The CSI was not associated with psychophysical measures or pain distributions indicative of altered central pain processing. However, there was a correlation of the CSI with the Beck Depression Inventory . Conclusion: Patients with CTS show signs of altered central pain mechanisms. The CSI seems unsuitable to detect changes in central pain processing but is rather associated with psychological factors in people with focal nerve injuries.Objective: Carpal tunnel syndrome (CTS) is the most common focal nerve injury. People with CTS may show alterations in central processing of nociceptive information. It remains unclear whether the central sensitization inventory (CSI) is capable of detecting such altered central pain processing. Methods: Thirty healthy volunteers were matched with 30 people with unilateral CTS from the orthopaedic waitlist. Changes to central pain processing were established through psychophysical sensory testing , conditioned pain modulation, temporal summation) and pain distribution on body charts. Patients also completed pain severity and function questionnaires, psychological questionnaires and the CSI. Results: Compared to healthy volunteers, patients with CTS have lower PPTs over the carpal tunnel bilaterally (t = −4.06,  Carpal tunnel syndrome (CTS) is the most common focal nerve injury ,2. It isCentral sensitization is a neurophysiological mechanism that cannot be directly determined in humans. However, in addition to the spread of symptoms, psychophysical sensory testing can be used to infer the contribution of central pain mechanisms to patients’ presentations. For instance, local and remote mechanical hyperalgesia such as measured with pain thresholds has been associated with central sensitization ,6. AdditIn addition to increased facilitation, a disruption of inhibitory mechanisms is another central mechanism that can lead to hyperexcitability. Conditioned pain modulation (CPM) is a psychophysical measure that examines the efficacy of endogenous inhibitory systems . CPM evaWhereas these psychophysical sensory tests can provide information about the potential involvement of central pain mechanisms, they are time consuming and involve costly equipment. Thus, self-completed questionnaires have been developed to identify the presence of “central sensitization”. For instance, the central sensitization inventory (CSI) has been suggested to identify patients with “central sensitivity syndrome” such as fibromyalgia, chronic fatigue syndrome, irritable bowel or temporomandibular joint disorders . In addiTo improve our knowledge of alterations in pain processing in focal nerve injuries and the construct validity of the CSI, this study has the following objectives: (1) Identify alterations in central pain mechanisms in patients with CTS using psychophysical sensory testing and pain mapping. (2) Investigate whether the CSI is associated with psychophysical parameters and pain distributions indicative of central pain mechanisms. (3) Investigate whether the CSI is associated with psychological parameters.Thirty patients with unilateral CTS were recruited from Hand and Elbow surgery units from 12 Octubre Hospital and Severo Ochoa Hospital, both located in Madrid. All patients were on the orthopaedic surgery waitlist, with at least one year of persistency of symptoms, had positive Tinel’s and Phalen’s sign and had electrodiagnostic confirmation of moderate to severe CTS on the affected side according to the American Association of Neuromuscular and Electrodiagnostic Medicine . PatientThe patients were matched for age and sex with healthy controls . Those were recruited through advertisements around the hospitals and university and through relatives of participating patients. All participants gave informed written consent prior to participating, and the study received ethical clearance from the two committees of the participating hospitals CPMP/ICH/135/95  and 20/092 .The Boston carpal tunnel questionnaire was used to assess symptom severity and functional deficits. The Boston carpal tunnel questionnaire consists of a symptom and a function subscale . This quThe presence of neuropathic pain was assessed with the Spanish version of Douleur Neuropathique 4 (DN4). This version has shown good internal consistency . The queThe central sensitization inventory (CSI) is a tool originally designed to identify patients with “central sensitivity syndrome” . It incl®, Wagner Instruments, Greenwich, CT, USA). This instrument measures the pressure in kg/cm2. The measurements were made bilaterally (affected and unaffected side) over the carpal tunnel  and the State-Trait Anxiety Inventory (STAI). The BECK consists of 21 elements related to depressive symptoms , specific thoughts  and physical symptoms ,36. STAITo assess pain-related fear of movement, the validated Tampa kinesiophobia scale (TSK) was used. Each item is rated on a four-point Likert scale ranging from “strongly agree” to “strongly disagree” with a cutoff of 29 points. This questionnaire has shown a good consistency ,39.t-test). This sample size is sufficient to detect large effects in correlation analyses .The sample size was estimated using the program G*Power 3.1.7  . The samWe performed the data analysis using the Statistics Package for Social Science . We checked data normality by visual inspection of histograms and the Kolmogorov–Smirnov test. Participants’ sociodemographic and clinical characteristics were summarized using descriptive statistics and summary tables.t-tests to identify differences between healthy and patient groups for psychophysical variables. The frequency of extraterritorial spread of symptoms (median/extramedian) was reported.To determine the presence of signs indicative of altered central pain processing, we employed independent Student’s t-tests and Chi squared or Fisher’s exact test statistics as appropriate.To identify associations between CSI and psychophysical signs indicative of altered pain processing, we performed Pearson’s correlation statistics in patient data only. Coefficients of 0.5 or above were interpreted as a strong correlation, 0.3 moderate and 0.1 small correlation. We corrected for false discovery rate using the Benjamini–Hochberg correction (FDR = 25%). We also grouped patients with CTS into those with CSI ≥ 40 and <40 and explored differences in psychophysical tests and symptom spread with independent p-values are reported for ease of interpretation.To explore the relationship between CSI and emotional wellbeing  in patient data, we calculated Pearson correlations coefficients and used Benjamini–Hochberg correction to correct for a false discovery rate. Unadjusted Thirty participants were healthy controls (8 men and 22 women with a mean age of 46.23 ± 1.36 years), and 30 patients diagnosed with CTS  and contralateral side .There were statistically significant differences between patients with CTS and healthy participants in the psychophysical variables related to central pain processing. PPTs were reduced in patients with CTS, indicative of mechanical hyperalgesia compared to healthy controls both on the ipsilateral . No differences were found for temporal summation . Data are shown in Similarly, CPM efficiency was reduced in patients with CTS compared to healthy controls . Eight patients (26.67%) had a score ≥ 40.p > 0.600).The CSI did not correlate with any psychophysical signs of altered pain processing . SimilarExtramedian distribution of symptoms was reported by 25 (83%) of patients with the remaining patients reporting a median distribution. No difference was identified for the proportion of patients with median/extramedian spread of symptoms according to the CSI cutoff .p = 0.893) and kinesiophobia according to TSK . There was, however, a moderate correlation between CSI and depression according to BECK , 24.30 (SD 5.05), and 25.93 (SD 7.62), respectively . The CSIOur cohort of patients with CTS has clear indications for the presence of central pain mechanisms as apparent by local and widespread mechanical hyperalgesia and impaired CPM compared to healthy volunteers. No changes were apparent for temporal summation. Of note, there was no association of the CSI with psychophysical measures or symptom spread indicative of central pain mechanisms. There was, however, a moderate correlation between the CSI and depression scores, suggesting that the CSI may be more closely related to psychological parameters than psychophysical measures indicative of central pain mechanisms in patients with focal nerve injury.Our cohort of patients with CTS had clear indication of a presence of central pain mechanisms, although there was heterogeneity among patients. We identified mechanical hyperalgesia both locally as well as remotely, extraterritorial spread of symptoms and lower efficacy of CPM. Extraterritorial spread of symptoms in patients with CTS is consistently reported in the literature ,42,43 anIntriguingly, this is the second study demonstrating impaired CPM efficacy in patients with CTS  . On the Of note, we did not identify an association between the CSI and psychophysical measures and symptom location indicative of altered central pain processing. The CSI was originally developed as a tool to identify central sensitization characteristics . It was A recent systematic review reports a high construct validity of the CSI . HoweverIntriguingly though, the CSI was associated with depressive symptoms determined on the BECK in our cohort. Such an association of CSI with psychological wellbeing has been consistently reported in the literature ,20,21,23Some limitations have to be taken into account. The sample size was calculated to detect differences in central pain processing between healthy people and patients with CTS. Whereas it was adequately powered to detect large effects on correlations between the CSI and psychophysical testing, small or moderate correlations would have been missed. Inspection of the data, however, clearly demonstrated the absence of trends, and even if larger samples may have detected significant correlations, these would likely have been weak.We recruited patients from surgery waiting lists, which is likely to include more severe profiles. However, symptom and function severity in our study was comparable with previous CTS cohorts from primary care  and secoOur study confirms the presence of central pain mechanisms in patients with focal nerve injury. This is of clinical relevance as their presence may be associated with poorer prognosis in some musculoskeletal conditions . It has Most studies of personalised management according to central pain mechanisms use time-consuming psychophysical testing. A low-cost self-reported questionnaire that identifies central sensitisation as measured by psychophysical tools would be ideal. Unfortunately, our study adds to the increasing body of evidence that questions the usefulness of the CSI in identifying central sensitisation according to psychophysical measures. Rather, our data, together with other studies, consistently suggest that the CSI better reflects emotional wellbeing. It is crucial that the distinct concept of emotional wellbeing is not conflated with the neurophysiological concept of central sensitisation in clinical practice. Nevertheless, even though the CSI may not be detecting “central sensitisation” in a strict sense, it may still be of value clinically. For instance, CSI scores seem to be associated with prognostic outcome in certain musculoskeletal conditions ,68, and Our results suggest that patients with CTS have changes indicative of altered central pain processing. The CSI does not seem to be associated with psychophysical measures of central sensitization. Rather, the CSI correlates with emotional wellbeing, in particular, depression scores. These data question the construct validity of the CSI in detecting central sensitisation in patients with focal peripheral nerve injury.


Various methods of analgesia can be used to reduce or prevent procedural pain in emergency department (ED). This study aimed to evaluate the effectiveness of topical lidocaine-diclofenac combination compared to lidocaine-prilocaine combination (Xyla-P) in reduction of the pain during central venous catheter (CVC) insertion.In this randomized clinical trial, 100 adult patients requiring CVC insertion in the ED were enrolled. These patients were randomly divided into two groups. The site of CVC insertion was covered with 2 g of topical Xyla-P cream in the first group, and 2 g of topical lidocaine-diclofenac cream in the second group. The primary outcome was the pain during CVC implantation. The secondary outcomes were physician satisfaction and the incidence of side effects. On the visual analog scale (VAS), the pain score during CVC insertion was significantly lower in the second group (p = 0.027). However, there was no difference in pain scores during lidocaine injection between the two groups (p = 0.386). Also, there was no significant difference in the rate of side effects between the two groups (p = 1.0). The physician’s satisfaction with the first group was significantly lower than the second group (p = 0.042).Although the CVC insertion pain was significantly lower in patients who received the topical combination of Lidocaine plus Diclofenac, there was no clinically important difference between the two groups and both topical anesthetics were effective and safe in reducing pain intensity. Also, lidocaine-diclofenac combination cream was more cost-effective than Xyla-P cream. Central venous catheter (CVC) insertion is one of the most frequently performed invasive procedures in the emergency department (ED), which is associated with pain, anxiety, and discomfort , 2. The Most clinicians believe that the local anesthetic injection will cause more pain than subsequent procedures, such as anchoring the catheter to the skin with sutures or eventually threading the dilator over the guidewire . Pain duVarious methods of analgesia can be used to reduce or prevent procedural pain. Using topical anesthetics is an available, low-cost, and effective method to achieve analgesia. Topical drug administration has clear advantages over other routes of administration, such as high levels of efficacy, more safety, and patient compliance. There is good evidence that adults benefit from reducing discomfort and anxiety by using an effective topical analgesic cream at the site of the procedure -9.For optimal pain management, EDs have a vast variety of protocols for reducing pain. Local anesthesia with Xyla-P cream 5% (2.5% lidocaine and 2.5% prilocaine) has been shown to effectively reduce pain associated with minor procedures such as needle punctures , 9. AnotBoth lidocaine and diclofenac have analgesic, anti-inflammatory, and antibiotic effects -13. Also2.1. Study design and settingThis prospective randomized double-blind clinical trial was conducted in the ED of two university teaching hospitals  in Isfahan, Iran, from January 2020 to April 2021. The study was approved by the Ethics Committee of Isfahan University of Medical Sciences (IR.MUI.MED.REC.1398.063). The trial was registered on the Iranian Registry of Clinical Trials under the number IRCT20180129038549N11. All patients provided written informed consent for participation in the trial.2.2. ParticipantsAll adult patients requiring CVC insertion in the ED consented to participating and were enrolled in the study. Patients were included in the study if they were older than 18 years, awake, alert, and oriented, and their medical condition was stable enough to allow CVC to be inserted within about 1 hour. Patients with visual, mental, or verbal disorders, a history of an allergic reaction to local anesthetics, a history of favism, methemoglobin, renal and liver disease, skin diseases at or around the CVC insertion site, and a history of drug addiction, a history of analgesic use within 24 hours before the procedure, were excluded. Also, patients were excluded if the venous catheter placement was not successful the first time (skin puncture was repeated more than once). 2.3. Intervention The patients were randomly allocated to receive one of the two topical anesthetics: Xyla-P cream (lidocaine 2.5% and prilocaine 2.5%), or lidocaine-diclofenac cream (2% lidocaine and 1% diclofenac). Randomization was based on a random-allocation software package (1:1).2 surface area over the procedure site in a thick layer and covered with an occlusive dressing for at least 45 min before the CVC implantation.In the first group (LP group), the site of CVC insertion was covered with 2 gr of Xyla-P cream . In the second group (LD group), the site of CVC insertion was covered with 2 g of a fixed-dose combination containing 1% diclofenac  and 2% lidocaine  cream. The topical anesthetic was applied on a 5 cm Lidocaine-Diclofenac cream was prepared in 30 g weighted tubes in collaboration with the Faculty of Pharmacology . It was matched with the Xyla-P cream in terms of color, smell, and shape, as well as labeling. An independent investigator who was not involved in clinical management and data collection did the randomization and prepared topical creams every day. After 45 minutes , the dre2.4. Data gatheringAll measurements were recorded by investigators blinded to randomization and the type of topical analgesia used. The pain was assessed using a Visual Analog Scale (VAS) from 0 to 10  , 7. The The pain scores were reported by the patient after initial subcutaneous lidocaine injection, and just after CVC insertion. The physician’s satisfaction was recorded after the overall procedure was completed. In the beginning of the study, patient characteristics ) were recorded. During the study, an investigator evaluated the local side effects . Systemic effects (heart rate and systolic and diastolic blood pressure) were also recorded before intervention and after CVC insertion. The patients, physicians, and nurses who participated in the trial were blinded to the randomization.2.5. Outcomes The primary outcome was the intensity of pain during CVC implantation. The secondary outcomes were physician satisfaction and the incidence of side effects.2.6. Statistical AnalysisCalculations showed that to detect a standard deviation of 0.90 for pain scores and a difference of 0.54  on the VFinally, the collected data was analyzed using SPSS software (ver. 25) and they were shown as Mean ± standard deviation (SD) or frequency (%). Chi-square test was used to compare qualitative data between the two groups, independent t-test and paired t-test were used to compare the mean of quantitative data, and univariate analysis was used to compare the mean pain score by adjusting confounding factors, such as age, sex, and BMI. The level of significance was considered less than 0.05.A total of 100 patients (50 patients per group) were enrolled in this study. All patients were included in the analysis . The meaThe mean pain scores during lidocaine injection and CVC insertion are reported in The physician’s satisfaction in the LD group was higher than the LP group (P = 0.042). There was no episode of urticaria and edema at the site of application in either of the groups. There was no significant difference in the rate of side effects between the two groups . Also, tAccording to the results of the present study, although the CVC insertion pain was significantly lower in patients who received the topical combination of Lidocaine plus Diclofenac, there was no clinically important difference between the two groups and both topical anesthetics were effective and safe in reducing pain intensity. Also, lidocaine-diclofenac combination cream is more cost-effective than Xyla-P cream.Procedural pain relief or control not only reduces anxiety and fear in patients but also increases their cooperation and contributes to the ease of the procedure and improves overall patient satisfaction. A CVC insertion can cause much pain and anxiety. One way to reduce this pain and anxiety is to use topical and local anesthesia.Linares-Gil et al. (2018) showed that a topical formulation containing lidocaine plus diclofenac was safe and more effective than the topical lidocaine alone for reducing the pain intensity during the first three days after surgery in benign anorectal surgery . Topical NSAIDs are effective in decreasing acute and chronic pain by inhibiting prostaglandin synthesis at the site of application . KhaliliBabaieasl et al. 2019) compared the efficacy of EMLA and Topical Diclofenac Patch (TDP) in attenuating peripheral venous catheters pain and phlebitis. EMLA and TDP had similar analgesic effects, but the incidence of phlebitis in the TDP group was significantly lower than the EMLA group  compared. These sThe pain caused by lidocaine injections is often considered a necessary problem, but there are several ways to reduce it. Buffering and warming of the lidocaine solution before injection are probably the simplest and most effective measures , 21. AnoCulp et al. (2008) compared various local analgesics regarding their efficacy of pain reduction during central venous catheter placement. There was no difference in pain scores during lidocaine injection between lidocaine and buffered lidocaine groups. Contrary to the present study, they showed that the mean score of pain during lidocaine injection was higher than pain during the insertion of the catheter . But in Selvi et al. demonstrated that topical vapocoolant spray can be used before digital nerve blocking to reduce procedural pain . HeydariThere was no episode of urticaria or edema at the site of application in either of the groups. Both erythema and irritation were observed in 2.0% of the participants in each group. There was no significant difference in the rate of side effects between the two groups. Similarly, Agarwal A et al. (2006) demonstrated no incidence of blanching at the site of DTP patch . In otheSmall sample size and evaluation of pain severity via a subjective method (VAS) can be considered as limitations of the present study. There was no control/placebo group for the comparison of VAS score to lidocaine injection. Minimum duration of 45 minutes was allowed for the application of both creams, which is a rather long period in the ED, as most of the studies using EMLA and NSAIDs for topical application have shown that 45-60 minutes is required for their full effect. The skin thickness affects topical absorption of the drug, so further studies can assess this matter more accurately. It is also suggested to do future studies to evaluate the effect of the present drug combination at different times and in different procedures to generalize the results of the present study to the community with more certainty.According to the results of the present study, although the CVC insertion pain was significantly lower in patients who received the topical combination of Lidocaine plus Diclofenac, there was no clinically important difference between the two groups and both topical anesthetics were effective and safe in reducing pain intensity. Also, lidocaine-diclofenac combination cream is more cost-effective than Xyla-P cream.The present article was extracted from the thesis by Dr. Maysameh Shahnazari Sani to achieve her specialist degree in emergency medicine from Isfahan University of Medical Sciences. The authors would like to express their gratitude to the staff of the ED of Al-Zahra and Kashani Hospitals, Isfahan, Iran. R.A., M.S.S., F.H., S.M., and M.S.; Contributed to conception, study design, and data collection and evaluation. R.A., M.S.S., F.H.; Contributed to statistical analysis, and interpretation of data. R.A., F.H.; Were responsible for overall supervision. F.H. and M.S.S; Drafted the manuscript, which was revised by R.A., M.S. and S.M. All authors edited and approved the final version of this paper for submission, and also participated in the finalization of the manuscript and approved the final draft.The authors declare no conflict of interest. This study was funded by Isfahan University of Medical Sciences.


Guideline-based best practice treatment for muscle invasive bladder cancer (MIBC) involves neoadjuvant chemotherapy followed by radical cystectomy (NACRC). Prior studies have shown that a minority of patients receive NACRC and older age and renal function are drivers of non-receipt of NACRC. This study investigates treatment rates and factors associated with not receiving NACRC in MIBC patients with lower comorbidity status most likely to be candidates for NACRC.Retrospective United States National Cancer Database analysis from 2006 to 2015 of MIBC patients with Charlson comorbidity index (CCI) of zero. Analysis of NACRC treatment trends in higher CCI patients was also performed.15.561 MIBC patients met inclusion criteria. 1.507 (9.7%) received NACRC within 9 months of diagnosis. NACRC increased over time (15.0% in 2015 compared to 3.6% in 2006). Higher NACRC was noted in females, cT3 or cT4 cancer, later year of diagnosis, and academic facility treatment. Lower utilization was noted for blacks and NACRC decreased with increasing age and CCI. Only 16.9% of patients aged 23-62 in the lowest age quartile with muscle invasive bladder cancer and CCI of 0 received NACRC.Although utilization is increasing, receipt of NACRC remains low even in populations most likely to be candidates. Further study should continue to elucidate barriers to utilization of NACRC. Nearly 80.000 people are diagnosed in the United States (U.S.) with bladder cancer annually , 15-20% Population-based reports demonstrate underutilization of both NAC and RC, 21-27% of MIBC patients ultimately undergo RC , far fewGiven the lack of data regarding non-clinical reasons for disparities in NACRC utilization, this study was designed to evaluate factors associated with NACRC utilization in a cohort with lower comorbidity status and therefore most likely to be clinically eligible for NACRC.This study is an Institutional Review Board-exempt 2006-2015 retrospective analysis of the National Cancer Database (NCDB). NCDB is a de-identified, standardized hospital-based registry of United States cancer cases, treatment, and outcomes from over 1.500 facilities across the United States representing 72% of newly diagnosed cancers and 70% of bladder cancers .Study patients had non-metastatic histologically confirmed transitional cell or papillary transitional carcinoma stages II-III cT2-4N0). Exclusions included pure or majority squamous cell carcinoma and adenocarcinoma subtypes, secondary malignancies, lack of treatment data and clinical stage lymph node involvement . To attrN0. ExcluPatients who died or were lost to follow-up within three months of diagnosis were excluded since it would not be possible to measure whether a complete course of chemotherapy was administered. NACRC was defined as cystectomy preceded by at least one course of multi-agent chemotherapy (NAC) both occurring within 9 months of MIBC diagnosis. This time interval was selected to capture patients whose treatment was most likely intended to be delivered primarily rather than as response to a treatment failure.Although we were able to select for several rounds of multi-agent chemotherapy, the specific multiagent chemotherapy regimen utilized, for example cisplatin based, is not available in NCDB and therefore was not assessed. Single agent chemotherapy was not considered NAC. Cystectomy included “simple/total/complete,” “radical,” “not otherwise specified,” or “pelvic exenteration.” All analyses were controlled for clinicopathologic stage, community, and patient age, gender, race, health insurance, treatment facility type, as well as whether treatment was delivered at more than one facility. Tumor characteristics included clinical T-classification  and grade. To avoid biasing the study by excluding patients with pathologic lymph node involvement found at time of cystectomy pre-cystectomy clinical staging was used. Community factors included rurality, quartile of educational attainment, and income metrics. Facility factors included treatment facility type and U.S. region. Year of diagnosis was analyzed for trends.Given concern for internal validity of CCI score in NCDB since only 11.302 patients were excluded for CCI greater than 0 from the initial 41.123 MIBC patients meeting cohort identification criteria, a sensitivity analysis to assess rates of NACRC in higher CCI patients was also performed. These patients represented those excluded from the main cohort for co-morbidity alone and otherwise meeting all other study inclusion and exclusion criteria.All variables were considered categorical and summarized with frequencies and percentages with comparisons between NACRC and non-NACRC using Chi-squared tests. To assess for independent associations of factors and control for clustering of patients within facility a mixed effects logistic regression modeling was performed . Models Among the 502.062 patients with bladder cancer identified, 41.123 had MIBC and no secondary malignancy. All treatment and data inclusion criteria including CCI score of 0 was met for 15.561 patients . NACRC wNACRC use increased from 3.6% in 2006 to 15.0% in 2015 among non-metastatic MIBC patients with CCI 0 . Only 16Over time, between the first half of the study period 2006-2010  and the second half 2011-2015  trends in odds of receiving NACRC in older patients compared to the youngest patients did not change. Black race was still associated in later years 2011-2015  with lower odds of NACRC compared to white race but this was higher than the first half of the study period (OR 0.58 p=0.02). Study patient's rates of receiving NACRC increased at academic facilities and community programs from 2006-2010  versus 2011-2015 . Using academic centers as referent, community cancer programs had increased odds of providing NACRC from 2011-2015  compared to 2006-2010  but this remained below academic centers. The increased rates of NACRC at community care facilities was proportionally less than the increased rates at integrated cancer programs from 2011-2015  versus 2006-2010 . Integrated cancer programs are in-between community and academic facilities in terms of facility medical resources. Rates of NACRC at integrated cancer programs also remained below academic centers. Female gender odds of NACRC receipt did not change over the study course. There was no statistically significant association with insurance status/type, level of education and household income, or tumor grade throughout the study.In sensitivity analysis of higher CCI patients while maintaining all other study criteria, higher CCI score was associated with lower rates of NACRC. Rates of NACRC were 7.3% for CCI 1, 5.7% for CCI 2, and 4.4% for CCI 3 or more . The oddOverall, 9.7% of patients with non-metastatic MIBC in patients with a CCI of zero received multiagent NACRC within nine months of diagnosis. Although NACRC use increased over time, consistent with other reports of NAC utilization  . This coGiven the long timescale of this study starting in 2006 when NAC recommendations were more recent, analysis of the first five years 2006-2010 compared to the last five years of the study period 2011-2015 was also performed to assess the nature of these. Between these two periods overall rates of NACRC increased 5.8% versus 12.6%, while still low this does represent implementation of recommendations over time. Over this time, black patients did become more likely to receive NACRC but were still not at likely as Caucasian patients to receive it at the end of the study period. When comparing the early study period to later, academic centers experienced greater NACRC implementation than community centers and integrated cancer centers . This likely represents improved implementation of guidelines at academic centers who are more specialized with higher volumes than community care centers.Overall, during the study patients treated at academic/teaching facilities were twice as likely to receive NACRC for non-metastatic MIBC. This adds to previous reports that care regionalized to high volume centers of excellence leads to decreased morbidity, mortality, decreased length of stay, and decreased readmissions -26. The Due to the multidisciplinary nature of NACRC requiring medical oncology, urology, social work, and nutrition expertise  to delivBoth clinical and non-clinical factors preclude patients from receiving NAC. In this study, some non-clinical factors that may preclude patients from starting or completing a NACRC treatment regimen were attempted to be isolated in order to examine them separately. There are racial and gender care disparities that may be unique to the United States, however disparities in guideline implementation by facility type is likely to be applicable to every health system. NACRC is a complex treatment modality that requires care coordination between multiple physician and non-physician medical specialty types. Even after initiating a NACRC treatment plan, patients, their families, and medical providers encounter numerous obstacles to completing the combined medical and surgical regimen. These pitfalls are all the more difficult to surmount at facilities without the resources of a centralized high-volume experienced facility.Compared to other recent studies already cited, this report is unique in that it selected for patients without documented CCI in order to only include patients with highest likelihood of NACRC eligibility. This study is not without limitations however and to fully interpret the results, it is important to understand CCI and other limitations within NCDB.Screening patients in this study by CCI only allows for the exclusion of patients on the basis of any one of 15 categories of comorbidity. This includes several important categories that may preclude eligibility for NACRC including any history of renal disease, diabetes, chronic pulmonary disease, myocardial infarction, congestive heart failure, and cerebrovascular disease. Renal disease may be the most relevant of the CCI conditions in terms of NAC eligibility. Careful evaluation of the specific Charlson definition of renal disease reveals a broadly inclusive definition including all stages, I (mild) though V (severe), renal impairment . It is iGiven concern for the accuracy of utilizing CCI as a proxy for likeliness of NAC eligibly, a sensitivity analysis of higher CCI patients otherwise meeting study criteria was performed. This did confirm patients with higher CCI had with lower odds ratio of receipt of NACRC as would be expected if NCBD CCI data had internal validity. Additionally, prior studies have evaluated the internal validity of CCI within NCDB . One stuAnother area of study limitation is the imperfect granularity of variant bladder histology within the NCDB. This study included only muscle invasive bladder cancers identified as transitional cell carcinoma or papillary transitional cell carcinoma. We may have included patients with a squamous cell component as long as it was a minority of the sample because these are coded within NCDB as TCC, we are unable to know how many patients fit into this category due to database limitations. Pure or majority squamous cell carcinoma and adenocarcinoma/signet ring cell sub-types are coded within the NCDB database and were specifically excluded. NCDB does not codify all subtypes in the database such as micropapillary, nested, plasmacytoid, or sarcomatoid which may be poorly suited for NAC and these may have been unknowingly included in the analysis.This study is also not able to determine what specific multi-agent chemotherapy regimen  a patient received because this data is not available within NCDB. Not all multi-agent chemotherapy would be standard of care, for example carboplatin-based regimens are specifically not recommended per guidelines  and if gOnly 9.7% of all patients and 16.9% of the youngest study quartile patients aged 23-62 with non-metastatic muscle invasive bladder cancer and low Charlson comorbidity received likely best practices treatment with timely multi-agent neoadjuvant chemotherapy followed by cystectomy. Utilization of neoadjuvant chemotherapy followed by cystectomy did increase over time. Identifiable factors associated with higher utilization were female gender, cT3 or cT4 cancer, later year of diagnosis, and academic or research facility treatment. Lower utilization was noted for blacks and NACRC utilization decreased with increasing age and CCI score. Academic treatment facilities exhibited a greater odds of NACRC treatment utilization than community centers over time. Community practice settings continue to lag further behind in NACRC application.Although utilization of NACRC is increasing over time, rates remain low even in populations most likely to be healthy enough to be treatment candidates. Rates varied but also remained low overall across treatment facility types. This data highlights the need for further quality improvement and implementation science studies to elucidate barriers to adoption of the complex care coordination treatment of muscle invasive bladder cancer with neoadjuvant chemotherapy followed by radical cystectomy.


Supraclavicular block (SCB) with long-acting local anaesthetic is commonly used for surgical repair of distal radial fractures (DRF). Studies have shown a risk for rebound pain when the block fades. This randomised single-centre study aimed to compare pain and opioid consumption the first three days post-surgery between SCB-mepivacaine vs. SCB-ropivacaine, with general anaesthesia (GA) as control.n = 90) with ASA physical status 1–3 were prospectively randomised to receive; SCB with mepivacine 1%, 25–30 ml (n = 30), SCB with ropivacaine 0.5%, 25–30 ml (n = 30) or GA (n = 30) with propofol/fentanyl/sevoflurane. Study objectives compared postoperative pain with Numeric Rating Scale (NRS) and sum postoperative Opioid Equivalent Consumption (OEC) during the first 3 days post-surgery between study-groups.Patients (p = 0.018). Further both median NRS and median OEC day 0 to 3 were significanly lower in the SCB-mepivacaine group as compared to the SCB-ropivacaine group during the first three days after surgery; pain NRS 1 (IQR 0.3–3.3) and 2.7 (IQR 1.3–4.2) (p = 0.017) and OEC 30 mg (IQR 10–80) and 85 mg (IQR 45–125) (p = 0.004), respectively. The GA-group was in between both in pain NRS and median sum OEC. Unplanned healthcare contacts were highest among SCB-ropivacaine patients (39.3%) vs. SCB-mepivacaine patients (0%) and GA-patients (3.4%).The three groups showed significant differences in postoperative pain-profile. Mean NRS at 24 h was significantly lower for the SCB-mepivacaine group .The online version contains supplementary material available at 10.1186/s12871-021-01499-z. A recent epidemiological study showed increasing incidences of DRF , with osf blocks .Peripheral blocks are increasingly popular after the introduction of ultrasound-guided techniques thereby increasing the success rate. Pain is often prominent when the effects of a single shot peripheral block wears off. The experience of this phenomeneon noted at block resolution is usually refered to as “rebound pain” . SeveralThe aims of the present prospective randomised study were to compare pain and postoperative opioid consumption during the first three days following open surgical repair of DRF in patients receiving SCB-ropivacaine vs SCB-mepivacaine with general anesthesia (GA) as control.The hypothesis´ to be tested was; a SCB-mepivacaine will be associated to a better postoperative pain progression and less postoperative opioid consumption compared to a SCB-ropivacaine following open surgical repair of DRF.This single-centre prospective randomised clinical trial was approved by the Gothenburg Ethical Committee May 31:st 2018, (registration number 214–18). It was also registered in the Sahlgrenska University Hospital GDPR  database August 28, 2018. The study was conducted in accordance with the tenets of the 1964 Declaration of Helsinki. It was retrospectively registered in clinicaltrials.gov (NCT03749174) the 21:st November 2018 with explicit information about start of patient inclusion the third September 2018. All patients aged between 19 and 86 years, with ASA physical status 1–3, and scheduled for Day Surgery of a distal radius fracture between September third 2018 and June 15th 2020 at Department of Anaesthesia and Intensive Care, Sahlgrenska University Hospital/Mölndal Hospital, Gothenburg, Sweden, were assessed for eligibility. A written informed consent with permission to publish was obtained from all patients before enrolment. All data generated and analysed during the current study are available from the corresponding author on reasonable request.All fracture-classification were made by an experienced orthopaedic surgeon. Opiod naïve patients were included when having a closed DRF, , ≤ 17 days from trauma and scheduled for operative fixation with a volar locked plate. Finally, maximum length-of-surgery had to be < 90 min and all surgeons used tourniquet. Exclusion criteria were; multifractures, pre-trauma inflammatory diseases, dementia, severe psychiatric disorder or cognitive dysfunction, ongoing drug/alcohol abuse, known local anaesthetic allergy, pregnancy and finally, no fluency of the Swedish language.Totally 142 patients were eligible for study enclosure. Twenty-two patients declined study participation leaving 120 patient to be included following written informed consent. Further, 30 patients were recruited to another part of the study, . Thus, 90 patients were randomised and included with 30 patients to one of three anaesthetic techniques using sequentially numbered opaque envelopes with a random allocation sequence in 2 blocks, by the investigator.Group 1: Supraclavicular block (SCB) given as a singleshot: mepivacain 1%, 25–30 ml and iv sedation using propofol (n = 30). Group 2: SCB given as a singleshot ropivacain 0.5%, 25–30 ml and iv sedation using propofol (n = 30). Group 3: General anaesthesia (GA) using propofol/fentanyl/sevoflurane and laryngeal mask and no local anaesthesia , etoricoxib 90 mg (if no contraindication) and meclizine 25 mg. All patients were given betamethasone 8 mg iv sedation with propofol perioperatively.All SCB-blocks were performed by senior anaesthetists skilled in ultra-sound guided blockade technique. Blocks were placed under ultra-sound guidance with in-plane technique with goal to have local anaesthesia spread around the nerv-trunk. All SCB-block patients were offered a mild iv (0.1 mg/kg) and received no additional local anaesthesia.GA was induced in the operation theatre by an anaesthetic nurse and an anaesthesiologist. Anesthesia was induced with propofol and fentanyl and maintained with sevoflurane. Patients were given oxycodone Patients were monitored in the Post-Anaesthesia Care Unit (PACU) until considered stable and adequately pain-relieved to be transferred to the step-down ward. SCB-patients, if sufficiently awake after sedation, by-passed the PACU and were taken directly to the step-down ward.All data were collected by the study nurse while patients were still in hospital and then by 3 follow-up telephone calls at 24, 48, 72 h after discharge. Data as; patient characteristics, NRS (0–10) for pain assessment at rest was performed; before surgery and 2, 24, 48, 72 h after surgery. NRS was also assessed at block resolution, when patients experienced full motor and sensory function.NRS for nausea and vomiting were assessed at the same time-points.Oxycodone consumption in hospital and after discharge, (the first 3 postoperative days), was collected. Oxycodone was iv administrated in PACU and orally administrated at the step-down unit and after discharge.Perioperative observations were registered; time anaesthesia nurse was occupied with the patient, theatre time, surgery-time including plaster, PACU-time and time-to-discharge, (only day-surgery patients). Moreover, total SCB effect-time and effect-time after surgery was noted as well as unplanned admissions and healthcare contacts during the first postoperative week.The patient obtained a protocol to note the type, dose and frequency of analgesic consumption at home and they all received the same postoperative pain management after discharge; oxycodone 5–10 mg and acetaminophen 1000 mg, respectively. (No NSAIDs or Coxibs was provided postoperatively.) They received a prescription of these medications to be taken ad libitum within a daily maximum dose of 30–40 mg oxycone and 4000 mg acetaminophen. All opioid analgesics were converted to opioid equivalents (mg of p.o. morphine). The specific conversion ratio used are shown in Additional file Primary endpoint; difference in pain (NRS) at rest at 24-h and further during the first three days after surgery between SCB performed with mepivacaine vs ropivacaine, with GA being control group.Secondary endpoints; Postoperative Opioid Equivalent Consumption (OEC) during the first three postoperative days. Differences in pain and opioid consumption between SCB’s and GA controls were also analysed. Post Operative Nausea and Vomiting (PONV) and Post Discharge Nausea and Vomiting (PDNV) during the first 3 postoperative days. Perioperative events described above, number of patients by-passing PACU, number of unplanned admissions and unplanned health care contacts postoperatively were registered.p < 0.05.Sample size calculation: The statistic was based on similar studies from public domain ,  for skewed data and categorical variables, number of patients in percent (%). For comparison between independent T-test and ANOVA for normal distributed continuous variables and the Mann-Whitney U-test and Kruskal-Wallis test was used for skewed distributed continuous variables. Normal distribution was assessed by the Shapiro Wilk test. Chi-square and Fischer’s exact test was used for non-ordered categorical variables.Primary outcome, difference in pain between SCB with ropivacaine vs mepivacaine, was assessed between groups mean NRS at 24 h and the median of the NRS values for the first three postoperative days for the analysis of pain pattern following resolution of the block (3 days NRS sum divided by 3). Opioid used was transposed into opioid equivalence in mg and median of oral opioid consumption for the first three days was used for analysis of opioid use difference between groups. Non-parametric test (Mann-Whitney U for two groups), was chosen for comparison of pain and OEC as Shapiro Wilk test for normal distribution was found significant for all NRS and OEC variables.p < 0.05 was considered statistically significant. All data was compiled into XL and statistical analyses were performed using SAS 9.4 .A Nighty patients were initially recruited and 84 patients, 10 males/74 females, aged 19–86 years completed the protocol to assess primary and secondary outcomes, Flowchart Fig. Five patients, (2 in SCB-ropivacaine group and 3 in SCB-mepivacain group), were excluded due to failed blockade and therefore received GA. One patient (GA group) was excluded as surgery time exceeded 90 min.The three groups were comparable in patients´ characteristics and preoperatively analgesic medication. There was only a slight difference in BMI between the 3 groups of patients studied, see Table p = 0.018), see Fig. Pain ratings at base-line, preoperative mean NRS was similar between the 3 anaesthetic technique groups. There was a significant differences in postoperative pain profiles during the 3-days postoperative study period. The pain rating (mean NRS) at 24 h (following resolution of blocks) was significantly lower in SCB-mepivacaine group of patients (p = 0.017). The GA-group median NRS was inbetween the SCB-ropivacaine and the SCB-mepivacaine groups, see Tables The median values for the first three postoperative days’ pain ratings (NRS) was significantly lower among the SCB-mepivacaine patients as compared to the SCB-ropivacaine group (p = 0.004) with the GA-group being in between see Table The oral opioid consumption during the first three postoperative days was also significantly lower for the SCB-mepivacaine group compared to the SCB-ropivacaine group  experienced associated to the resolution of the local anaesthesia analgesia effect was similar between groups, Table Except for PACU-time, there were no differences in any other perioperative time events studied between study groups, Table All GA patients required PACU-observation with mean duration 114.7 (± 44.0) min. Only one SCB-ropivacaine and four SCB-mepivacaine patients needed PACU monitoring, mean 42 (±0) and 13.4 (± 35.4) min, respectively, Table p < 0.0001). Pain, (mean NRS), at time when plexus block wore off did not differ between the two SCB-groups, Table Plexus block total duration time and remaining duration time after surgery, were significantly longer in the SCB-ropivacaine group, mean 18.9 and 16.4 h, respectively vs the SCB-mepivacaine group, mean 4.6 and 2.7 h, respectively (Four 4.8%) patients were admitted overnight after surgery: 1 (3.4%) in the GA-group, 1 (3.6%) in the SCB-ropivacaine group and 2 (7.4%) in the SCB-mepivacaine group. The GA-patient was admitted because of pain, while the 3 SCB-patients were admitted as of social reasons, Table .8% patien = 1) contacted healthcare because of fever the first postoperative day. The SCB-ropivacaine patients contacted healthcare because of pain (n = 2), great discomfort with having a “dead arm” hours after surgery (n = 2) and one patient had a burn-damage on 2 fingers. (This latter patient touched a hot kettle with a still anaesthetized arm and needed repeated contacts (n = 6) because of blisters).Twelve unplanned healthcare contacts were required during the first week after surgery; one in GA-group, 11 in SCB-ropivacaine group and none in SCB-mepivacaine group. The GA-patient , had a significantly longer duration compared to a SCB with a short-acting anaesthetic agent (mepivacaine). The most important finding was that the pain progression following resolution of the SCB’s was significantly worse in patients given ropivacaine compared to those given mepivacaine, both in median mean NRS and in the higher postoperative opioid consumption. Interestingly, the GA-patients show a median sum opioid consumption just in between the two SCB groups. Thus, GA-patients were not found to have worse pain scores the first three days after surgery compared to those given SCB’s. Finally, SCB-mepivacaine patients had no unplanned health care contacts after discharge during the 3-day follow-up, whereas SCB-ropivacaine patients had several visits.The risk for rebound, i.e. worse pain at blockade resolution, in patients similar to ours, has been suggested by Galos et al. . They foOther randomised studies have shown a difference in experienced postoperative pain between GA and brachial plexus block with long-acting local anaesthetics for surgical treatment of DRF , 8, 16. Previous studies have shown no difference in opioid consumption between GA and SCB, (with long-acting anaesthetic agents), during the first 3 postoperative days , 17. Theiv opiods must be supplemented peri-operatively.The findings of time-slots per se in perioperative period confirm those by Galos and colleagues , who alsSunderland and coworkers showed in 2016 that SCB-patients had a higher rate of unplanned healthcare contact because of pain compared to GA-patients for DRF-surgery . We confDespite extensive information about the long-acting block, one patient visited the emergency department in the evening on day of surgery because of disconfort of the arm paralysis and one patient called us by telephone next day wanting hospital admission because of similar discomfort. Dissatisfaction because of long-acting motor block has been studied earlier , where tThis study had a prospective randomised clinical design. It was a single-centre design without any loss to follow-up reducing the risk of selection and information bias, and this warrants generalisability of this study. Investigator selection was avoided as only two investigators collected all data, ensuring consistency and a high standard of data collection. However, the trial was not blinded to any of the anaesthesia/surgery staff nor to the study nurse or the patients. We excluded patients with poor Swedish comprehension and severe pre-existing medical conditions and 22 patients declined to participate of different reasons. We only report on consumption of opioids and not on nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. This is supported by results from a recent study  in whichOur findings must naturally be put in perspective. Pain was over all low and differences between groups are significant different when compared for the period studied but the clinical diffrences may be argued. The low pain ratings must however be put in perspective of the significantly higher opioid use in the ropivacaine group. The groups were similar in demographics and all experienced pain prior to surgery. Surgery was performed by senior orthopeadic surgeons and all patients followed the same care pathway. Six patients in the SCB-groups were lost to follow-up, 5 because of failed block, insufficient block for surgery and subsequently was given GA in addition. One patient was lost because of prolonged surgery. Still the number in each group was in line with the power calculated numbers needed.Future studies should explore if a short-acting local anaesthetic agent, proposedly with an adjuvant addition, in the SCB could make the initial postoperative recovery less painful and with less opioid consumption after discharge. It could also prevent unplanned healthcare contacts and make the recovery more safe and comfortable in day surgery. As pain is multidimensional, studies on pain should assess several outcome domains. Thus, future studies should include a more extensive evaluation of multidimensional pain-related patient reported outcomes, e.g. intensity of pain related to movement but also its interference with activities, side effects and perception of care , 21.Day surgery is expanding, including improved anaesthesia techniques, to facilitate safe and effective surgery and at the same time offering rapid, safe and effective recovery with a minimum of pain and other residual symptoms. In this study we found that the potential benefit of longer duration of analgesia, associated to the use of a long-acting local anaesthetic agent, during the early postoperative course must be put in perspective of potential worse pain course and a higher opioid consumption following resolution of the block after discharge from hospital. Thus, our hypothesis is confirmed that SCB with mepivacaine, a short-acting LA, is associated with less rebound pain. From our results we recommend short-acting local anesthetic agents to be used in SCB for surgical treatment of DRF to mitigate postoperative opioid-consumption and enhance patient comfort.Additional file 1 Equianalgesic conversion ratios. Oxycodone administered to patients in PACU and/or step-down unit and/or consumed by patients after discharge within the first three postoperative days were converted into mg of peroral (p.o.) Morphine. i.v. intravenous.


Coronectomy of a mandibular impacted third molar is a surgical treatment to minimize the risk for inferior alveolar nerve damage. We aimed to determine whether this procedure affected the oral health-related quality of life (OHRQoL) within the first postoperative week. This prospective study included 50 patients that underwent a coronectomy for an impacted mandibular third molar. The patients completed the Oral Health Impact Profile-14 (OHIP-14) questionnaire and questions about pain and analgesic intake on every day during the first postoperative week. Mean OHIP-14 scores were highest during the first three postoperative days; the highest mean score  was observed on the first postoperative day. Mean OHIP scores gradually declined during the first postoperative week, and the mean OHIP-14 score was 9.82 (SD: 9.15) on the seventh day. Physical pain was the highest contributor to the overall OHIP-14 score. Pain gradually declined with time; the lowest mean pain score  was observed on the seventh day. OHIP-14 and pain scores were not significantly different between sexes or between different grades of impaction. OHIP-14 scores were positively correlated with pain scores. A mandibular third molar coronectomy had a strong effect on patient OHRQoL, particularly during the first three postoperative days. Key words:Third molars, coronectomy, pain, OHRQoL. Surgical removal of the mandibular third molar is a very common oral surgical procedure. Postoperative inflammatory conditions, like alveolar osteitis and surgical site infections, are frequent complications after this procedure, but they are typically easy to manage. A less common, but more serious complication is an inferior alveolar nerve (IAN) injury, which can lead to a neurosensory deficit. In 1-3.6% of IAN injuries, the neurosensory disturbance is permanent . The risThe IAN is located deep in the mandible; thus, a coronectomy can minimize the risk of IAN injury -11. The Previous reports on the mandibular third molar coronectomy were mainly focused on the surgical technique, root migration, postoperative IAN function, socket healing, and postoperative inflammatory parameters ,6,13. LiThe present study aimed to investigate whether an impacted mandibular third molar coronectomy would affect the OHRQoL during the first postoperative week. We surveyed patients with the Oral Health Impact Profile-14 (OHIP-14) questionnaire. Previous studies have demonstrated the effect of surgical removal of mandibular third molars on OHRQoL with the OHIP-14 questionnaire, but no study focused on the mandibular third molar coronectomy . In addi- ParticipantsEligible patients were referred by their dentist to the Department of Oral and Maxillofacial Surgery of the Amstelland hospital in Amstelveen, The Netherlands, for removal of an impacted mandibular third molar. Patients with asymptomatic impacted mandibular third molars that underwent a coronectomy between January 2019 and December 2019 were included. Inclusion criteria were age 18 years or older, healthy (American Society of Anesthesiologists (ASA) 1), willing to participate, and able to read, understand, and answer the questionnaire. Exclusion criteria were: known allergies to ibuprofen or chlorhexidine; smoker; periodontitis; a medical history involving renal failure, blood diseases, or chronic liver disease; taking anti-aggregants or corticosteroids, currently, or in the 15 days prior to surgery; breastfeeding or pregnant; local infection, preoperatively or in the 15 days prior to surgery; previous radiation therapy to the maxillofacial region; uncontrolled diabetes; taking antibiotic prophylaxis for endocarditis; or any local pathology.This prospective study was reviewed and approved by the institutional Medical Ethics Committee of the Amsterdam University Medical Center. The study was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki, as amended in Somerset West, Republic of South Africa, in 1996. Patients were provided with information to explain the study, and all patients consented to participate in the study. Patients also agreed to attend two appointments (the surgery and a control visit). All patients were fully informed about the surgical procedure, postoperative care, possible complications, and follow-up examinations. Each patient was informed that they had the opportunity to withdraw from the study at any time, without consequences regarding the treatment.- Study procedureThis study included 50 patients. Preoperatively, patient demographic and medical information was recorded, and the patients were labeled patient 1 to patient 50, to ensure confidentiality of patient information during the study. We recorded the location of the impacted third molar, and we performed an X-ray orthopantomogram to assess the degree of impaction (Pell and Gregory’s classification). We also recorded the proximity of the IAN to the third molar roots. With 3-dimensional computed tomography, we confirmed the relationship between the IAN and the roots of the impacted mandibular third molar.- Surgical procedureThe impacted mandibular third molar coronectomy was performed with the patient under local anesthesia. All surgeries were performed by one surgeon in a standardized fashion, with a similar technique in all cases. All patients received a standardized, mandibular nerve block injection, with additional local infiltration of the buccal nerve. The location, temperature, type, and amount of anesthetic , and the type of needle (27 gauge/.40 × 35 mm) were all standardized, according to the hospital protocol. A triangular flap was used in all patients. Briefly, an incision was started at the distobuccal edge of the second molar, then dropped at a slight oblique angle, and then curved forward into the mandibular vestibule. The second part of the incision started from the mandibular ramus and ended at the distobuccal aspect of the second molar. Any bone overlying the crown of the impacted third molar was removed with a round surgical bur, which exposed the cementoenamel junction of the tooth. Next, a fissure bur was used to separate the crown from the roots. The root was shortened to 3-4 mm below the bony margin and checked for mobility. Copious irrigation with sterile saline was performed with rotary instrumentation. Dental follicular soft tissue was removed, and the socket was thoroughly irrigated with saline. The surgical site was primarily closed with 3/0 Undyed Vicryl Rapide . Immediately after surgery, the details of the procedure were recorded.- Postoperative managementAfter surgery, all patients were instructed to bite on a gauze for 30 min. They were also instructed not to rinse or spit during the first 24 h postoperatively. Ibuprofen  was prescribed three times a day. No postoperative antibiotics were prescribed. The day after surgery, patients began rinsing the mouth with a 0.12% aqueous chlorhexidine mouth rinse for 1 min twice per day for 7 days. Patients were given verbal and written postoperative instructions, and they were recalled for follow-up at 1 week.- Follow-upOne week after surgery, patients were examined to assess surgical site wound healing and to check for alveolitis and wound infection. At that time, the completed OHIP-14 questionnaires were collected.- Outcome measurementsThe outcome measurements included the OHIP-14 score, the pain score, based on the numeric rating scale (NRS) and the daily analgesic intake. OHRQoL was assessed with the OHIP-14 questionnaire. It involved the following parameters: problems pronouncing words, altered sense of taste, difficulty in chewing, pain/aching, worry about dental problems, psychological discomfort, problems affecting the diet, interruptions in meals, difficulty relaxing, feeling embarrassed, feeling irriTable, job-related difficulties, less satisfaction in life, and functional inabilities. The short form of the OHIP-14 consisted of 14 items within 7 domains, including: functional limitations, physical pain, psychological discomfort, physical disability, psychological disability, social disability, and handicaps -16. Pati- Data managementAll patient data on infection, alveolitis, analgesic intake, pain scores and OHIP-14 scores were collected between January 2019 and December 2019 and imported into a database. The data also included two demographic variables: the age at surgery (years) and sex. Gregory and Pell’s classification of the third molar position was used to describe the degree and type of mandibular impaction.- Statistical analysisp>0.05). Repeated measures ANOVA was used to assess the mean differences of OHIP- and pain scores over time from day 1 to day 7. If the overall p-value of the repeated measures ANOVA was smaller than 0.05, pairwise comparison was used to test differences between any two time points. Pearson’s correlation test was performed to analyze correlations between different variables. The independent sample t-test was used to determine if there was a significant difference in OHIP-14 scores, pain scores and analgesic intake between the male and female variables on each postoperative day.Conventional descriptive statistics were performed to characterize the patient sample. The Shapiro-Wilk test showed that all the outcome variables in this study were normally distributed  males and 37 (74%) females. The mean ages were 25 years (range: 19 to 35) for males and 25 years (range: 18 to 36) for females. The treated third molar was on the left side in 30 patients and on the right side in 20 patients. The treated molar alignments included 60% mesioangular, 24% horizontal, and 16% vertical . The deg- OHIP-14 and Pain scoresp<0.01).Results from the repeated measures ANOVA test showed this decline in pain score was significant (p<0.01), which was statistically significant on each postoperative day (p<0.05). No significant differences between males and females in the total OHIP-14 scores and the pain scores on each postoperative day were found.The repeated measures ANOVA test also showed this decline over time in the mean OHIP-14 scores  . Then, aet al. , patients had difficulties in opening the mouth or chewing. Most patients required liquefied or soft foods that could be swallowed without much chewing.et al. (An important question is whether a coronectomy of an impacted mandibular third molar might impact the QoL or pain score more than the surgical removal of an impacted mandibular third molar. Only one previous study reported on QoL after a coronectomy. Manor et al.  comparedet al. . A potenet al.  pointed et al. -8. Howevet al. ,12.In the present study, no patient experienced sensory impairment of the IAN after the mandibular third molar coronectomy. Previously, a randomized study compared surgical removals to coronectomies in 128 patients. They found that 19% of the surgical removal group sustained IAN damage and no IAN symptoms were reported among the successful coronectomies . Other set al. (In the present study, only one patient experienced a postoperative infection: an abscess occurred on the third postoperative day. The abscess was drained, and amoxicillin was given 3 times per day for 5 days. Postoperative infection rates after a mandibular third molar coronectomy have varied between 3.2 and 5.8 % ,25. The In a coronectomy, the roots remain in place; over time, this situation can lead to symptoms and pain. Due to this potential complication, some patients and oral surgeons might hesitate in selecting this treatment . On the et al. (In the present study, no cases of alveolitis were observed. The incidence of dry socket after a coronectomy was previously reported to be relatively low, due to the facts that the wounds were small, little alveolar bone was exposed, and primary wound closure was performed . Leung &et al.  reportedet al. .The main limitation of this study was that we included only 50 participants. Although the procedure was similar in all cases, a small sample size increases the margin of error and affects the reliability of the study results.In conclusion, the results of the present study showed that a coronectomy of an impacted mandibular third molar affected the OHRQoL of patients, particularly in the first three postoperative days. This information should be considered, when assisting patients in planning their schedules and preparing themselves psychologically. A coronectomy seems to have a greater impact on the OHRQoL than the total surgical removal of mandibular third molars.


The LBP cohort had significantly stronger MC in the connection between right precuneus and left opercular part of inferior frontal gyrus (p < 0.05). LBP patients had significantly stronger degree in left anterior cingulate gyrus and left rectus gyrus (p < 0.05) while had significantly weaker degree than PHN patients in left orbital part of middle frontal gyrus, left supplementary motor area and left superior parietal lobule (p < 0.05). LBP and PHN patients had significant differences in the brain’s GMV, MC, and network properties, which implies that different PNPs have different neural mechanisms concerning pain modulation.The purpose is to explore the brain’s structural difference in local morphology and between-region networks between two types of peripheral neuropathic pain (PNP): postherpetic neuralgia (PHN) and lower back pain (LBP). A total of 54 participants including 38 LBP and 16 PHN patients were enrolled. The average pain scores were 7.6 and 7.5 for LBP and PHN. High-resolution structural T1 weighted images were obtained. Both grey matter volume (GMV) and morphological connectivity (MC) were extracted. An independent two-sample t-test with false discovery rate (FDR) correction was used to identify the brain regions where LBP and PHN patients showed significant GMV difference. Next, we explored the differences of MC network between LBP and PHN patients and detected the group differences in network properties by using the two-sample t-test and FDR correction. Compared with PHN, LBP patients had significantly larger GMV in temporal gyrus, insula and fusiform gyrus ( Moreover, different types of chronic pain might alter different brain regions and networks, which was called brain biomarkers or pain matrix49. Investigation on brain network alteration have benefits for revealing central modulation mechanism of pain as well as for further research of precise and targeted therapy38.Increasing incidence of chronic pain has drawn more and more attention worldwide. It was demonstrated that chronic pain could alter brain activity and networks40 has typic characteristics of spontaneous pain due to inflammation, such as postherpetic neuralgia (PHN)22, or due to injury of nerve roots, such as lower back pain (LBP) caused by compression of lumbar discs55. Both PHN and LBP may have the same pain mechanism and clinical symptoms, but they still induce different central activity and pain biomarkers. A large number of neuroimaging studies have explored the brain activity and network changes46 in PHN and LBP, and have exposed their neural mechanism of pain modulation. However, most previous studies have conducted research on pain patients with healthy subjects as control30, or used self-control before and after therapy27. As we know, pain disorders could bring pain feeling and some negative emotion such as depression, insomnia and anxiety, which would also alter the brain’s structure and functions49. Therefore, it remains unclear whether previous findings of altered brain patterns in pain patients were caused by pain or accompanying negative emotion. To solve this problem, using two types of pain diseases as control for each other could help exclude emotional influence and facilitate exploring specific brain regions or networks for different types of pain. Pain patients always suffer from negative emotions, it is helpful to offset the effects by enrolling patients with comparable pain intensities and emotion scores by questionnaires as control. In addition, making PHN and LBP as controls for each other might be more possible to obtain the specific brain biomarker for different pain even though both of them belong to PNP. To our best of knowledge, there was no neuroimaging study concerning both PHN and LBP.As a common type of chronic pain, peripheral neuropathic pain (PNP)46, and it can reveal the functions and structures of the brain from different aspects. Compared with function MRI (fMRI) and diffusion tenson imaging (DTI), T1 weighted imaging (T1WI) has the advantages of easier access, higher resolution, and relative insensitivity to artifacts . However, few studies29 have explored the GMV changes in PHN from T1WI, let alone MC.Multimodal MRI is the most commonly used neuroimaging method in previous pain-related studies43, MC could help characterize structural connectivity and reflect synchronized development15. Previous studies have shown MC could be important brain biomarkers of perception26, neurological diseases52, and pain sensitivity58. However, MC has not been conducted in pain patients. Considering the mounting evidence on the close relationship between pain disorders and other types of structural or functional brain connectivity 35, it is reasonable to hypothesize that MC is a promising brain biomarker of neuropathic pain.By calculating the inter-regional similarities of local brain morphology from T1WIIn our study, we explored both the GMV and MC patterns of PHN and LBP patients and gauged the differences of structural networks between these two types of PNP to find out the possible structural MRI biomarkers which were more specific to the diseases. Because PHN and LBP have different causes, we hypothesized that PHN and LBP would have different structural networks even if they both belong to PNP.This prospective study was approved by an institutional review board  and was conducted in compliance with the Declaration of Helsinki. All participants in this study provided written informed consent.32. Pain was primary localized within the lumbar or lumbosacral region, accompanying with or without radiation to the buttocks, thighs or legs. In addition, all the LBP patients also underwent lumbar MR scanning to identify the herniation of lumbar discs.Consecutive patients which were confirmed as PHN or LBP by anesthesiologists were included. All the subjects were right-handed. For PHN cohort, all participants reported a history of shingles, associated pain, and varicella zoster virus infection. All participants reported a history of persistent pain for at least 2 months after resolution of the acute shingles episode. For LBP cohort, all participants were suffering from chornic lower back pain for at least 6 months according to IASP criteriaNone of them had a history of psychiatric or neurological disorders. Individuals with a history of any disorder with a potential impact on brain structure  were excluded from this study. The clinical symptoms of pain were assessed using a numerical rating scales (NRS), with a range from 0 (no pain) to 10 (the highest tolerable pain). All of the patients underwent neurological and psychological examinations and fulfilled the mini-mental state examination (MMSE). Only the patients with the scores above 27 in MMSE were included. Patients with any abnormality detected on brain MRI were excluded from our study.57 for measuring anxiety and depression.For further characterization of patients, all individuals were asked to complete the Chinese version of the Hospital Anxiety and Depression Scale (HADS)0; slice thickness = 1 mm without a gap; field of view (FOV) = 240 × 240 mm2; matrix size = 256 × 256. A total of 160 axial slices were acquired for each patient.All the brain MRI examinations were performed on a 3.0 T scanner  with a 32-channel phased-array head coil. High-resolution structural T1WI were obtained by using a three-dimensional magnetization-prepared rapid gradient-echo (3D-MPRAGE) sequence with the following parameters: repetition time (TR) = 8.1 ms; echo time (TE) = 3.7 ms, flip angle = 8https://www.fil.ion.ucl.ac.uk/spm/software/spm12/) Toolbox in MATLAB-R2018b . The preprocessing procedure was as follows. First, the MRI data of each subject were segmented into grey matter (GM), WM and cerebrospinal fluid (CSF). Second, the GM segments were non-linearly co-registered by using the inbuilt high dimensional Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL)5. Third, GM images were normalized to standard Montreal Neurological Institute (MNI) space to make the GM images in the same space. Thereafter, the resulting GM images were modulated by the Jacobian determinants. Fourth, the GM images were smoothed with an 8 mm full-width-half-maximum (FWHM) Gaussian kernel. The GM images of all subjects were used for the further analysis.All structural MRI data processing routines were carried out by using the Statistical Parametric Mapping 12  were defined in this analysis.We used the Automated Anatomical Labeling (AAL) atlas to define the whole brain parcellation for later MC network analysis10 was used to calculate the probability density function for each ROI11. Third, the morphological connectivity for each pair of ROIs was estimated as the similarity between the two probability density functions of this pair of ROIs by using Kullback–Leibler divergence23. The Kullback–Leibler divergence was defined as:In our study, we extracted two types of features using the preprocessed GM images: GMV and MC. GMV of each subject was estimated by voxel-based morphometry (VBM) in the whole brain as the local morphological feature. MC is a measure of structural connectivity, and it was calculated in the following steps. First, we quantified the GM intensity of each voxel within each ROI in preprocessed GM images. Second, the kernel density estimation with automatically chosen bandwidths24:Moreover, Kullback–Leibler divergence was converted to a similarity metric asThe range of Kullback–Leibler-based similarity (KLS) is from 0 to 1, where 1 indicates two identical distributions while 0 implies two completely different distributions. Finally, a MC matrix with a size of 90 × 90 was acquired for each participant.51. First of all, a thresholding procedure is commonly used to binarize the MC network before performing topological characterization on the morphological connectivity matrices. A sparsity threshold, which was defined as the ratio of the number of existing edges divided by the maximum possible number of edges in a network, was used to binarize the divided MC network23. We binarized the MC network within a wide range of the sparsity threshold  because an automated method to determine the sparsity threshold is lacking50. Then, we calculated the network properties of MC within different sparsity thresholds.Next, we applied graph theory to estimate the network properties of MC, and the network properties including degree, small-worldness, network efficiency, clustering coefficient and characteristic path length. The calculation of network properties on MC matrices across all participants were performed with the GRETNA Toolboxt-test was used for the comparisons of age and scores for pain, anxiety and depression between groups.Independent-8. Furthermore, we detected the group differences in network properties  at different sparsity thresholds by using the two-sample t-test and FDR correction.An independent two-sample t-test with an accompanying false discovery rate (FDR) correction was used to identify the brain regions where LBP and PHN patients showed significant GMV difference. Meanwhile, the total intracranial volume (TIV) of each subject was estimated and used as a covariate to remove the effect of variations in brain intracranial volume. Next, in order to explore the differences of MC network between LBP and PHN patients, we performed an independent two-sample t-test with FDR correction to correct the problem of multiple comparisonsNext, for each the feature showing significant group differences, we calculated the Pearson’s correlation coefficients between these features (including MC and degree) and pain scores in LBP or PHN group, separately. On the other hand, the standard general linear model (GLM) was used by creating design matrices for multiple regression analysis of GMV, with pain scores and TIV as regressors. The GLM was used to construct pseudo t statistic images, and significant clusters were extracted with voxel-level p < 0.005. FDR was finally used to correct the problem of multiple comparisons.Ethical approval was obtained from the institutional review board .All participants in this study provided written informed consent.t = − 1.852, p = 0.07 > 0.05).A total of 54 participants including 38 LBP patients  and 16 PHN patients  were enrolled in the experiment. There was no statistical significance between age comparison .The average pain scores were 7.6 ± 1.6 (rang from 5.5 to 10) in LBP patients, and were 7.5 ± 1.9 (rang from 6 to 10) in PHN patients. There was no statistical significance between them .The clusters with significant differences in GMV between LBP and PHN were shown in Table Group differences in MC network between LBP and PHN were shown in Fig. p < 0.05), and had significantly weaker MC in cluster 3  and cluster 4  (p < 0.05). However, after FDR correction, we only found that the LBP cohort had significantly stronger MC than PHN in the connection between right precuneus (PCUN. R) and left opercular part of inferior frontal gyrus (IFGoperc. L) , and the results were shown in Fig. Compared with the PHN cohort, the LBP cohort had significantly stronger MC in cluster 1  and cluster 2  , while LBP patients had significantly weaker degree than PHN patients in left orbital part of middle frontal gyrus (ORBmid. L), left supplementary motor area (SMA. L) and left superior parietal lobule (SPG. L) . In addition, there were no significant differences in other network properties  between LBP and PHN patients.The group differences in degree between LBP and PHN patients were shown in Fig. The correlations between pain scores and the features that showing significant group differences were shown in Fig. In our study, we investigated the brain’s regional characteristics (GMV) and the brain’s inter-regional structural connections (MC) of PHN and LBP. Our results revealed that GMV and MC are capable of detecting the differences of the brain structure between two types of pain disorders, and the structural differences might be the specific areas for pain modulation.46 has been widely explored in pain research. It has been widely recognized that pain is modulated by brain networks which consist of a set of inter-connected brain regions, not only by the separate brain areas56. Brain connectivity analysis, such as small-world networks and WM tractography, has become popular in investigating pain-related changes. Previous studies have shown that sMRI-derived MC is a promising measure of individual-level structural connectivity to investigate cognition, perception, and neurological disorders53. Some studies used fMRI-derived functional connectivity in the prediction of individual pain thresholds44, while it was also found that MC is related to functional connectivity37. Therefore, it is reasonable to consider the use of MC in pain research. A recent study58 has also found that the predictive capability of MC was significantly higher than the regional morphological features like GMV in prediction of individual pain sensitivity.In recent years, the whole brain connectivityFor the number of MCs in cluster, the different MCs between LBP and PHN patients were scattered in the whole brain, while only a few clusters could be clearly observed. By counting the number of clusters with the same number of MCs, we found a cluster containing 5 MCs was an inflexion point of the number of clusters, which means that most clusters only had 1–4 MCs. Actually, the number of clusters with 1, 2, 3, 4, or ≥ 5 MCs was 92, 40, 10, 4, and 4, respectively. Therefore, to better illustrate the different MCs between two types of patients, we only discussed significant clusters with more than 4 MCs .48: anatomically connected brain regions are modulated by a mechanical force, resulting in similar morphological properties. This theory could also be applicable to pain patients: brain regions involving pain modulation showed similar morphological distribution. In our study, most of brain regions detected, including ACG, medial frontal gyrus, SMA and superior parietal lobule, have been demonstrated to have a relationship with pain in previous studies. Our results could further prove the capability of MC in detecting brain connectivity involving pain modulation in two types of PNP disorders (PHN and LBP).As for the physiological principle of inter-regional MC, some researchers have proposed the axon tension theory46 have utilized various MRI techniques to reveal the brain’s structural and functional abnormalities of PHN and LBP from different perspectives. Previous two PHN studies29 have shown that reduced GMV was found in the bilateral insula, precentral gyrus and right middle frontal gyrus (MFG) while increased GMV was found in the bilateral thalamus, right PHG, lentiform nucleus of PHN patients, as compared with normal controls. There were also a number of sMRI studies with various results in investigation of LBP. Generally, LBP patients had larger GMV than healthy people in bilateral putamen and left posterior thalamus39, and in temporal lobes, S1, S2, M146. On the other hand, PHN patients also showed greater GMV in both thalamus and basal ganglia29, which suggested that these two regions were the main parts involved in pain modulation of both PHN and LBP. That could be the explanation for why both the GBV and MC results of these two areas showed no significance in PHN-LBP comparison in our study. These two regions may play the same role in modulating either PHN or LBP. In the following, we will discuss some major regions and connections identified in the present study.46. The same results could be found for fusion gyrus30. In addition, temporal gyrus was reported to have a great relationship with hearing ability. Therefore, LBP might affect auditory regions’ activity while PHN might not.Temporal gyrus. Many regions in the temporal gyrus showed greater GMV for PHN than for LBP, as shown in our study. In previous studies with healthy controls, temporal gyrus showed no significant changes in PHN, while showed greater GMV in LBP29. However, from PHN-LBP comparison in our study, insula seemed to be affected more by PHN because the GMV of insula was larger in LBP than in PHN.Insula. Insula has been involved in modulating various types of pain diseases, including LBP and PHN. Previous studies showed that the GMV of insula was smaller in both PHN and LBP, as compared with healthy people34, showed more MC patterns in LBP, as compared with PHN. In Luchtmann’s study30 with 12 LBP patients, GMV of ACG was larger than that of healthy people. Also, ACG showed increased functional connectivity in LBP54. However, ACG was not found to lead to any change of GMV in PHN patients, and was also hardly found to have significant activity during other BOLD or CBF studies. Our results also showed ACG had more increased MC in LBP. Therefore, ACG might have specific connectivity in LBP patients as compared with PHN.ACG. ACG, which is often regarded to have a close relationship with acute pain or visceral pain46 with 45 LBP patients, left medial orbital gyrus was reported to have decreased GMV than healthy people. However, few studies have mentioned change of medial orbital gyrus in PHN. From the results in this study, we speculated that medial orbital gyrus might be affected much by LBP.Medial orbital gyrus. In Ung’s study54 and nodal efficacy28 in LBP, in comparison with healthy controls. SMA also showed decreased MC in LBP compared with PHN. Therefore, SMA, which was repeatedly reported to have been involved in pain modulation, might also have specific connectivity alteration in LBP when compared to PHN.SMA. In previous connectivity studies, SMA showed decreased functional connectivityMany studiesThere were several limitations in our study. First, we lacked healthy subjects with matched age and gender as normal control. Our results could only demonstrate that the brain alterations were the differences between PHN and LBP. However, most previous studies have already showed the aberrant brain structure and activity in pain patients compared with normal control. Besides, using patients as control has the benefits of offsetting negative emotion influence. In further study, we would also enroll normal controls for exposing more specific and comprehensive brain alterations for PNP. Second, we lacked a detailed evaluation scale for emotion, such as the questionnaire for sleep, anxiety and so on. In future study, we would also collect more behavioral data for investigating pain intensity and emotion evaluation. Third, we just investigated the MC in one modality of MRI (T1WI). If multimodal MRI, such as BOLD and DTI, can be acquired, the results might be more persuasive and accurate.In conclusion, we compared structural characteristics and network features between PHN and LBP by using GMV and MC, respectively. We have obtained reasonable results, which are consistent with previous studies and add new knowledge. For example, ACG might be involved more in LBP modulation, while the network efficacy of medial orbital gyrus might be disrupted more in LBP compared with PHN. Our results showed that, LBP and PHN have different neural mechanisms concerning pain modulation. T1WI-based MC and GMV could be potentially used as neural markers to classify pain disorders.