by others or society” did not differ between patients with or without chronic pain, but in the group with major depression and chronic pain the score was higher than for those without chronic pain.The results showing that depressive symptoms were stronger in the group with chronic pain are consistent with the results of previous studies . Our stuThe clinical manifestations, response to pharmacotherapy or psychotherapy, staging, and functioning of patients with depression are widely varied, and the development of personalized treatment modalities is necessary . To optiBecause this was an exploratory pilot study, its findings are limited. First, we did not assess the cause of chronic pain because the study was done in a psychiatric clinical setting with patients whose chief complaints were not pain. The sample size of MDD patients was relatively small, which limited the statistical analysis and does not allow us to draw conclusive findings. In addition, we did not use multiple test correction to avoid the risk of false negatives: the purpose of this study was to do a wide-ranging analysis of psychological traits as an exploratory pilot study as the basis for future validation studies. Despite the small sample size, we have found useful, statistically significant data. With the psychological trait candidates we were able to identify, follow-up studies with greater sample size will be able to be done to verify our preliminary findings.We found that psychiatric patients with chronic pain tend to have MTD-related psychological traits, notably “complaint to others.” Interestingly, patients with MDD who have chronic pain have a stronger tendency to be motivated by competitive aims than those without chronic pain. Our findings show that a complaining and competitive personality are related to chronic pain and depression, both of which are related to maintaining healthy relationships with others. MTD is known to be related to severe social isolation, hikikomori , 31, andThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was approved by Ethics Committee of Kyushu University, Fukuoka, Japan. The patients/participants provided their written informed consent to participate in this study.TK initially designed the study, oversaw data analysis, participated in data interpretation, and writing of the manuscript. RK participated in study design and statistical analyses. KF conducted the statistical analyses, the literature searches, and wrote the manuscript. MH, TM, and KM participated in data interpretation and writing of the manuscript. TN and NS reviewed the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.This work was partially supported by Grant-in-Aid for Scientific Research on KAKENHI - the Japan Society for the Promotion of Science , The Japan Agency for Medical Research and Development (AMED) , and SENSHIN Medical Research Foundation (to TK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Physical activity (PA) may best be promoted to patients during clinical consultations. Few studies investigated the practice of PA advice given by physicians, especially in China. This study aimed to investigate the prevalence and contents of PA advice given by physicians in China and its association with patients’ characteristics.Face-to-face questionnaire asking the prevalence and contents of PA advice given by physicians was administered to adult patients in three major hospitals in Shenzhen, China. Attitude of compliance, stature, PA level, and socio-demographic information were also collected. Data was analyzed via descriptive statistics and binary logistic regression.n = 87) reported receiving PA advice, whereas 21.8%, 23.0%, 32.2%, and 55.2% of patients received advices on PA frequency, duration, intensity, and type, respectively. Male patients were more likely to receive PA advice from physicians , whereas patients who were unemployed , and who already achieved adequate amount of PA  were less likely to receive PA advice.Of the 454 eligible patients (Age: 47.0 ± 14.4 years), only 19.2% (Prevalence of physicians providing physical activity advice to patients is low, there is a pressing need to take intervention measures to educate healthcare providers.The online version contains supplementary material available at 10.1186/s12889-021-12185-7. Chronic diseases are the leading causes of death worldwide . In 1990Physical activity (PA) reduces the incidence and complications of chronic diseases among adults and offers other multiple health benefits including the prevention and treatment of psychiatric diseases, neurological diseases, pulmonary diseases, diabetes, musculoskeletal disorders, and cancer , 8. In cPhysicians are influential sources of health information . The ExeAlthough PA promotion in clinical settings is effective, only a small number of patients received PA advice from their healthcare providers in western countries. It was reported that only 18.0, 32.8, and 56.0% of patients received PA advice from healthcare providers in Australia, Germany, and United States (U.S.), respectively –18. ReasThe prevalence of PA advice and its associated patients’ characteristics are understudied in Eastern countries like China. Furthermore, only a few studies investigated the contents of PA advice being provided to patients , 21, 22.Adult patients with chronic diseases were recruited from the three largest general hospitals in Shenzhen, China to participate in an in-person survey. These hospitals were selected because of their high patient volume. Patients were interviewed immediately after their visit with the physician, outside the clinic consultation room, in a randomized order.Patients that met the following inclusion criteria were included in the study: 1) ≥18 years of age, 2) presence of chronic disease (i.e diseases that identified by EIM) , 3) who Patients with chronic disease were identified through the following series of questions: “Did you see a physician?” Those who answered “yes” were further asked, “What is your primary purpose for your visit to physicians?” Patients who self-reported having a chronic disease, including heart disease (heart failure), peripheral arterial disease, hypertension, pre-diabetes, type 2 diabetes, blood lipid disorders, osteoarthritis, osteoporosis, rheumatoid arthritis, low back pain, fibromyalgia, asthma, chronic obstructive pulmonary disorder (COPD), cancer , depression or anxiety, chronic kidney or liver disease, inflammatory bowel disease, Parkinson’s disease and Alzheimer’s disease were invited to participate in the study .1-α/2)2p(1-p)]/d2, in which Z1-α/2 is standard normal variate (1.96 were used), p is expected proportion of patients received PA advice , and d is absolute error/precision .By assuming the prevalence of PA advice was 50% (which would require the largest sample size), with a precision/absolute error of 5%, and at type I error of 5%, a total of 385 patients were required as according to the Charan and Biswas formula  for sampWritten informed consent was obtained for all participants. All participation was voluntary and no incentive was involved. Ethical approval for the study was granted by the Survey and Behavioral Research Ethics Committee, the Chinese University of Hong Kong (Reference number. SBRE-20-026). All methods were carried out in accordance with the Declaration of Helsinki.Data were collected between September 2020 and October 2020. A total of 454 patients completed the questionnaire. The questionnaire was developed based on the Anderson’s Behavioral Model of Health Services Use, items from the Behavioral Risk Factors Surveillance System (BRFSS) questionnaire and previously published surveys from Canada and Australia , 26–30. The presence of PA advice was detected by the following question: “Did the physician provide PA advice to you just now?” Those who answered “yes” were then asked about the details of the advice including its frequency , its intensity , its duration  and its type .Patients who received PA advice from their physicians were asked “How likely is it that you will follow the PA advice given by your physician?” Response options included, “I will follow the advice”, “I will not follow their advice”, and “I don’t know”.2), normal weight (18.5 to 22.9 kg/m2), overweight (23.0 to 24.9 kg/m2), and obese (≥25 kg/m2), according to latest relevant World Health Organization (WHO) guideline   . LogistiOut of 670 patients contacted, 187 patients were excluded due to not meeting inclusion criteria, not have sufficient time for completing the questionnaire, or not interested in the survey  was 47.0 ± 14.4 years-old. A majority of respondents were women  and were employed . Those who completed post-secondary education accounted for 47.7% (n = 215) whereas secondary school 32.6% (n = 147). A total of 19.4% (n = 88) and 26.2% (n = 119) of the respondents were classified as overweight and obese, respectively. Furthermore, 18.3% (n = 76) of the respondents met PA guidelines within the last 6 months (Table The mean age of the respondents (n = 87 out of 454). Less than one-fifth of patients received PA advice during physician visits. Among the 87 patients who received PA advice, 50 (57.5%) of them reflected that they would follow the physician’s PA advice, whereas only 8 (9.2%) of them reflected that they wouldn’t follow. The rest  were either “don’t know” or “not sure”  : 0.29; 95% confidence interval (CI): 0.10–0.84], had longer time as a patient , and had adequate PA in the last 6 months  were less likely to receive PA advice from their physicians (n = 8) provided by physicians contained all of the important elements of PA prescription . Although the type of exercise was most frequently specified , most PA advice was missing either frequency, intensity or duration  received comprehensive recommendations in accordance with the WHO aerobic PA and muscle-strengthening PA guidelines Table .Table 4The present study investigated the prevalence of PA advice received by patients with chronic diseases, and key factors associated with the provision of this advice. To address limitations in previous studies, we also report on the content of the PA advice being given by physicians, which, to our knowledge, has not been previously examined in China.healthcare provider advised you to exercise within the past 12 months’ [physicians. It is possible that other healthcare providers  may have provided our patients with PA advice during their hospital visits. Moreover, the low prevalence of giving PA advice may reflect the fact that exercise prescription in clinical setting has not yet receive much attention in China. Unlike the Green Prescription (GRx) project of New Zealand and the National Physical Activity Plan of U.S. [A main finding of our study is that less than one-fifth of the patients (19.2%) reported receiving PA advice from their physician. Among them, only two patients received full-details of PA advice from their physicians. This prevalence of PA advice is lower than that reported in other countries, where a total of 31.0%, 32.8%, and 57.7% of patients reported receiving PA advice in United Kingdom (UK), Germany and U.S., respectively , 36, 37. months’ , 38, 39; of U.S. , 41, whi of U.S. .n = 50/87, Fig. n = 8/87) indicated not willing to follow physician’s PA advice. Such a large gap suggested that physician’s PA advice is a powerful channel to motivate PA participation among patients. Similar to previous ACSM survey reported that 65% of American who visited doctors indicated willingness to follow PA advice [Perhaps one encouraging result from this study, was that nearly 60% of respondents  [The present study revealed that patients who were male were more likely to receive PA advice from their physician. This finding is consistent with previous studies involving adults of different ages , 30, 44. groups) , hence pAssociation between employment status and receiving PA advice was not found in American patients , 21, 48.Lastly, the present study revealed that meeting PA guidelines within the last 6 months was negatively associated with receiving PA advice. This result is consistent with several other studies, that suggest sedentary patients are more likely to receive PA advice , 50, 51.We found that only 9.2% patients reported receiving complete PA advice  from their physicians. The lack of completed PA guidance may suggest that Chinese physicians do not receive sufficient training on exercise prescription. Previous studies suggest that healthcare providers may feel uncomfortable or lack confidence in giving specific rather than general advice , 57. OthFindings from the present study showed that a majority of patients (25.0%) were advised to participate in walking, which is generally consistent with previous studies , 29. ThiThis is the first study to investigate the prevalence of PA advice provision for patients with chronic diseases in China. The receipt of PA advice was captured at the completion of the clinic visit, reducing the risk of recall bias. Furthermore, the individual components of the PA advice were examined in this study, providing a glimpse into the type and quality of PA advice being provided to patients by their physicians.However, there are some limitations with this study that deserve mention. The results of the study are based on self-reported data, which may lead to an overestimation of the prevalence rates of PA advice due to social desirability bias. Additionally, there may be other factors, not captured by this survey, that influence the receipt of PA advice, such as characteristics of the healthcare providers or the self-rated health status of the patients . Only thOnly a small proportion of patients are receiving PA advice and guidance from their physicians in healthcare settings in Shenzhen, China. In patients who received PA advice, frequency, intensity, duration, and type of activity were not commonly provided. Although patients who are most likely to benefit from PA reported receiving advice at a greater rate, there is still much room for improvement . ComprehAdditional file 1. Provision of Physical Activity Advice for Patients with Chronic Diseases. Additional file 1 is the questionnaire that we developed and used for data collection.


IntroductionOne of the major psychological factors that can affect the outcome of hip arthroplasty is postoperative kinesiophobia, which is defined as a fear of movement. The effect of kinesiophobia and excruciating pain has not been widely explored in hip arthroplasty literature especially in Saudi Arabia.AimThis study aimed to investigate kinesiophobia and pain catastrophizing after total hip arthroplasty (THA) in King Fahad Hospital, Hofuf, Saudi Arabia.Materials and methodsThis is a retrospective cross-sectional study conducted at King Fahad Hospital, Hofuf, Saudi Arabia. Using a validated self-administered questionnaire, participants were questioned telephonically. Questionnaires included basic demographic characteristics, Tampa Scale of Kinesiophobia (TSK), and Numerical Analogue Scale (NAS). Data were tabulated in MS Excel and all statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 21 .ResultsSeventy-four patients were recruited . The TSK mean score was 40.7 (SD 8.88) while the mean NAS score was 5.45 (SD 2.79). The prevalence of kinesiophobia was 62.2%. The statistical test revealed that there was a statistically significant positive correlation between TSK score and NAS score . Furthermore, kinesiophobia was widely prevalent among patients who had avascular necrosis (p<0.001) and among those who underwent physiotherapy (p=0.044).ConclusionThere was a high prevalence of kinesiophobia among patients who underwent THA. Pain intensity directly correlated with the presence of kinesophobia. The hip joint is a ball-and-socket type diarthrodial joint that is known for its stability and ability to bear body weight. It influences the body mechanics and plays a major role in the function of the lower extremity. Total hip arthroplasty (THA) is one of the most successful interventions in orthopedics nowadays and has contributed massively to improving patient’s quality of life, morbidity, and mortality. THA has come a long way since its first implantation in the 1950s, including improvements in surgical technique, technology, and postoperative rehabilitation, which all led to increasing the effectiveness and success rate of hip arthroplasty [The outcomes of hip arthroplasty are highly influenced by patient-specific factors, such as sex, age, body stature, and co-morbidities. It is also influenced by patient psychological factors, which can affect their compliance, rehabilitation, and pain perception .in a study of 850 patients who underwent a total hip replacement, it was reported that depression, poor emotional health, and symptomatic osteoarthritis of another joint played a major role in predicting dissatisfaction one year following arthroplasty .Another major psychological factor that can affect the outcome of hip arthroplasty is post-operative kinesiophobia, which is defined as a fear of movement, and physical activity that had resulted in injury or pain in the past. This is an adaptation of the patients in an acutely painful situation. However, once this becomes a habit, patients tend to get into a vicious cycle of avoidance, that can lead to the development of chronic pain and disability affecting functional outcome and return to the previous level of physical activity ,5.The cognitive fear-avoidance model that describes a painful experience is interpreted as threatening or alarming, and it can generate catastrophizing cognitions activity that will result in more pain and re/injury . The patAs far as we found, the effect of kinesiophobia and pain catastrophizing have not been widely explored in hip arthroplasty literature especially in Saudi Arabia. Therefore, we aim to assess kinesiophobia in patients who underwent THA in four to eight weeks post-operatively in the Al-Ahsa region of Saudi Arabia.Study area and data collectionThis is a cross-sectional study that was conducted at King Fahad Hospital Hofuf to investigate kinesiophobia and pain catastrophizing after hip arthroplasty and if it is associated with negative functional outcomes.Following institutional review board approval (20-589E) and IRB registration with OHRP/NIH, USA (IRB00010471), consecutive patients undergoing primary THA for the treatment of avascular necrosis, osteoarthritis, rheumatoid arthritis, and traumatic fracture by a fellowship-trained surgeon were retrospectively enrolled in the study. The survey was via telephone, begin with explaining the aim of the study and taking the consent from all the participants before answering any question. Then, the participants were asked to answer seven socio-demographical questions , and whether physiotherapy was taken).Kinesiophobia was assessed using the Tampa Scale of Kinesiophobia (TSK) which is a therapist administered scale; consists of 17 questions graded by 4 points ranging from “strongly disagree to strongly agree.” The score varies from 17 to 68 and a score of 37 or above is an indicator of the high level of Kinesiophobia. The intensity of post-operative pain will be assessed using the Numerical Analogue Scale (NAS) for pain where 0 is no pain and 10 is the worst pain imaginable.All data were collected by medical graduates who received prior training for this task. The time required to complete the questionnaire was 10 minutes.Patient selectionSeventy-four male and female patients in the age group of 18-75 years who had undergone THA during the study period were included. Patients with any neurological deficit, polytrauma involving the lower extremity, and psychiatric disorders were excluded from this study. No measures of co-morbidity or any specific origin or site of pain were includedStatistical analysisDescriptive statistics were presented using numbers, percentages, means, and standard deviation, whenever appropriate. The prevalence of kinesiophobia was compared with the baseline characteristics of the patients by using Fischer exact test. P-value <0.05 was considered statistically significant while <0.01 was considered highly statistically significant. A correlation procedure was also conducted to determine the linear agreement between the TSK score and the NAS score. All data analyses were carried out using Statistical Packages for Software Sciences (SPSS) version 21 .The prevalence of kinesiophobia was measured using the TSK which is a therapist administered scale consisted of 17 questions graded by 4 points Likert scale ranging from “strongly disagree to strongly agree.” Questions 4, 8, 12, 16 are inversely scored. The score range was from 17 to 68 and a score of 37 or above was considered as kinesiophobia. The intensity of postoperative pain was assessed using the NAS where the participants were asked to mark on a scale of 0-10 where the higher the score the higher the intensity of pain.We analyzed 74 patients to measure the prevalence of kinesiophobia among patients who underwent THA. As described in Table The prevalence of kinesiophobia was shown in Figure Figure Figure When measuring the relationship between kinesiophobia and the baseline characteristics of the patients, it was found that indication of operation showed a significant relationship with kinesiophobia (p<0.001) where the prevalence of avascular necrosis were statistically significantly higher. Similarly, respondents who seek physiotherapy treatment were statistically significantly more of having kinesiophobia (p=0.044). Other baseline characteristics did not show a significant relationship with kinesiophobia , and 37.8% had a score of ≤37 points which consider them as no kinesiophobia. This result is consistent with the paper of Olsson et al. . The stuFurthermore, we also noted that the prevalence of kinesiophobia was significantly more on patients who had been diagnosed with avascular necrosis (p<0.001) and those patients who sought physiotherapy treatment (p=0.044). However, the prevalence of kinesophobia were similar across the socio-demographic characteristics of the patients and that includes age, gender, level of education, BMI level, and occupation. These reports are not consistent with the study of Morri et al. , based oMoreover, the findings of this study will contribute to the current evidence that demonstrates kinesiophobia, along with other psychological factors, can prolong or hinder functional improvement in patients who have undergone hip surgery ,10,12. ILimitations of the studyFirst, strict inclusion and exclusion criteria that were used for the patient selection may have introduced selection bias. Second, no measures of co-morbidity or any specific origin or site of pain were included. Third, multiple factors other than kinesiophobia and pain catastrophizing can affect patient-reported outcomes following hip arthroplasty. Fourth, an a priori power analysis was not performed, so the analysis may be underpowered. Lastly, all of the surgical procedures were performed by a single fellowship-trained surgeon, with extensive experience in hip arthroplasty and the outcomes of this study may not be generalizable.There was a high prevalence of kinesiophobia among patients who underwent THA. Pain intensity directly correlated with the presence of kinesophobia whereas patients who had avascular necrosis and those who underwent physiotherapy were the most affected by kinesophobia. High pain intensity was associated in correlation with kinesiophobia and the result of this study will help the orthopedic surgeon in identifying who is most likely to suffer from high kinesiophobia. The results indicate that potential interventions regarding kinesiophobia should aim to decrease pain intensity. Further researches are needed in order to determine the exact prevalence rate of kinesiophobia in our region.