Community-based care fills an important service gap for patients living with chronic pain. Better understanding of unmet patient needs in the community may inform improved policy and resource allocation.The aim of this study was to describe patients presenting to a community-based, multidisciplinary chronic pain clinic in Vancouver, British Columbia.This is a retrospective cross-sectional study of 935 unique consecutive patients who completed an intake questionnaire between January 2016 and March 2017. All data were patient reported.Nine hundred thirty-five patient records were analyzed for descriptive characteristics. The mean age of the population was 49.5 (SD = 14.9) years; 70% were female. Approximately 50% of patients lived below the poverty line in Vancouver; 30% were not working due to disability, 51% had pain for more than 5 years, and 63% reported severe functional impairment.Substantial unmet need is demonstrated in this patient population accessing a community-based chronic pain clinic. The population described is mainly of working age with significant functional impairment, reflecting a high level of need due to severity and duration of symptoms, poverty, and other characteristics described. For example, an Australian study demonstrated that in a one-year period, emergency department (ED) visits among chronic pain patients were five times greater than for patients with no chronic pain.3 The magnitude of the health and socioeconomic impacts of chronic pain has justified the description of a chronic pain epidemic.4One in five Canadians suffers from chronic non-cancer pain, which is referred to here as chronic pain.9 Contributing to the complexity of presentation and treatment of chronic pain is socioeconomic status (SES). Higher severity of chronic pain is reported by patients with lower SES and in patients experiencing homelessness or with lower household income.11 Research also indicates that patients of lower SES have greater functional impairment compared to patients of higher SES at the same self-reported level of pain intensity.12 Indicators of lower SES, such as applying for disability benefits or lower educational attainment, are also predictors of poorer outcome in multidisciplinary treatment programs.14 Significant or ongoing socioeconomic stressors—such as trauma, ongoing financial hardship, a history of adverse childhood experiences, or pain or injury in childhood—are correlated with increased complexity and worse outcomes.15 The wealth of evidence on the impact of chronic stress and social determinants of health underscores the importance of assessing and describing these characteristics in a population with chronic pain.Previous studies in Canada have described the clinical and social characteristics of patients with chronic pain presenting to tertiary pain clinics as “complex,” with multiple comorbidities and moderate to severe biopsychosocial and functional impairments.16 The gold standard of care for patients with chronic pain is multidisciplinary treatment; these programs are commonly provided in the hospital setting.17 However, access to chronic pain programs in British Columbia is limited due to prohibitive wait lists,18 compounded by the small number of publicly funded programs.19 In British Columbia, income inequality is among the highest in Canada and growing, making noninsured or alternative pain services requiring out-of-pocket expenses unaffordable to many,20 even with private or employer-paid extended benefits.21 Hence, there is critical need for the development of sustainable, publicly funded, community-based chronic pain services to better serve patient needs.There is critical unmet need among chronic pain patients in Canada.In Vancouver, CHANGEpain is a chronic pain clinic attempting to fill this service gap. CHANGEpain is community based, multidisciplinary, and “secondary” level—defined as a short-stay health service provided by medical specialists and requiring referral from a primary care provider. Operating since May 2013 and seeing over 5200 new patients since inception (May 2013–March 2018), the clinic was developed to provide comprehensive treatment services to patients suffering from chronic pain, given the inaccessible alternative of hospital-based programs as described above.For the treatment of chronic pain in British Columbia, public funding through the Medical Services Plan is only available for physician services; other multidisciplinary non–Medical Services Plan treatment options require private payment or extended care coverage. CHANGEpain thus employs a step-by-step approach that includes publicly funded consultations, interventional procedures, group medical visits, and medication management; services insured through extended benefits such as movement therapies and nutrition consultations; and private-pay, uninsured services such as self-management and education programs, advanced pain procedures, and infusion therapies.This study is the product of practice-based research integrated into clinic workflow that seeks to describe the characteristics and unmet needs of patients referred to this unique community-based clinic that aims to serve patients with insufficient access to care.14 of patients attending this clinic is a first step in identifying unmet needs of patients with chronic pain in the Greater Vancouver area of British Columbia. In addition, describing a community-based population of patients with chronic pain can inform efforts to improve quality of care within the clinic and may inform the development of appropriate financially sustainable pain services to meet the needs of these patients.We believe that describing characteristics, including SES,The primary objective of this study is therefore to describe the patient population referred to a secondary-level, community-based, multidisciplinary chronic pain clinic based in Vancouver, British Columbia, with a focus on socioeconomic characteristics.All patients included in this study were first-time consecutive patients referred by their primary care provider to the clinic who completed an intake questionnaire between January 2016 and March 2017 as part of the standard intake process.Patients were excluded if they were under an active WorkSafeBC claim or were seen at the clinic solely for an independent medical examination. Intake questionnaires were also excluded from the analysis if they were completed in less than 4 minutes. This cutoff point was determined through an audit of a sample of incomplete questionnaires, which represented duplicates or patients who were not eligible to attend the clinic and also represented patients who only filled out basic contact information and confirmation of treatment eligibility. This early cutoff point does not guarantee that records included were not duplicates; however, we believe that it eliminated a significant portion of duplicates and patients who never attended the clinic. It also allowed all questionnaires with any relevant demographic data to be included in the sample, while eliminating the need for further, technically difficult matching of incomplete intake questionnaires with patient records to determine individual record eligibility for the study.22 Specifically, this study was minimal risk and did not involve intervention but rather secondary use of clinical data, which prohibits obtaining consent retrospectively; finally, the lack of consent is unlikely to have adverse effects on patients and such a study may improve patient care received at the clinic. The study was fully compliant with the consent process outlined by the Tri-Council Policy Statement and the University of British Columbia Clinical Ethics Review Board policy.This study received prior approval by the University of British Columbia’s Clinical Research Ethics Board. Informed consent to use retrospective anonymized data was not required as outlined in TCPS 2 article 3.7A.This is an observational, retrospective, cross-sectional study conducted at a secondary-level, community-based, multidisciplinary chronic pain clinic in Vancouver.n = 379), and on Ocean from June 29, 2016, to March 31, 2017 (n = 556). The upgrade to Ocean was completed due to its ability to securely link intake questionnaire data with the electronic medical record (EMR) (SYNC data) so that patient-reported data could be more readily used in the clinic visit and the practice population data could be more easily analyzed. The second questionnaire (the SYNC survey) includes pain-related baseline outcome measures and is completed by patients on in-clinic computers at the time of their first appointment; data are stored in the clinic EMR system. We were able to extract and analyze these data after switching to the Ocean platform described above  were those that were blank, duplicates (n = 155), or completed in less than 4 minutes  reported pain for more than 5 years before starting treatment at the clinic . At the Past medical, surgical, and injury data revealed that the majority of patients (60.8%) reported a past or current medical condition (most common were hypertension and inflammatory/irritable bowel disease/syndrome), previous surgery , and previous injury  data indicated that the majority (84.3%) of patients had moderate to severe pain intensity (4–10/10).23 PHQ-9 (n = 374/414) data indicated that three in five patients (59.9%) reported symptoms indicative of moderate to severe clinical depression (10–27/27).24 BPI (n = 371/414) results demonstrated that two thirds (63%) of patients experienced severe functional disability  PSEQ (/60) was 29.2 (13.56), greater than a score of 25/60 seen in a sample of 4645 chronic pain patients.26 Mean (SD) PRSS-ACT (/5) was 2.80 (0.93) greater than a score of 2.7/5 seen in a sample of 3713 chronic pain patients.26 Mean (SD) PRSS-CAT (/5) was 2.61 (1.15), less than a score of 2.7/5 seen in a sample of 4051 chronic pain patients  reported severe functional impairment due to pain (defined as BPI > 42/70). Additionally, 54% of patients reported not having a person to help them get to a doctor regularly, which may indicate further barriers in accessing care.Patients referred to multidisciplinary pain clinics carry a significant burden of disability and psychosocial consequences due to pain,31 Given that the majority (60%) of our patients met criteria for moderate to severe depression, there is great need to provide targeted and timely therapies for both depression and pain.32Experiences of chronic pain often include increased emotional distress and impaired emotional processing that may also influence the outcome of pain therapies.Patients presenting to this secondary clinic reported high levels of pain severity, with 84.3% of patients suffering moderate to severe chronic pain, 50.7% of patients having pain of five or more years in duration at the time of consultation, and 11.9% reporting pain since childhood. Most patients already tried alternative care options at the time of referral; 96% tried one or more physical therapy modalities . The majority (65%) also reported reliance on episodic urgent care including the ED and walk-in clinics. At the first consultation, 73.4% of patients were managing pain with medications and 33.5% were using opioids.33 We believe that the high level of medication reliance, high levels of disability affecting a working-age population, and financial barriers identified by this patient population are a further call for appropriately funded and timely multidimensional solutions. Furthermore, services that treat chronic pain problems earlier and more effectively35 may prevent long-term biopsychosocial complications.35CHANGEpain aims to reduce reliance on medications by providing nonpharmacological, multidisciplinary treatment alternatives. A priority action in the context of the opioid crisis is developing solutions that reduce reliance on opioids to treat pain.36 Limitations listed below reflect challenges in our resource-limited setting, with improvements and mitigating factors described.In summary, this clinic was developed to address neglected needs of patients in the community suffering from chronic pain. Initially, both demographic data and pain-related outcomes were collected to inform clinical practice. Software and database capabilities at the clinic allowed us to study trends in patient characteristics and outcomes, and a small practice-based research team was established to analyze data and improve clinic procedures to meet both clinical and research needs. Challenges faced in this study outlined below  led to subsequent improvements that led to improved data quality without affecting clinical workflow. We hope that this process example encourages other clinicians to develop, study, and share practice-based data to contribute to a growing knowledge base of community-based pain services.n = 414) was lower than the sample for sociodemographic data collected in the intake questionnaire (n = 935), because unlinked SYNC survey data could not be extracted for the analysis. The exclusion of 283 records (A primary limitation in this study was the inability to link SYNC survey data (stored in the EMR) to intake questionnaire data until midway into the data period when codes were written with the new survey platform, Ocean, to reliably and securely integrate these surveys. Due to this limitation, our sample size for pain-related, patient-reported outcome measures , it is unlikely that excluded surveys were representative of the practice population, because a sample audit of incomplete Fluidsurveys questionnaires identified that excluded surveys were from patients who met our exclusion criteria or those unable to attend a first consultation. Analysis of intake data through Ocean software confirmed that all patients who attended a first appointment had a completed intake questionnaire, likely due to the success of software reminders and clinic procedures that supported patients to complete the Ocean intake questionnaire at home or in clinic if unable to do so. However, for unknown reasons (reported by software as a “random error”), only 414 SYNC charts were extractable through Ocean. This may be due to software error or missing or corrupted files.As a cross-sectional study, no causality may be inferred. Some patients did not complete one or both questionnaires, which may indicate a selection bias toward patients who were literate, fluent in English, and able to spend the necessary time to complete the questionnaires. However, this was mitigated by clinic volunteers who were intermittently available to help patients complete the questionnaires in person if incomplete or if they were unable to complete it at home. For incomplete intake questionnaires hosted on Fluidsurveys  a median (interquartile range) of 14.4 (4.3–36.6) days prior to the first appointment. This was important for clinic workflow to ensure that the data were available to the clinician by the time of first appointment. Some patient characteristics may have changed within this time interval, however, given that half of our patient population had pain for 5 years or more and that the content of the early survey was on less time-sensitive content, we believe that the data appropriately represent patients’ conditions and circumstances at the time of intake, prior to treatment at the clinic.Some questions were more prone to being answered incorrectly due to use of unknown or technical language  or ambiguity . However, the likelihood of misclassification error was primarily a concern with more complex questions pertaining to past medical and surgical history that we excluded from our analysis; thus, we do not believe that this has a substantial impact on our findings. Items with poor response rates or lack of relevance were excluded from the study; this included, for example, self-reported susceptibility to infection, pregnancy, Internet access, needle phobia, and patient goals.37 any self-reported data are vulnerable to recall bias. This is particularly relevant in self-reported past experiences and medications; thus, we do not draw substantial conclusions from these results and will use the data to inform further research and more robust future data collection. Notably, a previous study found that patients with chronic widespread pain recall much of their past experiences as attributed to their pain experience, especially childhood experiences.38 Secondly, it has been shown that patient recall of medications usually underreports what is listed in the pharmacy database39; we recommend linkage with Pharmanet data for future research.Although patient self-reported data are increasingly recognized as valuable in practice-based research,This secondary-level, community based, multidisciplinary pain clinic fills an important service gap in the community for patients with complex chronic pain who have tried other options, including tertiary pain clinics, yet present with persistent unmet medical need due to ongoing severe pain and disability. Financial stress is prevalent in our practice population; thus, appropriate interventions for chronic pain should also address socioeconomic barriers to facilitate equitable access to gold standard, evidence-informed, multidimensional pain care. Future research should focus on outcomes of pain therapies to meet the unique needs of different groups of patients with chronic pain.


Pictorial Representation of Illness and Self Measure (PRISM) is a tool that can be used to visualize and evaluate the burden of suffering caused by an illness. The aim of this study was to identify which aspects of the burden of chronic pain patients are associated with Self/illness separation (SIS), an indicator of the magnitude of suffering. We also examined the effectiveness of PRISM for evaluating changes in the relationships between patients and their medical care and significant others due to our inpatient treatment.Seventy-two patients with chronic pain who were outpatients or admitted to the Department of Psychosomatic Medicine completed PRISM, depression and anxiety scales, and three types of pain-related self-assessment questionnaires . Outpatients were queried at the time of outpatient visits and inpatients at the time of admission. In addition to PRISM disks related to illness, we asked each patient to place disks related to things important to them and their medical care. Of the inpatients, 31 did PRISM at the time of discharge. Among the reported important factors, which significant other was placed at the time of admission and discharge was evaluated. The distances of self/medical care separation (SMcS) and self/significant others separation (SSoS) were measured.Of the 21 scales measured, 10 showed a significant correlation with SIS. Factor analysis of these 10 scales extracted three factors, Life interferences, Negative affects, and Pain intensity. The SMcS and SSoS distances were shorter at discharge than at admission.PRISM for patients with chronic pain is an integrated evaluation method that reflects three aspects of pain. By adding medical care and significant others to the usual method of placing only illness on the sheet it became possible to assess changes in the quality of interpersonal relationships. Chronic pain is a disease that causes great damage to a patient’s mental and physical health. The prevalence of chronic pain has been reported to be 22.5 to 40% of all adults –4. It isThe pain experience is a complex product of various experiences. Not only the pain intensity, but also the negative emotional experience caused by it, the catastrophic cognition of pain, and the disabilities due to the pain that are experienced at the same time. Therefore, multidimensional evaluation of the effect of treatment for patients with chronic pain is recommended. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)  listed sIn routine clinical practice, it can be difficult for patients suffering from pain to fill out long questionnaires. Depending on the patient’s readiness, it may be difficult to assess the psychological aspects of their disease. An example is the orthopedic field. It deals with common physical illnesses such as low back pain and knee pain, but such patients are often reluctant to have psychological evaluations. Therefore, a simple evaluation method that can be tolerated by and provide a clear picture of the patient is required. The visual analogue scale and face scale of pain are well known, simple pain evaluation methods, but they do not include scales for the deterioration of quality of life (QOL) or psychological function and are not multidimensional, but evaluate only one aspect of pain.Furthermore, pain is a subjective experience and the patient’s suffering is noteworthy. The Pictorial Representation of Illness and Self Measure (PRISM) has been reported from the viewpoint of evaluating the suffering of patients with chronic diseases , 8, and Based on these considerations, the current study investigated the possibility that PRISM can be used as an integrative measure for patients with chronic pain. We hypothesized that various pain outcomes, including pain intensity, physical functioning, and emotional functioning, would contribute the SIS of the PRISM in patients with chronic pain.PRISM can also reflect the quality of relationships with others . We measThe first aim of this study is to clarify which factors contribute to the SIS of PRISM in patients with chronic pain. The second aim is to examine if PRISM enables longitudinal assessment of the patient when inpatient treatment is given.The participants were recruited from inpatients and outpatients treated for chronic pain in the Department of Psychosomatic Medicine, Kyushu University Hospital. Eligibility criteria included: 1) a three month or more history of pain; 2) an ability to read and write Japanese; 3) being 20 years old or older; and 4) a willingness to participate in the study. Exclusion criteria included: 1) the presence of psychotic symptoms; 2) an inability to read due to visual impairment; and 3) lack of consent for study participation. All patients, both inpatient and outpatient, who met the criteria were invited to participate, and all accepted.Data collection was done between November 2005 and January 2011. Outpatients were asked to complete the pain related measures and did PRISM while waiting for their consultation. Inpatients completed the measures and PRISM within 10 days after admission, then again within 10 days before discharge. This study was done with the approval of the Kyushu University Institutional Review Board for Clinical Research.Participants were shown a white A4-size paper with a yellow disk 7 cm in diameter at the bottom right-hand corner Fig. . Each paFinally, the evaluator instructed the participants to think about how they feel about their current medical care, select one of the colored disks, and place it on the sheet. After completing the PRISM task, patients were asked why they had placed the medical care and significant other disks where they were. The distance between the “self” and “illness” disks (ie SIS) was measured from the center of the “self” disk to the center of the “illness” disk. Similarly, the distance between the disk representing their self and the significant other (Self/Significant others Separation: SSoS) and the distance between those representing their self and their medical care  was measured. The possible range was 0 to 27 cm. Participants did this task on admission and discharge. The PRISM evaluator identified the highest valued person and the order of priority, as follows: (1) most important person at present, (2) current spouse or partner, (3) mother, father, or both, (4) children, (5) siblings, (6) family (including multiple members).The level of depression was evaluated by the Center for Epidemiologic Studies Depression scale (CES-D) , 14. ThiA Japanese version of the Brief Pain Inventory  was usedThe SF-MPQ is used to assess the sensory and affective dimensions of pain experience . It consThe PCS consists of thirteen items referring to thoughts and feelings that a person may have when experiencing pain . ParticiN = 18, 40.9%) who were judged to have established a relationship of trust. The point of discharge is when we can better understand the psychopathology of the patient.We provide general medications, such as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), anticonvulsants, antidepressants, anxiolytics, and hypnotics, to treat the pain of patients with chronic pain from the time of outpatient treatment Fig. . When a Statistical analysis was done with SPSS ver.14.0 J for Windows . We first computed Pearson’s correlation coefficients between SIS and the pain related scales. Factor analysis was done to identify the latent factors present in the variables that were significant in the bivariate correlation. At the same time, factor scores were computed through the factor analysis. Pearson’s correlation coefficients were computed for the SIS and factor scores in order to specify factors correlated with SIS. Changes in PRISM-KV variables  from admission to discharge were analyzed by Wilcoxon signed rank test. The frequency of positive and negative SIS differences between discharge and admission was tested by chi-square test. The relation between ΔSMcS and ΔSSoS (difference between admission and discharge) was analyzed by calculating the Spearman’s rank correlation coefficient.One hundred and twelve patients were admitted for treatment in our section specializing in pain within the Department of Psychosomatic Medicine, of whom 59 met the inclusion criteria. Forty-four of them (74.6%) completed PRISM-KV and the other pain-related questionnaires. Of the 44, 31 (70.5%) completed PRISM-KV at both admission and discharge. Of the outpatients, 28 who met the criteria were asked to cooperate in the research, and valid data were obtained from all 28  identified 10 subscales that had a significant relation to SIS Table . Three fThe first factor that had high factor loadings included the work-related interference items BPI and interference with relations with others. We designated this factor “Life interference”. The second factor that had high factor loading included the trait anxiety and state anxiety subscales of STAI and CES-D, respectively. We designated this factor “Negative affects”. The third factor that had high factor loading was the worst pain and current pain items of BPI. We designated this factor “Pain intensity”.P < .01) for Life interferences and SIS, −.420 (P < .01) for negative affects and SIS, and − .392 (P < .01) for Pain intensity and SIS.Pearson’s correlation coefficients were calculated for the SIS and factor scores computed in the process of factor analysis Table . The corThe PRISM evaluator identified eleven spouses, seven parent(s), seven family members, three children, one sibling, and one boss as significant others. Only one patient did not place the same significant other in both PRISMs. Comparison of the PRISM-KV variables at admission and discharge showed statistically significant changes in SMcS and SSoS Table . Both weThe same was true for SSoS, with it becoming shorter at discharge than at admission, when the importance of significant others was reported by the participant to be greater. There were no significant changes in SIS.n = 17) or negative (n = 11). Zero (n = 2) was invalidated and excluded. When the encoded data was analyzed with Chi square testing, the frequency bias was not significant (χ2(1) = 1.29, p = 0.26).The difference between the SIS values at admission and discharge was calculated (discharge minus admission) and encoded as positive (p = 0.440). Furthermore, the amount of change was encoded as positive or negative to investigate if the SSoS of the participants whose SMcS was shortened was also shortened. Two participants with zero change were excluded. SMcS was shortened for 24 of the 28 participants, of whom 19 had shortened SSoS.No significant correlation of variables at admission and discharge was found between ΔSMcS and ΔSSoS  after treatment than before treatment. Kassardjian et al.  showed tWe previously reported that patients with chronic pain admitted to the Department of Psychosomatic Medicine had perceived lower care, higher overprotection, and affectionless control-type care from their parents at an early age than did a painless control group . It has This study did not show significant change in the correlation of SIS with inpatient treatment. Previous longitudinal studies of PRISM report a sensitive response of SIS to treatment , 27–29. The tertiary medical facility inpatient management of the patients of this study focused on psychosomatic assessment and the establishment of a therapeutic relationship, which may be the reason there was little change in pain suffering. To our knowledge, no longitudinal study of SIS in chronic pain has yet been done. Further investigation is needed to determine if successful psychosomatic interventions can change the SIS in chronic pain patients.This study has the following limitations. First, there were only 72 participants, and only for 31 of them were we able to examine the effectiveness of treatment. There may be some selection bias because not all subjects could be included in the analysis. To generalize the results, it will be necessary to compare the change from before to after treatment for all consecutive participants. Second, a more detailed understanding of the properties of medical care and significant others when taken up as PRISM variables is needed. The selection of significant others was made by the PRISM evaluator, but it would be better if the patients were to do it themselves. Strategic examinations are needed on what factors are involved in the change of the distance of SSoS on PRISM, such as support for treatment and a change of partner. Third, we only applied qualitative analysis to determine the relationship with the medical care staff or significant others. Further investigation using a questionnaire on the relationship directly with various members of the medical care staff or significant others is needed to clarify that the distance actually reflects interpersonal relationships.Despite these limitations, we found our evaluation method based on PRISM to be useful in the evaluation of the suffering of patients with chronic pain. Our investigation sheds light on the possibility that this modified PRISM can be used to assess the improvement of patient-therapist and patient-significant other relationships in response to supportive and empathic psychotherapy.PRISM for patients with chronic pain is an integrated evaluation method that reflects three aspects of pain: “Life interference”, “Negative effects”, and “Pain intensity”. By placing medical care and significant others discs in addition to the usual method of placing an illness disc on the sheet, it was possible to assess change in the quality of interpersonal relationships, which is an important factor in the pathology of patients with chronic pain.


In non-small cell lung cancer (NSCLC) patients treated by immune checkpoint inhibitors (ICIs), tumor mutation burden (TMB) has been found to have predictive potential for survival. When compared to TMB detection in tissue (tTMB), detecting TMB in the blood (bTMB) has practical advantages; yet, the results of various studies are conflicting. The question of whether bTMB can be utilized as a predictive biomarker is becoming increasingly contentious. To confirm the predictive efficacy of bTMB, researchers did a systematic review and meta-analysis to look into the relationship between ICIs and bTMB.From the inception to March 2021, Cochrane Library, PubMed, EMBASE and other databases were systematically searched. The predictive value of bTMB in ICIs, or the efficacy of ICIs against chemotherapy, was studied. The results were presented as pooled ratio rate (RR) and hazard ratio (HR) with 95% confidence intervals for the Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Subgroup analysis, heterogeneity analyses, and sensitivity analysis were also performed.P = 0.774) or PFS  between high and low bTMB groups in the ICIs cohort. When ICIs were compared to chemotherapy, ICIs were found to enhance OS , but the improvement in PFS and ORR was only a numerical trend . NSCLC patients treated with ICIs in the high bTMB group had better survival benefits than chemotherapy patients in terms of OS , PFS , and ORR , while in the low TMB group, the results were no different or even reversed .A total of 2,610 NSCLC patients were studied in seven trials. There were no significant differences in OS (HR = 1.09; 95% CI: 0.62–1.91, TMB could predict the enhanced survival benefit of NSCLC patients treated with ICIs; however the role of bTMB is limited at this stage. For NSCLC patients with high TMB, ICIc may be a better option than chemotherapy. Immunotherapy has attracted increasing attention from clinical oncologists in recent years as a revolutionary therapy, particularly with immune checkpoint inhibitors as a successful representative. Immune checkpoint inhibitors (ICIs) that target programmed cell death-1 (PD-1) or its ligand (PD-L1) as monotherapy or in combination with anticytotoxic T-lymphocyte-associated antigen-4 therapy have been shown to be more effective than standard therapies in several cancers, particularly non-small cell lung cancer (NSCLC) . AlthougSeveral biomarkers, including but not limited to the status of microsatellite instability (MSI)/DNA mismatch repair (MMR) and PD-L1 expression, have been reported to predict ICI efficacy in multiple malignancies. Currently, the Food and Drug Administration (FDA) has approved the two biomarkers as predictive biomarkers for immunotherapy in certain cancers –11. The In summary, we conducted a systematic review and meta-analysis to assess the value of bTMB in order to better understand the predictive efficacy of bTMB on ICI therapy in patients with NSCLC.A comprehensive systematic review and meta-analysis were carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline . PubMed,To identify eligible studies, the following inclusion criteria were used: 1) patients with NSCLC who accepted ICIs treatment; 2) TMB is precisely defined, and the sample used to test TMB must be blood; 3) at last one or more main evaluation indicators were available comparing low bTMB against high bTMB in ICIs cohort group or comparing ICIs treatment and chemotherapy (any kind of chemotherapy); 4) the hazard ratio (HR) with 95 percent confidence interval (CI) of OS and PFS, as well as the relative risk (RR) of ORR, could be obtained directly; and 5) only recent studies were chosen when authors from the same institution published multiple articles.Due to a lack of information, reviews, guidelines, letters, expert opinion, comments, meeting abstracts, animal studies and so on were excluded.Two investigators (NZ and XY) independently reviewed the included studies and extracted the following data: the surname of the first author, publication year, type of study, sample size, study design, country of origin, drugs, line of therapy, bTMB cutoff value, and the main reporting outcomes. HR and 95% CI for OS and/or PFS or RR for ORR were extracted for pooled analysis. The two investigators (NZ and XY) then independently examined all of the data. Any disagreements were discussed with another author (XH) and resolved. The Newcastle–Ottawa Scale (NOS) recommended by the Cochrane Non-Randomized Studies Methods Working Group  and CochZ-test was used to determine the statistical significance of the pooled HR and RR. If P <0.05, the results are considered statistically significant. The Q test and 2I value, which is a quantitative measure of inconsistency across studies, were used to assess study heterogeneity. The fixed effect model (Mantel–Haenszel method) was used if P <0.10 in the Q test or 2I was <50% , a random-effects model was used. Three studies . The pooled HR was 0.73  as seen in the forest plot  and progression-free survival (PFS) were compared between low TMB and high TMB patients. Only three of the seven studies involved in the bTMB assay , 28, 35  studies  with a tP = 0.006; 2I = 71.2%, random-effects). Subgroup analysis revealed that patients with high bTMB improved more than patients with low bTMB  (P = 0.173), with significant heterogeneity . However, subgroup analysis revealed that patients with high bTMB could benefit more from ICIs than chemotherapy , but not patients with low bTMB  (P = 0.372), patients with high bTMB responded better to ICIs than chemotherapy . Patients with low bTMB, on the other hand, responded better to chemotherapy than ICIs, and the difference was significant   with multiple sets of data to evaluate the PFS, ORR, and OS. The pooled outcome for OS suggested that ICIs therapy can significantly improve long-term survival status of NSCLC patients when compared to chemotherapy  has been repeatedly demonstrated as a predictive biomarker , 49, desIn 2016, the open-label, randomized, phase III KEYNOTE-024 trial found that pembrolizumab was more effective than platinum-based chemotherapy in NSCLC patients with high levels of PD-L1 expression [tumor proportion score (TPS) of 50% or higher] . On the TMB is a feasible and reliable predictive biomarker for identifying NSCLC patients who are candidates for ICIs therapy. Although bTMB has the potential to predict, its role at this stage is limited. More prospective data is required. ICIs may be a better option than chemotherapy for NSCLC patients with high TMB.The original datasets presented in the study are included in the article/supplementary material. Further inquiry can be directed to the corresponding author.NZ helped to conceptualize and design the work. NZ and JZ helped to write the draft manuscript. NZ, XY, and XH helped with the literature search and data collection. XH, YM, and GW helped with data analysis and interpretation. NZ and JZ contributed to the supervision and critical revision of the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.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.


The EMPOWER protocol requires an efficient process for ensuring that collaborative opioid tapering would be offered to the most appropriate patients while identifying patients who should be offered alternate treatment pathways. As a first step, clinicians need a screening tool to identify patients with Opioid Use Disorder (OUD) and to assess for OUD severity. Because such a tool is not available, the study team composed of eight chronic pain and/or addiction experts has extended a validated screening instrument to develop a brief and novel consensus screening tool to identify OUD and assess for OUD severity for treatment stratification. Our screening tool has the potential to assist busy outpatient clinicians to assess OUD among patients receiving long-term opioid therapy for chronic pain.Growing concerns about the safety of long-term opioid therapy and its uncertain efficacy for non-cancer pain have led to relatively rapid opioid deprescribing in chronic pain patients who have been taking opioid for years. To date, empirically supported processes for safe and effective opioid tapering are lacking. Opioid tapering programs have shown high rates of dropouts and increases in patient distress and suicidal ideation. Therefore, safe strategies for opioid deprescribing that are more likely to succeed are urgently needed. In response to this demand, the EMPOWER study has been launched to examine the effectiveness of behavioral medicine strategies within the context of patient-centered opioid tapering in outpatient settings ( Additionally, we will examine data for patients who are screened as having no or mild OUD severity using our two-step protocol and will characterize their opioid taper and pain reduction outcomes.In the absence of existing validated methods, we provide our consensus screening protocol in response to the urgent societal need for such tools so that (a) clinicians may offer appropriate treatments to a heterogeneous patient population receiving long-term opioid therapy for chronic pain , Step 3,Achieving optimal results for prescription opioid tapering requires careful assessment of patients and their opioid-taking behaviors because such assessment ensures that effective individualized opioid tapering or opioid addiction treatments are delivered to patients according to their individual needs. The EMPOWER study team found a gap in existing approaches for practical, individualized opioid deprescribing due to the lack of a brief tool to identify OUD and stratify severity for patients with chronic pain receiving long-term opioid therapy. Our study team has developed a streamlined consensus protocol to identify OUD and assess for OUD severity for clinical and research use.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.DY: conceptualization, writing—original draft, review, and editing. AM: conceptualization, methodology, writing—original draft, and review and editing. BD: conceptualization, methodology, writing—review and editing, and project administration. C-YC, KD, PF, AK, JM, JP, RPS, and RLS: conceptualization, methodology, writing—review and editing. M-CK: conceptualization and methodology. SM: conceptualization, methodology, writing—review and editing, project administration, and supervision. All authors: contributed to the article and approved the submitted version.RPS reports serving as a consultant to Verily Life Sciences, Ltd. The remaining 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.


Background: The definition of dental hypersensitivity is “pain derived from exposed dentin in response to chemical, thermal tactile or osmotic stimuli which cannot be explained as arising from any other dental defect or disease”. One of the treatments proposed is tubular occlusion. The aim of this in vivo split-mouth randomized clinical trial was to evaluate the clinical efficacy of a in-office application of a fluoride varnish (Bifluorid 10) and a bonding resin (Futurabond U) in adults with dentin hypersensitivity. Material and methods: A total of 180 teeth were treated with Bifluorid 10 and 160 with Futurabond U. Outcome measurements were taken one or two weeks before treatment, at baseline at the application days, at 1 week and at 1–6 months after first treatment. Results: Both treatments reduced pain intensity. Bifluorid 10 and Futurabond U have similar efficacy in reducing SCHIFF-measured pain reduction, while Bifluorid 10 is significantly more efficient for VAS-measured pain reduction, mainly due to long-term pain reduction. Patient age has a significant negative influence on pain reduction, while the influence of patient gender and BEWE of the tooth is insignificant. Conclusions: Bifluorid 10 and Futurabond U are effective in the treatment of dental hypersensitivity. The RCT was registered at the US National Institutes of Health  #NCT04813848. The definition of dental hypersensitivity is “pain derived from exposed dentin in response to chemical, thermal tactile or osmotic stimuli which cannot be explained as arising from any other dental defect or disease” . DespiteNo specific pathogenesis has been assigned to dental hypersensitivity from nerve fiber conduction, dentine fiber conduction, dentine tubule lymphatic conduction; however, most of the studies gave support to Brannstrom’s hydrodynamic theory ,8,9. In Hypersensitivity is a problem which makes everyday existence difficult. It lowers general wellbeing, influences food choices, social life and even the patient’s overall self-esteem . For thiboth VOCO, Cuxhaven, Niedersachsen, Germany) on long-term pain reduction and the secondary aim was to evaluate possible personal factors that can influence the effectiveness of the therapy.The primary aim of the present study was to compare the effectiveness of two products for in-office use  and all patients have signed an informed consent. All the procedures were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The experimentation followed CONSORT guideline and was registered at the US National Institutes of Health  #NCT04813848.(a)Inclusion criteriaThe inclusion criteria was healthy adults, aged ≥ 18, with ≥1 sensitive tooth and with exposed dentin in the upper or lower dental arches. The presence of an equivalent contralateral tooth for comparison to the examined tooth with exposed dentin was mandatory to include a patient in this study. Schiff sensitivity score needed to be ≥2, indicating that application of a jet of air makes the patient respond and move or requests discontinuation of the stimuli application.(b)Exclusion criteria-domestic or in-office fluoride application and bleaching 6 months before beginning of treatment;-long-term use of anti-inflammatory, analgesic and psychotropic drugs;-allergies to product ingredients;-eating disorders, systemic conditions that cause or predispose patients to develop dentin hypersensitivity ;-excessive dietary or environmental exposure to acids (vegan or vegetarian or diet with daily use of fruit and vegetable smoothies/extracts);-orthodontic appliance treatment within the previous three months;-periodontal surgery within the previous three months before the study.Sample size calculation was performed for 2-paired means with a 1:1 allocation ratio, assuming normality, for a 2-sided test with a split-mouth design. The present study was a paired observation case, with the participant serving as control, since both intervention and comparison treatments are applied in the same patient. This design is efficient, since the sites that receive interventions are similar, thus reducing variance and sample-size requirements. The following formula was applied n = f*\sigma^2/(differenza^2)), where \sigma was the standard deviation of the within-person differences and f was a function of power and significance level. In the present study, detecting a clinically significant difference of 0.53 units following treatment as measured on the Schiff sensitivity scale, with a standard deviation of 1.06 units, requires a sample of 30 subjects, each with two different treatment methods. Considering a dropout rate of 10%, a total of 40 subjects will be enrolled.A split-mouth design was performed: the two treatments were randomly allocated on the left and right side of the dental arches. Whenever possible, the operator selected study teeth in both the maxillary and mandibular dental arches of each subject. The allocation was done on the basis of the year of birth date: the even numbers started with the left side , while the odd numbers started with the application of the varnish on the right side. In both cases, the bonding resin was applied on the opposite dental arch.Blinding of patients, data collectors and outcome adjudicators were achieved.-Two different desensitizers were used: Bifluorid 10 (VOCO GmbH) and Futurabond U (VOCO GmbH). The desensitizers were applied by one dentist (MM) experienced in conservative and preventive dentistry and in epidemiologic surveys.-Bifluorid 10 is a single dose transparent, colophony-free varnish with 5% sodium fluoride (22.600 ppm fluoride) and 5% calcium fluoride.-The application was performed according to the manufacturer’s instructions. The varnish was applied on a clean and dry surface, then left for 10–20 s to allow the fluoride varnish to be absorbed, then it was dried with air. Patients were instructed not to brush their teeth for the next 12–24 h. In this study, the application was repeated 3 times at intervals of 7 days according to the manufacturer’s instruction. Repeated applications should only involve drying of surfaces and reapplication of the varnish.-Futurabond U is a single dose dual curing universal adhesive. Futurabond U application was performed according to the manufacturer’s instruction for cases with hypersensitive tooth necks. The bonding was applied without etching, on a clean and dry surface. After 10 s, any excess material was removed and then light cured for 30 s.The domestic oral care of the participants was standardized: the same toothpaste, toothbrush and interproximal cleaner were delivered to all the subjects. Patients received instructions concerning domestic oral hygiene procedures based on the tailored brushing method (TBM) .Basic erosive wear examination index (BEWE), Schiff sensitivity scale and Vas scale were assessed on the vestibular surfaces of incisors, cuspids and bicuspids with accessible cervical regions.(0)no surface loss;(1)initial loss of surface texture;(2)distinct defect, hard tissue loss less than 50% of the surface area;(3)hard tissue loss in more than 50% of the surface area.Basic erosive wear examination (BEWE) is a tool for screening for erosive tooth wear and recording clinical findings and assisting in the decision making process as a guide for management. It is a four-level score that grades severity of erosive wear:Buccal/facial, occlusal and lingual/palatal surfaces were examined in sextants  and the highest score was recorded (maximum sum score = 18). From the sum score, four categories were defined; the first two categories required monitoring and general advice, whereas the two latter comprised complex strategies until the maximum approach, including restorative measures .The Schiff sensitivity scale was used to assess dentin hypersensitivity. A score of 0, 1, 2 or 3 was assigned by the participant. A score of 0 = no subject response to stimulus; 1 = subject response but will continue; 2 = subject responds and moves or requests discontinuation; 3 = painful response to stimulus, discontinuation requested. The lower the score, the lower the hypersensitivity. Air-blast stimulus was used: the response to a jet of cold air was rated by the examiner .VAS scale Magnitude estimation requires subjects to indicate the level of pain experienced along a continuum represented by a visual analog scale (VAS). At each evaluation, subjects recorded the sensitivity of each tooth to timed (5 s) applications of compressed air  and a cold stimulus (ice stick contacting the tooth surface) on the VAS . Primary outcome in pain/sensitivity changes was assessed by the patient on application of cold and air-blast stimuli. Magnitude estimation required subjects to indicate the level of pain experienced along a continuum represented by VAS and according to the Schiff sensitivity scale. The outcome measurements were assessed and collected by another experienced dentist with skills in conservative and preventive dentistry (AN).The study period was 6 months. Patients were treated at baseline (T0) and at 7 days (T1), 1 month (T2), 2 months (T3) and 6 months (T4). Clinical variables were recorded at the enrollment, at baseline and at all times of follow-up.p < 0.05. The efficacy of treatment in both groups and between-group differences was assessed using Student’s t-test. Regression models were used to estimate the effect of age and gender and BEWE of a tooth on pain reduction in both groups according to both scales. The results were considered statistically significant at The R statistical package  was used for the calculations. A total of 300 patients were screened, 50 of those fulfilled the inclusion criteria and were enrolled in the protocol. Twenty-two patients were lost at follow-up, due to problems arising from the COVID-19 pandemic.A total of 340 teeth were treated in 28 adult patients aged 23.3–69.3 years . There were 21 female patients aged 23.3–69.3 years  and 7 male patients aged 25.2–64.1 years . The number teeth treated in a single patient varied from 6 to 18 with mean = 12.2 and SD = 4.0.There were 180 teeth treated by Bifluorid 10 and 160 by Futurabond U. At baseline, pain was slightly stronger in teeth treated with Bifluorid 10. Both treatments in both scales (SCHIFF and VAS) reduced pain intensity at each stage .Mean Schiff-measured pain reduction was statistically significant at each stage in both groups. At three of the four stages, total pain reduction was larger in Bifluorid 10 group, but the difference was not significant .3–T4) pain reduction in Futurabond U group was very small and, at this stage, VAS-measured pain intensity became lower in Bifluorid 10 group .3.Patient’s age has a significant negative influence on pain reduction (both SCHIFF and VAS-measured), while influence of patient’s gender and BEWE of the tooth is insignificant.


Persistent postoperative pain (PPP) after cardiac surgery is a significant complication that negatively affects patient quality of life and increases health care system burden. However, there are no standards or guidelines to inform how to mitigate these effects. Therefore, in this review, we will discuss strategies to prevent and manage PPP after cardiac surgery. Adequate perioperative analgesia may prove instrumental in the prevention of PPP. Although opioids have historically been the primary analgesic approach to cardiac surgery, an opioid-sparing strategy may prove advantageous in reducing side effects, avoiding secondary hyperalgesia, and decreasing risk of PPP. Implementing a multimodal analgesic plan using alternative medications and regional anesthetic techniques may offer superior efficacy while reducing adverse effects. According to the International Association for the Study of Pain, PPP is defined as pain that persists beyond 3 months after surgery, can be continuous or intermittent, and is attributable to the surgical insult, excluding other potential etiologies. Up to 43% of patients suffer PPP at 3 months after cardiac surgery. A meta-analysis that included 11 057 cardiac surgical patients across 23 studies demonstrated a 37% incidence of PPP in the first 6 months and up to 17% at 2 years after surgery. A retrospective analysis of 35 817 cardiac surgical patients registered in a national administrative claims database of private payers revealed that nearly 1 in every 10 patients who were previously opioid naïve developed opioid use that persisted >3 months after surgery and associated higher oral morphine equivalents prescribed with an increased risk of persistent opioid use. Patients with PPP experience decreased health-related quality of life, effectively rendering the surgical intervention a means to displace the focus of their suffering instead of alleviating it. Beyond suffering, pain impedes critical postoperative rehabilitation, resulting in functional disability that prevents return to work and a normal life. On a larger scale, PPP can result in medicolegal actions, disparate economic impact, and increased medical costs and resource utilization.Persistent postoperative pain (PPP) is a devastating complication that affects both patients and health care systems. The incidence of moderate to severe PPP can vary widely based on surgery type, from <5% to >80% of cases performed. Risk factors for PPP after cardiac surgery include young age, female gender, preexisting pain, anxiety, a catastrophizing mindset, higher body mass index, and a history of osteoarthritis.7 Of note, more intense acute postoperative pain has been associated with a greater incidence and severity of PPP.7Of cardiac surgical patients with PPP, half have reported it to be moderate to severe and most have described it as neuropathic in quality, the primary location of pain in the chest, the next being the leg in patients having undergone saphenous vein harvesting.9 Likewise, aggressive preventive analgesia has been associated with decreased PPP. Therefore, adequate understanding and management of perioperative pain constitutes a fundamental strategy in PPP prevention following cardiac surgery. Risk factors for acute postsurgical pain include young age, longer duration of surgery, and thoracotomy, as compared with surgical access at other sites  receptor blocking activity of methadone, which has been associated with the prevention of opioid-induced hyperalgesia. A perioperative, opioid-sparing strategy utilizing analgesic alternatives and adjuncts may ultimately mitigate the risk of developing PPP and additional opioid-induced side effects, while also conferring additional benefits versus opioids alone.24 It is important to clarify, however, that prevailing evidence and expert opinion support opioid-sparing but not opioid-free techniques. Not only do opioids, when dosed in moderation, have longstanding efficacy, the absolute avoidance of them has actually been shown to cause harm.Cardiac anesthesia has historically relied on significant opioid administration due to their potent analgesia amid a favorable hemodynamic profile,tion see .15 Whe24 Acetaminophen, gabapentinoids, and ketamine have all been previously described as providing both effective analgesia and offering opioid-sparing benefit.28 Rafiq and colleagues conducted a prospective randomized controlled trial (RCT) examining multimodal analgesics versus opioids following cardiac surgery through median sternotomy. The authors found a combined regimen utilizing dexamethasone, gabapentin, ibuprofen, and acetaminophen provided superior analgesia (decreased numeric rating pain scores) through postoperative day 3 and decreased incidence of nausea and vomiting versus morphine and acetaminophen alone. Despite these findings during the acute pain period, a recent systematic review and meta-analysis regarding gabapentinoids observed no clinically significant analgesic effect to support their routine perioperative use. Further literature remains limited or not yet assessed regarding gabapentinoid use in the prevention of chronic poststernotomy pain.30The application of multimodal analgesics may play particular importance in preventing PPP as this more inclusive approach has been described as providing optimal acute pain management with potentially fewer side effects when compared with a traditional opioid-based strategy. With regard to acetaminophen (paracetamol) administration, the authors found 2 of 4 RCTs demonstrating significantly decreased Visual Analogue Scale (VAS) scores and one of these publications demonstrating significantly decreased opioid consumption.3134 Of 3 RCTs examining nonsteroidal anti-inflammatory drug (NSAID) analgesics and cardiac surgery, 2 trials demonstrated decreased VAS, and opioid consumption with NSAID use.36 Although the authors acknowledge the literature remains sparse regarding acetaminophen and NSAID use specific to cardiac surgery, Bignami and colleagues conclude that the use of multimodal analgesia provides synergistic pain relief with fewer adverse effects. Although VAS scores permit readily obtainable data gathering, more comprehensive assessments including functional and disability data may provide more reliable and objective measures in assessing pain. Direct comparisons of differing pain-related studies are often complicated by heterogeneity in outcome assessment and the use of non-patient-centric endpoints such as morphine equivalents. There are numerous validated patient satisfaction and quality of life questionnaires that better capture more meaningful outcomes related to improved pain control rather than relying on VAS scores alone.39A subsequent systematic review conducted by Bignami and colleagues examined perioperative pain management modalities and cardiac surgery including multimodal analgesics. Among the 40 RCTs with analgesics including NSAIDs, gabapentin, pregabalin, lidocaine, steroids, ketamine, NMDA blockers, fentanyl, nitrous oxide, venlafaxine, and the antiarrhythmic mexiletine, only intravenous ketamine provided a statistically significant, albeit modest, reduction in the incidence of postsurgical chronic pain. In a subsequent review of postoperative chronic pain prevention, Reddi similarly concluded that ketamine may reduce chronic pain after surgery while suggesting gabapentin and pregabalin as promising but requiring additional robust studies prior to recommendation. In a recent review of chronic poststernotomy pain, Kleiman and colleagues similarly found no evidence to support the use of transdermal lidocaine, glucocorticoids, or dexmedetomidine in decreasing chronic pain. In contrast, the authors acknowledge the effectiveness of acetaminophen, gabapentinoids, and ketamine in providing opioid-sparing analgesia, but describe their utility in preventing chronic poststernotomypain as limited or not yet examined.Beyond the acute postoperative period, the role of systemic pharmacologic therapies in preventing the development of chronic pain after surgery has also been examined. Chaparro and colleagues conducted a meta-analysis of RCTs with systemic drugs administered perioperatively and evaluated pain 3 or more months following surgery. Multimodal analgesics have often been combined with targeted regional anesthetic techniques to reduce opioid requirements, enhance pain control, and potentially reduce systemic analgesics and their accompanying side effects including delirium, hypotension, bradycardia, bleeding, and sedation. Neuraxial anesthesia serves as one regional technique that may be considered in cardiac surgery via thoracic epidural analgesia (TEA) or spinal anesthesia.44 TEA has been shown to provide effective analgesia with decreased VAS scoring and reduced opioid consumption postoperatively,27 yet no evidence supports a definitive decrease in developing chronic pain following TEA or intrathecal opioid administration. The risk of spinal hematoma has historically been shown to be 1:1528 for TEA and 1:3610 for spinal anesthesia, but the risk for TEA has more recently been shown to be as low as 1:3552. The 2018 guidelines released by the American Society of Regional Anesthesiologists states there is insufficient evidence to determine whether the risk of epidural hematoma with neuraxial procedures is increased with the use of the level of anticoagulation required for cardiopulmonary bypass (CPB). The decision to employ neuraxial anesthesia as part of any opioid-reducing analgesic strategy should always consider a risk-benefit calculation regarding epidural hematoma formation in the vulnerable cardiac surgery patient population.49The application of regional anesthesia provides a diverse array of potentially opioid-sparing pain management methods in accordance with a multimodal analgesic strategy. The ability to administer local anesthetics through regional anesthesia may be particularly favorable in high-risk surgical candidates as these techniques may reduce or outright avoid adverse effects associated with opioid administration.4952 The risk of epidural hematoma formation proves notably relevant within cardiac surgery due to the frequent anticoagulation requirement for patients undergoing cardiopulmonary bypass. Similar to TEA, there exists no evidence to support thoracic PVB in the prevention of chronic poststernotomy pain.Thoracic paravertebral block (PVB) serves as alternative regional anesthetic technique utilized for analgesia related to cardiac surgery. Thoracic PVB consists of a type of peripheral nerve block with option for continuous catheter placement similar to TEA, yet PVB may be performed under direct ultrasound guidance. When compared with TEA, thoracic level PVB has been found to provide comparable analgesic efficacy and improved side effect profile, including theoretically less risk of epidural hematoma formation in the anticoagulated patient.27 without effect on chronic pain development. Similarly, ultrasound-guided parasternal intercostal nerve block performed presternotomy has demonstrated significantly lower postoperative pain scores versus saline injection or nonregional, morphine-based regimen. Studies assessing intrapleural block for sternotomy pain are limited, and similar to continuous wound catheters, have not yet examined their relationship with regard to developing PPP.Various other regional anesthetic techniques including emerging, ultrasound-guided peripheral nerve blocks have been applied for poststernotomy analgesia and cardiac surgery at large. Surgeon administered parasternal block has been shown to provide improved postoperative analgesia and reduced opioid requirements,55 The erector spinae plane (ESP) block presents a novel fascial plane block that was first described in 2016 for thoracic neuropathic pain and has since been applied as an easier to perform alternative to PVB to multiple procedure types involving the chest wall and abdomen.57 Few clinical studies assessing the ESP block for cardiac surgery have taken place, but initial data reveal promising analgesic efficacy and reduction in opioid consumption, while the need for replication via blinded RCTs persists.58 Similar analgesic studies have evaluated both the pectoral nerve and serratus anterior fascial plane blocks with encouraging results. The pectoralis (Pecs) nerve block entails dual interfascial plane injections (Pecs I and Pecs II) with the aim of anesthetizing the chest wall. Kumar and colleagues examined postoperative bilateral pectoralis nerve block following midline sternotomy, demonstrating both significantly decreased duration of ventilator dependence and improved pain scores utilizing the regional technique. Currently, no published evidence exists evaluating the more laterally performed serratus anterior nerve block approach specific to sternotomy pain, yet studies have shown improved pain scores following other thoracic surgical interventions.Promising, emerging peripheral nerve blocks of the chest wall occur most often using direct visualization with ultrasound guidance, potentially adding to their safe application.62 Through incorporation of multiple individuals, a multidisciplinary, perioperative pain team may optimally treat complex pain through specialization, communication, and education among providers and patients. Such a team would be well positioned to combine clinical management with pain research.In addition to the consulting anesthesiologist’s role in managing opioid-sparing, multimodal analgesia, a multidisciplinary approach may provide the ideal strategy in preventing PPP in the cardiac surgery patient.63 Because mediastinitis has been associated with developing chronic pain, the more selective skeletonization harvest may prove warranted, particularly in the diabetic patient population. Minimizing sternal retractor trauma, removing sternal wires posthealing, and prophylactic sternal plating in high-risk individuals has been suggested to minimize chronic pain contributions. Minimally invasive techniques have been used to decrease the degree of tissue traumatization, acute postoperative pain, intraoperative time, perioperative bleeding, and the incidence of sternal wound infections and recovery time. In addition, the removal of chest drainage tubes on the first postoperative day, as compared with days 2 or 3, has been associated with improved pain scores without an increased risk of requiring chest tube reinsertion.Procedural considerations should be discussed with surgical colleagues as multiple operative variables may influence the development of PPP. For example, obtaining bilateral internal thoracic artery grafts via pedicled harvest rather than skeletonization has been associated with an increased risk of developing mediastinitis after coronary artery bypass graft (CABG). exacerbates acute postoperative pain. Despite the likelihood of a link between this altered pathophysiologic state and sensitization to pain signaling, this mechanism has not been investigated. There have been numerous studies comparing patients having undergone CABG surgery performed either with or without CPB, but none have specifically evaluated differences in pain following these techniques.Surprisingly, it is unknown if the well-described state of heightened systemic inflammation associated with the use of CPB68 Interestingly, patients on cannabinoids may have higher tolerance to opioids and NSAIDs, requiring higher doses.There are some classes of home medications that may affect perioperative analgesia. To optimize analgesia while minimizing relapse and overdose, it is recommended for patients taking low-dose buprenorphine and methadone to continue those medications throughout the perioperative period.7074 Early involvement of a pain psychologist or integrative pain team may offer valuable insights to both identify and address these psychological risk factors outside of the cardiothoracic anesthesiologist and surgeon’s area of expertise.75Addressing patients’ psychological comorbidities may also play a key role within a multifaceted approach to PPP prevention after cardiac surgery. Patients may present with preexisting psychological risk factors for the development of chronic pain including anxiety, depression, posttraumatic stress disorder, and pain catastrophizing.7679 Multimodal analgesia has remained central to ERAS protocols as this strategy may offer decreased opioid exposure in addition to potentially reducing recovery times, complications, and improving cost expenditures with surgery.81 Similarly, regional anesthesia has been increasingly implemented as part of a multimodal strategy in cardiac surgery and related ERAS protocols to reduce opioid consumption.83 The addition of emerging truncal fascial plane blocks for pain optimization presents a promising new area within cardiac ERAS.84 Because cardiac ERAS pathways often highlight opioid-sparing strategies and acute pain management optimization,86 implementation of these protocols aligns with addressing the aforementioned factors thought to contribute to PPP.Many of the aforementioned pain management components and multidisciplinary approach relevant to cardiac-related PPP have been integrated as part of comprehensive, enhanced recovery after surgery (ERAS) protocols. ERAS pathways including those specific to cardiac surgery continue to gain popularity and aim to incorporate multiple objective variables to optimize patient experience, perioperative efficiency, and improve outcomes.Although prevention is likely the most impactful strategy to decrease the burden of PPP after cardiac surgery, this may not always be possible. There are a variety of treatment options for PPP including medications see , surgery88 Indeed, the most updated 2015 Food and Drug Administration (FDA) black box warning for non-ASA NSAIDs advises against their use in patients prior to or after CABG, emphasizing the potentially increased risk for heart attack or stroke in patients with underlying cardiovascular disease. Furthermore, the use of non-ASA NSAIDs for cardiac surgical patients has been associated with acute kidney injury, whereas ASA use has been shown to be protective.Medical management of PPP involves targeting the various pathways and mechanisms of pain. NSAIDs decrease the production of inflammatory cytokines and chemokines such as prostaglandins. This may be particularly helpful in the acute phase of injury for patients, but also plays a role in chronic musculoskeletal pain and associated flares. Both the acute and long-term risks of NSAID use needs to be considered, especially in the cardiac surgery population, and the distinction between acetylsalicylic acid (ASA) and other NSAIDs is warranted. Renal injury, increased risk of myocardial infarction and stroke are all potential adverse events that the cardiac surgery population may already have a higher baseline risk for developing when using non-ASA NSAIDs. There is evidence that it inhibits COX centrally and acts through other non-COX mechanisms as well. This agent has a better safety profile without a demonstrated association with hepatic dysfunction, although caution should be taken in patients with acute liver injury.Acetaminophen or paracetamol is a known cyclooxygenase (COX) inhibitor, although it does not exert its effect through peripheral inhibition of this enzyme as the non-steroid anti-inflammatory class of medications.5 These agents have a generally favorable safety profile with nausea, sedation, and dizziness being some of the more common side effects and caution should be taken for patients with baseline renal dysfunction.Gabapentin and pregabalin bind to the alpha2delta subunit of calcium channels and are used in treating many different types of chronic pain. They are most well studied and effective for neuropathic pain. For cardiac surgery patients that have a neuropathic component to their pain, these may be a reasonable treatment option and studies have shown that approximately half of cardiac surgical patients with PPP do have a neuropathic component to their pain. The primary site of action is likely augmentation of the descending inhibitory pathways, although there are likely additional mechanisms of action that provide analgesic benefit. SNRIs including duloxetine have been studied for a variety of neuropathic pain conditions and shown to provide significant benefit. For most patients, SNRIs are better tolerated and have a better side-effect profile when compared with TCAs.Additional neuropathic agents including serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) may also play a role in the management of PPP that has a significant neuropathic component.There is limited evidence regarding the use of dexamethasone specifically regarding the treatment postoperative pain in cardiac surgery patients. One randomized double blinded, placebo-controlled study of 300 postoperative patients who had coronary revascularization surgery did not find a difference in opioid consumption or severity of postoperative pain for the first 2 days after surgery. Patients should have treatment goals that may include pain reduction and functional improvement and they should respond favorably to low doses of opioids. Practically, the number of patients who should require and would benefit from chronic opioid therapy is likely low, although this has not been studied in this population.Chronic application of opioids needs to be carefully weighed with the risks. Chronic use needs to be carefully monitored and the appropriateness of ongoing therapy evaluated by pain management specialists.99 Cryoablation of neural tissue has been utilized for treatment of various painful conditions. The first study of cryoablation of the intercostal nerves was done in 1980 for pain associated with thoracotomy and reported significantly reduced analgesic use in the group that received the intercostal cryoablation. Perhaps the most relevant study pertinent to this review was done in 2000 for patients undergoing minimally invasive cardiac surgery via minithoracotomy. This study reported reduced pain scores, although no difference was seen in analgesic consumption. Neuromodulation is a field that has continued to develop and there are case reports and small studies of patients who may benefit for spinal cord stimulation for chronic, refractory angina or in one case truncal complex regional pain syndrome following sternotomy.103 A limitation of these techniques may be anticoagulation for patients with cardiovascular disease and further research is needed to determine which patients would benefit most from these advanced and more invasive techniques. Surgery can also be an option for a small subset of patients who have a clear mechanical component to their pain. This would include patients with sternal malunion or sternal wire fracture, although these are relatively rare complications and are likely not significant contributors to PPP for most patients.Beyond medical management, interventional pain procedures may be appropriate for certain patients. Patients who have had a minimally invasive procedure performed via thoracotomy may develop intercostal neuralgia or post-thoracotomy pain. Treatment with intercostal nerve blocks, paravertebral blocks, trigger point injections, or thoracic epidural steroid injections may be treatment options. Treatment of chronic pain is an off-label use for most of these therapies given the relatively limited evidence, but for patients with refractory pain they may be appropriate to trial. Depending on the characteristics and location of the patient’s pain, topical agents such as lidocaine, diclofenac, or capsaicin can be considered. In patients with muscle spasms or myofascial pain, muscle relaxants  can provide some symptom relief. Physical therapy is important for recovery in strength and function after surgery, but there can be further benefits for patients who go on to develop chronic pain. Dry needling can target pain with a myofascial component and therapists can work to improve function in patients who are deconditioned due to inactivity from their pain. Psychological therapy in the form of cognitive behavioral therapy, cognitive function therapy, acceptance and commitment therapy, biofeedback, and mindfulness can be helpful for patients with chronic pain, particularly when there are complicating psychosocial factors. The importance of a comprehensive approach to the treatment of chronic pain with therapy , medication, interventions, and adjunctive therapies cannot be understated.For refractory neuropathic pain antiepileptic agents , NMDA receptor antagonists such as memantine and infusions including ketamine or lidocaine are treatment options to consider.PPP and opioid use remain vital pain management concerns in providing optimal anesthetic care surrounding cardiac surgery. Further best practices data are required through future research study in multiple areas including the following:Further studies identifying patient risk factors for the development of PPP after cardiac surgeryResearch needed to assess the effect of cardiac surgical procedure type and intraoperative interventions on pain outcomesResearch examining the inflammatory state and role of intraoperative CPB use in the development of chronic painResearch addressing the consequence of acute pain management and its effect on the development of PPPLarge-scale RCTs assessing systemic, multimodal analgesics in the development of chronic pain following cardiac surgeryLarge-scale RCTs evaluating regional anesthesia applied to cardiac surgery and the development of chronic painHead-to-head comparative studies assessing novel, ultrasound-guided regional anesthetic techniques with cardiac surgeryResearch assessing secondary hyperalgesia therapies as potential preventative measures to developing chronic painResearch needed to assess the effect of psychological and behavioral interventions on the development of chronic postsurgical painLarge-scale RCTs assessing ERAS pathway implementation and the development of chronic painLarge-scale RCTs evaluating neuromodulation and spinal cord stimulator therapy for chronic poststernotomy pain106 Current literature suggests both prevention and treatment of PPP should optimally include multimodal pharmacology, regional anesthesia, and multidisciplinary involvement.62 Future research is required in this vulnerable patient population to confirm best practices in PPP prevention and treatment as part of an enhanced recovery after cardiac surgery pathway.Persistent postoperative pain after cardiac surgery represents a significant complication negatively affecting patients and health care systems. Adequately treating acute pain following cardiac surgery remains paramount as severe postoperative pain and opioid-induced hyperalgesia may increase the risk of developing PPP.


P < 0.001). Active joint sites with higher SUVs than the median value of each joint group were the most common in RA (55.1%). RA showed the greatest hSUV in the PIP (3.0 ± 2.4), MCP (3.5 ± 3.4), and wrist (3.3 ± 1.9) joint groups. FM was characterized by the lowest hSUV of all joint groups. In ROC curve analysis, the cumulative hSUV of the PIP, MCP, and wrist joint groups showed good performance for evaluating RA (area under the curve (AUC), 0.668; P = 0.005). The summation of the hSUVs at all joint groups had an excellent predictive performance for FM . Consequently, the arthritic activity of the hand and wrist joints based on SUV differed according to specific rheumatic diseases. Quantitative SPECT/CT may provide objective information related to arthritic activity for differentiating specific rheumatic diseases.We investigated the diagnostic value of the maximum standardized uptake value (SUV) at hand and wrist joints for differentiating rheumatic diseases via bone single-photon emission computed tomography (SPECT)/computed tomography (CT). A total of 84 patients manifesting hand and wrist pain  were finally diagnosed with rheumatoid arthritis , osteoarthritis , fibromyalgia , and other rheumatic diseases (n = 24). The SUV of each patient was measured in 32 joints including the distal interphalangeal (DIP), proximal interphalangeal (PIP), metacarpophalangeal (MCP), and wrist joints bilaterally. Differences in pain and SUVs between specific rheumatic diseases were assessed using the chi-squared test or one-way analysis of variance. Using the highest SUV (hSUV) in each patient, the diagnostic performance in differentiating specific diseases was evaluated by receiver operating characteristic (ROC) curve analysis. Pain symptoms were present in 886 (33.0%) sites in a total of 2688 joints. In four joint groups , the SUVs of joints with pain were significantly higher than those of pain-free joints (all  However, the visual assessment of SPECT/CT remains subjective because it is based on relative tracer uptake. In state-of-the-art SPECT/CT, quantitative measurements using the maximum standardized uptake value (SUV) have been reported to provide useful information due to greater objectivity in the interpretation3.Bone scintigraphy imaging using Tc-99m-labeled bone tracers such as Tc-99m methylene diphosphonate (MDP) has been widely used to investigate active bone formation. It is highly sensitive but not always specific, for the assessment of musculoskeletal disease. Single-photon emission computed tomography (SPECT)/computed tomography (CT) is potentially more accurate than planar scintigraphy imaging, as it is based on anatomical information in the CT scan5. The clinical assessment of joint lesions based on pain characteristics facilitates the detection of possible rheumatic diseases7. However, pain perception is not necessarily related to inflammation or structural changes reflecting tissue damage because it is also affected by environmental and psychological factors9. In these cases, the maximum SUV of joints measured using quantitative SPECT/CT provides more objective information for arthritic activity related to peripheral joint damage, independently of pain symptoms. The severity of pain sensitization and arthritic activity can also differ according to various pathophysiological mechanisms of specific rheumatic diseases. This feature may be useful in narrowing the possible rheumatic conditions in patients who are initially classified with undifferentiated arthritis.Hand or wrist pain is one of the most frequent symptoms and reason for admission in rheumatology. It may occasionally be difficult to identify the cause of pain because of the extensive differential diagnosis and similar clinical manifestationsIn this study, we compared joint SUVs and pain symptoms in patients with rheumatic disease manifesting as hand and wrist joint pain. In addition, we also evaluated whether the joint SUVs differed according to specific rheumatic diseases, and could assist in its differential diagnosis.We retrospectively reviewed the medical records of 87 consecutive patients who underwent bone SPECT/CT of the hand and wrist region requested by our rheumatologist between September 2016 and March 2020. The patients had hand or wrist pain as the chief complaint with a known or suspected rheumatic disease at the time of the test. The primary indications for bone SPECT/CT were to evaluate scintigraphic activity of the hands that reflect articular inflammation and/or increased bone turnover and to confirm a clinical diagnosis. Among the candidates, three patients who had other possible causes  besides rheumatic conditions for hand or wrist pain were excluded. Consequently, 84 patients with hand or wrist pain related to rheumatic disease were finally included. This study was approved by the Institutional Review Board (IRB) of Soonchunhyang University Hospital (IRB No. 2020-04-020) with an exemption for obtaining written consent from the study subjects. All retrospective analyses involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.10. The SPECT voxel counts based on accurate correction were also converted to activity concentrations (Bq/mL) using a system planar sensitivity correction factor measured with a 57Co source during reconstruction11. Finally, the SPECT and CT images were co-registered as fusion SPECT/CT images.All imaging data were acquired using a Symbia Intevo16 hybrid SPECT/CT system  comprised of an integrated dual-head SPECT camera with a 16-slice helical CT scanner. In all patients, the field of view (FOV) covered both hand and wrists completely, and immobilization materials were placed between patient’s fingers to minimize motion of hand during SPECT/CT imaging . The joint uptake of each patient was quantified using the maximum SUV at a total of 32 joints in four joint levels including the distal interphalangeal (DIP) (n = 8), proximal interphalangeal (PIP) n = 10), metacarpophalangeal (MCP) (n = 10), and wrist (n = 4). Using the CT images as an anatomic reference, a spherical volume of interest (VOI) was drawn over the periarticular region including the epiphysis, placing the joint space at the center of the VOI, which was automatically reflected on the SPECT/CT fusion images , osteoarthritis (OA), fibromyalgia (FM), and other rheumatic conditions. A pain localization diagram displaying the 32 joints of the hand and wrist was used to identify the pain location. The subjects marked the painful joint sites on the day they underwent SPECT/CT.Continuous variables were compared using the Student’s t-test (two variables) and analysis of variance (ANOVA) (more than two variables). Pearson’s chi-squared test was used for the comparison of categorical variables. Diagnostic performance of joint SUVs for predicting specific rheumatic diseases was assessed by the area under the curve (AUC) of the receiver operating characteristics (ROC) analysis. All statistical tests were two-sided with a significance level set at 0.05 and were performed via the Statistical Package for the Social Sciences version 23.0  and MedCalc version 15.5  software programs.The baseline demographic and clinical characteristics of the 84 study subjects are summarized in Table P < 0.001). A total of 1254 joints (46.7%) were classified as active joint lesions based on the median SUV at each joint group.Six-hundred seventy DIP, 840 PIP, 840 MCP, and 336 wrist joints were analyzed in 84 patients. The mean values of SUVs gradually increased from distal to proximal in all joints: 1.5 ± 0.7  in DIP, 1.8 ± 1.0  in PIP, 1.8 ± 1.1  in MCP, and 2.3 ± 1.5  in the wrist joints. In all of four joint groups, the SUVs of joints with pain were significantly higher than those of pain-free joints , followed by other rheumatic diseases (35.0%), RA 29.8%), and FM (12.5%). However, the rheumatic disease with the most active joint lesions was RA (55.1%), followed by other rheumatic diseases (42.1%), OA (36.5%), and FM (4.7%). Although there were fewer painful joint lesions (33.0%) than active joint lesions (46.7%) in the entire joint sites, it was the opposite in OA and FM , and RA had the highest arthritic activity of joint lesion (3.0 ± 2.4). According to individual joint groups, the PIP , MCP , and wrist joints  showed higher hSUVs in RA than in non-RA diseases, but did not reach statistical significance. FM showed the least arthritic activity among all joint groups.The hSUVs of each joint group were used to compare the disease activity according to specific rheumatic conditions in patient group Table . When thP = 0.005; Fig. Using summed hSUVs at individual joint groups, we analyzed the best predictive performance of ROC analysis for RA and FM. The cumulative hSUV of the PIP, MCP, and wrist joints showed good predictive performance 13. In recent studies, lesion SUVs measured via quantitative bone SPECT/CT showed high accuracy for distinguishing malignant conditions from benign lesions15. It also appears to be useful to objectively evaluate disease severity in arthritic disease in the knee or temporomandibular joints3. In the present study, the quantitative method using the SUVmax showed the potential for differentiating articular problems from pain perception in rheumatic patients with hand and wrist pain. To our knowledge, this was the first clinical study to evaluate the diagnostic utility of quantitative bone SPECT/CT in patients with hand or wrist pain. Especially, this finding may provide objective information to differentiate soft tissue rheumatism such as FM from inflammatory arthritis including RA and OA.In medical imaging, quantitative measurements can potentially overcome the subjective bias of purely visual analysisPain is a significant component of many rheumatological conditions and is the result of a complex physiological interaction between central and peripheral nervous system signaling. Due to the very large inter-individual differences in these central nervous system factors that influence pain perception, the severity of pain is often not consistent with the degree of tissue inflammation or damage. In this trend, joint SUV measured via quantitative SPECT/CT may objectively and directly represent inflammation and/or damage in peripheral structures, rather than pain perception. In our study, painful hand and wrist sites were significantly associated with relatively high joint SUVs. However, there were also considerable lesions with inconsistency between the presence of pain and the magnitude of the joint SUV. This large overlap between painful and pain-free joint SUVs may suggest that there are various pathophysiological causes for painful hand and wrist joint symptoms besides altered bone and joint activity. Related to this finding, distribution and intensity in joint SUV differed from pain according to specific rheumatic diseases. In particular, RA showed higher joint SUVs and FM lower SUVs, presumably associated with less arthritic activity and more pain sensitization.17. FM may show higher measures of pain intensity and disease status for the same degree of inflammation or structural damage as the central pain processing system18. Therefore, to distinguish FM from other inflammatory arthritis conditions, it is more helpful to determine the degree of joint inflammation than to assess pain. Bone scintigraphy is a useful imaging tool to recognize the presence of joint problems. However, visual assessments have interobserver variability in determining the presence of abnormal joint lesions. For example, diffusely increased physiologic uptake without definite focal activity in the small joints of the hand can sometimes be misinterpreted as diffuse joint problems. In comparison, quantitative analysis can provide more objective information for arthritic activity than visual assessments. ROC curve analysis using the cumulative SUV of all joints showed the best performance in differentiating FM from other rheumatic diseases. However, further studies including a large number of subjects are required to elucidate the diagnostic utility of this quantitative parameter for FM due to the small sample size in the present study.FM is one of the most common types of non-articular rheumatic disorders and can be misdiagnosed as other inflammatory arthritis conditions associated with several overlapping features20. In addition, the cumulative highest SUV of the PIP, MCP, and wrist joints displayed an AUC of 0.668 in ROC analysis for distinguishing RA from other rheumatic conditions including OA. However, our study also demonstrated considerable overlap in the joint SUV magnitudes between RA and OA. Therefore, the joint SUV may have limited clinical value for evaluating RA and OA. A better strategy using a quantified method for the clinical utility of bone SPECT/CT in distinguishing RA from other diseases including OA in patients with hand and wrist pain should be explored in future studies.RA and OA are the two most common forms of arthritis involving hand and wrist joints. RA is an autoimmune and inflammatory process involving joints, especially synovial membranes, whereas OA is caused by mechanical wear and tear of the joints. Despite varying pathogenesis, the differentiation of these conditions can be challenging because they often cause similar symptoms, particularly in the early stages. In our study, RA consistently showed higher frequency and intensity of arthritic activity based on SUV measurements compared to OA. This result may be associated with the higher bone turnover caused by greater inflammatory reactions or specific bone loss in RA21. However, the degree of radiotracer uptake in the reference background region can often be affected by blood flow and the rate of new bone formation23. Especially, the presence of inflammatory conditions or age-related changes such as osteoporosis may potentially lead to an overestimation or underestimation of joint activity. Therefore, the joint SUVmax may reflect arthritic activity better than patient-specific measurements. Consistent with this, a previous study reported that the joint SUVmax on SPECT/CT had better performance in evaluating temporomandibular joint disease than the relative uptake ratio3. However, the threshold of the SUVmax to define abnormal activity has not yet been established in hand and wrist joints. Although the active joint site in our study was categorized using the median SUV in the same joint group  in the total population, it is not actually abnormal lesion but site with relatively high uptake in preselected clinical patients. To differentiate abnormal activity from normal physiologic uptake, the normal reference for joint SUV should be investigated in future studies including normal controls.In this study, the radioactive uptake of hand and wrist joints on quantitative SPECT/CT was measured as the SUVmax, which has been widely used in previous studies. In previous studies using bone scintigraphy, the quantification of abnormal joint activity was evaluated by specific patient measurements such as the joint-to-background activityThe major limitations of this study were its retrospective design and a rather modest number of subjects. Our study population was also highly selected by clinicians, which might have influenced the results as selection bias. The SUVmax threshold and performance in hand and wrist joints were derived from patient groups with rheumatic conditions. Future studies with more adequate control patients are required to strengthen our findings and further confirm the potential utility of bone SPECT/CT in the evaluation of patients with hand and wrist pain.The joint SUVs in hand and wrist on bone SPECT/CT images exhibits lower magnitude in FM with non-articular pain than in inflammatory arthritis with articular pain. Our preliminary result demonstrated the quantitative bone SPECT/CT might be considered as more objective and standardized technique in assessing joint activity for rheumatic disease patients. In the future, prospective studies with a larger sample size including normal controls should be conducted to confirm the diagnostic efficacy of quantitative bone SPECT/CT for patients with hand and wrist pain.Supplementary Figure S1.