The dynamic nature of neck pain has so far been identified through longitudinal studies with frequent measures, a method which is time-consuming and impractical. Pictures illustrating different courses of pain may be an alternative solution, usable in both clinical work and research, but it is unknown how well they capture the clinical course. The aim of this study was to explore and describe self-reported visual trajectories in terms of details of patients’ prospectively reported clinical course, their SMS-based pattern classification of neck pain, and patient’s characteristics.Prospective cohort study including 888 neck pain patients from chiropractic practice, responding to weekly SMS-questions about pain intensity for 1 year from 2015 to 2017. Patients were classified into one of three clinical course patterns using definitions based on previously published descriptors. At 1-year follow-up, patients selected a visual trajectory that best represented their retrospective 1-year course of pain: single episode, episodic, mild ongoing, fluctuating and severe ongoing.The visual trajectories generally resembled the 1-year clinical course characteristics on group level, but there were large individual variations. Patients selecting Episodic and Mild ongoing visual trajectories were similar on most parameters. The visual trajectories generally resembled more the clinical course of the last quarter.The visual trajectories reflected the descriptors of the clinical course of pain captured by weekly SMS measures on a group level and formed groups of patients that differed on symptoms and characteristics. However, there were large variations in symptoms and characteristics within, as well as overlap between, each visual trajectory. In particular, patients with mild pain seemed predisposed to recall bias. Although the visual trajectories and SMS-based classifications appear related, visual trajectories likely capture more elements of the pain experience than just the course of pain. Therefore, they cannot be seen as a proxy for SMS-tracking of pain over 1 year.The online version contains supplementary material available at 10.1186/s12998-022-00443-3. Non-specific neck pain is costly and common –3. CloseTrajectories appear to be stable over time , 19, as A recent study on low back pain has introduced a novel and simple alternative to long-term follow-ups with frequent measurements to identify clinical course, namely, to use pictures illustrating the different pain trajectories  . PatientTo our knowledge, no study has explored the association between SMS-based and visual trajectories in neck pain patients. While SMS-based trajectories describe the prospectively reported course of pain, visual trajectories provide the patients' retrospective perception of the course. Visual trajectories may represent anything from a recall that is largely disconnected from the experienced course, to a recall that closely resembles the patient’s SMS-based trajectory. For visual trajectories to be useful in research and clinic, it is essential to understand what they capture regarding the clinical course from prospective frequent measures. Thus, the aim of this study was to explore and describe self-reported visual trajectories in terms of details of patients’ prospectively reported clinical course, their SMS-based pattern classification of neck pain, and patients’ characteristics.We used data from a 1-year observational, multi-center, practice-based cohort consisting of patients with neck pain in a chiropractic care setting in Norway. Seventy-one chiropractors located across Norway invited eligible patients with neck pain to participate in the study between September 2015 and June 2016. The chiropractors provided written and verbal information to patients interested in participating. Patients accepting to participate signed a written consent form. Decisions regarding treatment and follow-up were at the chiropractors' discretion, and unaffected by participation in the study. Descriptions of cohort recruitment and study procedures are published in a previous paper . The RegWe included patients aged 18 years or more, presenting with bothersome neck pain as their primary or secondary complaint, independent of being acute or long-term or in a treatment plan. Patients had to have basic Norwegian reading and writing skills and be able to operate a mobile phone. We excluded patients with suspected inflammatory diseases, fractures, systemic pathology, or nerve root involvement requiring referral to surgery. The chiropractors recruited 1478 patients with neck pain. Of these, 888 (60%) had completed both 1-year and baseline questionnaires and provided enough SMS responses to be classified to an SMS-based pattern, and thus, constituted the study sample  at the same day and time every week over a 1-year period, with a reminder 2 days later should they fail to respond to the initial SMS. We collected the following patient demographics at baseline: age, sex, history of neck pain and consultation type, as well as pain intensity at recruitment. History of neck pain was categorized into those with a history of neck pain less than 5 years, and those with equal to, or more than, 5 years history. We defined patients recruited at their first visit for a new episode of neck pain as "first consultation".We measured current neck pain intensity on a 0–10 Numeric Rating Scale (NRS)  . FunctioIn the 1-year questionnaire, we asked patients to identify their neck pain course over the previous year, using a self-reported visual trajectory pattern questionnaire developed for LBP  hereaft. The quePatients received the following questions weekly via SMS: “How many days the last week has your neck been bothersome? Please answer with a number between 0 and 7” (hereafter ‘paindays’). If the answer was between 1 and 7, the patient received a second SMS: “How intense has your neck pain typically been the last week? 0 = no bother, 10 = worst possible bother” (hereafter ‘pain intensity’). A third SMS (not used in the present study): “How many days this last week has your neck limited your daily activities? Please answer with a number between 0 and 7”.For the descriptors of the course of pain, we calculated the total number of paindays, the mean pain intensity across the 52 weeks, the duration and frequency of pain-free and painful weeks, as well as the proportion of the weeks that were pain-free, in the minor, mild, moderate, and severe pain range (defined below) for each patient. As a measure of variation in pain intensity within individuals, we calculated the standard deviation (SD) of the mean of the individual’s weekly pain intensity (1-year and the last quarter) (hereafter ‘intensity variation’).We described the patients’ clinical course, using the same criteria as in recently published articles , 17, 19.We have previously found that patients in an episodic pain course have large individual and group variations in painful- and pain-free periods . We therFew of our variables were normally distributed and accordingly we present descriptive variables as frequencies and percentages or median with interquartile range (IQR) when appropriate. We combined the visual trajectory alternatives “None of the above” and “Do not know” into one group, called “Neither” for analytical purposes. The methods used for imputing the missing values on the weekly pain intensity measures for the SMS-based pattern is described in detail in Additional file We cross-tabulated visual trajectories with the eleven SMS-based patterns to explore and describe the distribution of SMS-based pattern classifications for each of the visual trajectories. We present the distribution of SMS-based patterns as a stacked bar graph for each of the visual trajectories at 1-year follow-up. To explore pain recall in relation to the selection of visual trajectory, we did the same cross-tabulation and stacked bar graph presentation between the visual trajectories and the last quarter SMS-based patterns.This study was part of a larger project aiming to identify prognostic factors for neck pain. The larger project aimed to assess 11 possible prognostic factors. The number of participants needed was calculated as follows: 10 patients per prognostic factor is required in multiple regression models gives n = 1100 . ExpectiWe carried out all analyses using STATA 16 .The 888 patients had a mean age of 45 SD 13) years and 663 (75%) were women. The mean pain intensity (SD) at baseline and 1-year follow-up was 4.1 (2.3) and 2.5 (2.4) respectively. Close to 50% reported previous neck pain duration of 1 year or longer at baseline. There were no substantial differences between the study sample and those lost to follow-up. For further details of cohort characteristics, see Table 3 years aIn total, 37% (n = 331) of patients selected the Episodic visual trajectory, 36% (n = 318) the Fluctuating trajectory, and 14% n = 121) the Single episode trajectory on the visual trajectory questionnaire. Furthermore, 9% (n = 82) selected Mild Ongoing and 2% (n = 14) selected the Severe Ongoing trajectory. Two percent of patients (n = 22) did not identify with any of the five visual trajectories. Using the SMS-based classification, 48% of the study sample were classified as Persistent fluctuating and 49% as Episodic. Examples of individual SMS-based trajectories for each of the visual trajectories are displayed in Fig. 1 the SinThe details of the clinical course varied largely among patients selecting the same visual trajectory. However, there were clear differences between the different visual trajectories concerning the mean course of pain and the descriptors of the clinical course for all, except between the episodic and mild ongoing visual trajectories Fig. .Fig. 3WeIn general, the visual trajectory resembled well the predefined clinical course descriptors on a group level. For instance, patients selecting the Single episode visual trajectory were likely to have the highest proportion of pain-free weeks  67–94%) with only short periods with pain, and they rarely or never reported painful periods with moderate or severe pain Table . HoweverFigure The data reported for symptoms, disability and psychosocial factors showed an increase in severity from those selecting the Single episode visual trajectory to the Severe Ongoing visual trajectory Table . In addiThe main differences between comparing visual trajectories to the last quarter instead of the 1-year SMS-based classifications was those patients selecting Single episode visual trajectory were more often recovered in the last quarter but had reported episodes of pain previously during the full year  and classified as Episodic SMS-based pattern for the full year, 62% were classified as Single episode in the last quarter. For patients classified as Episodic for the full year, there was an increase in the number classified as Persistent fluctuating in the last quarter .The visual trajectories reflected the descriptors of the clinical course of pain captured by weekly SMS measures on a group level. Patients seemed to a large extend to recall both the pain variation and intensity dimensions of their neck pain. Patients' selection of the visual trajectories also appears to form groups that differ on other symptoms and patient characteristics. However, there were large variations in symptoms and characteristics within each visual trajectory and overlap rather than leaps between the trajectories. Thus, we cannot at this point conclude that the visual trajectories fully reflect the experienced course of NP. However, our results support that the visual trajectories and the SMS-based classifications are related on a group level.Patients selecting Severe ongoing and Fluctuating visual trajectories reported the highest pain intensity and few to no pain-free weeks throughout the follow-up year. Hence, these two visual trajectories seem to be selected by patients with the highest disability and psychosocial risk factors, and with very low expectations of recovery. In addition, the large majority of these patients were classified as Persistent fluctuating throughout the follow-up year. However, we had only 14 patients selecting the Severe ongoing visual trajectory. They reported no pain-free weeks, more than half of their reported weeks were with severe pain, and all were classified as Persistent fluctuating. These are the only patients we can be certain had selected a visual trajectory that mostly reflected their clinical course. Still, a few of these patients reported some weeks with mild pain.In contrast, only 18% of the patients selecting the Single episode visual trajectory actually reported only one single episode of pain during the 1-year follow-up (classified as Single episode/Recovery pattern). They typically reported several short episodes of pain on SMS throughout the follow-up year. Furthermore, one of these episodes most often occurred within the last quarter. One could thus hypothesize that recall bias plays a role in patients with few and short pain episodes, as such short episodes are less likely to be remembered over time . Since tThe patients selecting the Episodic and Mild ongoing visual trajectories were comparable on most parameters, in particular: they reported mild to no pain most weeks, interspersed with flare-ups of pain that varied greatly in duration. The painful episodes also varied in intensity among patients in both visual trajectories, but weeks with severe pain were rarely reported. In addition, patients in both the Episodic and Mild ongoing visual trajectories scored moderate to low on all health-related factors. There are several possible explanations for these similarities. First, previous studies show that steady pain with minimal fluctuations is rare , 17, andThirty-eight percent of patients selected a visual trajectory that did not closely resemble their 1-year SMS-based classification. The visual trajectories are not simply a measure of pain, but more likely includes aspects of the pain experience, and have been shown to carry prognostic information as well as being related to expectation of pain –22. The The strength of this study is the large cohort and the good response rate. We have used descriptors and definitions for SMS-based patterns based on weekly measures over 1 year, which can easily be repeated based on previous published recommendations . This haThe weaknesses of the study are that the visual trajectories used have not been validated, and there are no studies for direct comparison. However, there is evidence of face, criterion, and construct validity of similar visual trajectories . We did In clinical practice, the visual trajectories are likely more applicable than frequent measures over time. The visual trajectories can be useful as a communication tool between patient and clinician regarding the course and prognosis of neck pain. They are simple to implement and seem easy to understand for patients and clinicians. The visual trajectories can potentially be used in clinic as a measure of pain history, but also as a picture of patients’ condition and illness perception here and now. Patients with similar observed clinical course have different recall of their neck pain experience, and it would be of interest to understand more regarding the factors that influence this difference in recollection. Based on our study and a very recent study showing that similar visual trajectories are relatively stable over time , the visHowever, our descriptive study indicates that both the visual trajectory pattern questionnaire and the SMS-based pattern definitions need more refinement. Patients classified as Episodic pattern but selected the Single episode visual trajectory reported more weeks with minor pain, longer pain-free periods, and were generally less afflicted by their pain than those selecting the Episodic visual trajectory. Furthermore, patients selecting Single episode visual trajectory but classified as Episodic pattern closely resembled the patients selecting the Single episode visual trajectory. Consequently, the text to the Single episode might be more appropriate, and more easily understood, if the wording was changed to “No neck pain or just very short episodes of neck pain”, instead of the present “…just a single episode…”. Also, it is likely that combining some of the illustrations, for instance Episodic and Mild ongoing visual trajectory, would be beneficial.Future studies should explore the differences between patients selecting a visual trajectory that closely matches their SMS-based clinical course pattern, and patients selecting visual trajectories more “positive” or more “negative” than their classified pattern.The visual trajectories used in this study generally reflect the patients’ clinical course defined by SMS data on group level. However, it is not a perfect match. This can be due to recall bias, but just as likely, that a patient’s experienced course of pain is not based on pain intensity alone. Our findings suggest that the visual trajectories and SMS-based classifications may capture different elements of the pain experience. The visual trajectories most likely represent pictures that encompass features of the patients’ course of pain, individual level of pain tolerance, and clinical condition at the time of reporting. Therefore, they cannot be seen as a proxy for SMS-tracking of pain intensity over 1 year. Rather, visual trajectories may be a suitable tool to attain a broader picture for prediction of NP or stratification of NP patients.Additional file 1. Imputation of the weekly SMS data before classification and Classification into patterns and subgroups. Table S1 Definitions of the SMS-based patterns. Table S2 Association between the Visual trajectories and the 1-year SMS-based patterns (n = 888). Table S3 Association between the Visual trajectories and the last quarter SMS-based patterns (n = 888)


Different multimodal pain management strategies following total hip arthroplasty(THA) and total knee arthroplasty (TKA) surgery are used in clinical practice. The optimal pain management strategy, however, remains unclear. This study aims to evaluate the differences in perioperative multimodal pain management strategies for THA and TKA in the Netherlands, and studies the associations between patient- and therapy related factors and pain outcomes.Data from the Dutch hospitals in the PAIN OUT network were used in this study. Demographic data, pain management strategy including perioperative medication use and anesthetic techniques were recorded and used in a multivariable regression analysis to study the association with maximum pain intensity, the duration of severe pain, pain interference in bed and postoperative nausea.In 343 hip arthroplasty patients and 301 knee arthroplasty patients in seven hospitals, respectively 28 and 35 different combinations of analgesic regimens were used. The number of different drugs prescribed was not related to postoperative pain intensity. Female sex, younger age and spinal anesthesia were associated with higher postoperative maximum pain scores  > 5). Hip surgery and ketamine use were associated with lower postoperative pain scores. The use of non-steroidal anti-inflammatory drugs (NSAIDs) and gabapentinoids, higher age, higher body mass index (BMI) and male gender were associated with less postoperative nausea (NRS < 3).In conclusion, our study demonstrated a large diversity of analgesic strategies following total joint arthroplasties in the Netherlands. Although no ideal strategy was identified, the use of NSAIDs, ketamine and dexamethasone were associated with less pain and less side effects. Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are increasingly performed orthopedic procedures and are expected to increase further in the near future . PreviouMultimodal analgesia is a pain management strategy including two or more different groups of analgesic drugs to improve perioperative analgesia and reduce opioid consumption and the related side effects. Multimodal analgesia regimens are strongly recommended for managing perioperative pain and are considered an important part of Enhanced Recovery After Surgery Programs . MultimoAlthough multimodal analgesia is widely studied, treatment strategies vary between hospitals. The optimal combination of analgesic therapies remains unclear. This study aims to 1) evaluate the differences in perioperative pain management practices for THA and TKA in the Netherlands, and 2) to evaluate the associations between patient- and therapy related factors and pain outcomes.www.pain-out.eu) network has been initiated to improve acute postoperative pain management [The PAIN OUT (nagement . The netnagement  (IPO-Q) We conducted a prospective cohort study, using data from the Pain Out registry of seven different hospitals in the Netherlands. Four hospitals were university medical centers, three were regional teaching hospitals. Ethical approval was obtained from the Institutional Review Board (IRB) in each hospital, based on the initial ethical approval of the IRB of the Radboud university medical center . The methodology is registered with the US National Library of Medicine .Patients who underwent knee or hip replacement surgery were included in the study. Patients were eligible for inclusion if they fulfilled the following criteria: 1) age 18 years or older; 2) on postoperative day one (POD1) they had returned to the ward from the post anesthesia care unit (PACU) for at least six hours; and 3) they consented to take part in the survey. All consecutive eligible patients were informed about the study on the first day after surgery and provided written informed consent. Exclusion criteria were daycare surgery and missing data about anesthesia type or surgery.In each hospital, study surveyors who were not involved in patients’ care, underwent training for approaching patients. Data collection took place from October 2017 until November 2019. Data were collected on POD1. Data consist of the validated International Pain Outcomes Questionnaire  (IPO-Q) International Classification of Disease procedure (ICD-9) codes were used to select cases of TKA or THA from the Pain Out registry. The database contained all information on baseline characteristics, comorbidities, surgical procedures, anesthetic management, medication used and results from the Pain Out questionnaire . This paThe following baseline parameters were used in the analyses: sex, body mass index (BMI), comorbidity, substance abuse, preoperative pain and preoperative opioid use. The following analgesic medication or analgesic strategies were registered: acetaminophen, NSAID, ketamine, dexamethasone, gabapentinoids , clonidine, local infiltration analgesia (LIA), locoregional anesthesia and combinations of those.Our primary outcome parameter was maximum pain intensity , 0 = no pain, up to 10 = most pain imaginable). Secondary parameters were time in severe pain (percentage of the time after surgery), opioid consumption  ), nauseaIn order to evaluate the differences in perioperative pain management practices, descriptive statistics were used to determine the frequencies of the demographic variables and multimodal analgesia strategies. Continuous variables are presented as mean with standard deviation (SD) and compared with the independent samples T-test. Normal distribution was explored using the Shapiro-Wilk test. In case of a non-normal distribution, data are presented as median with inter-quartile range (IQR), and compared using the Kruskal Wallis test.Binary logistic regression analysis was performed to evaluate whether patient- and treatment characteristics  were associated with postoperative pain characteristics (i.e. maximum pain intensity > 5 (NRS), time in severe pain > 20%, nausea score > 3 (NRS) and interference with moving in bed > 3 (NRS)). Cut-off values were defined according to PAINOUT standard analyses criteria , 13.To prevent overfitting of the models, we performed univariable binary logistic regression analyses of all potential factors. Only those factors with a significance level of p ≤ 0.2 were entered into a final multivariable binary logistic regression analysis. To prevent multicollinearity, pairwise correlations between the parameters to be entered into the final models were calculated. Of those with a bivariate correlation of ≥ 0.7 only the parameter with the highest univariable significance level were entered into the final models.For all statistics, alpha is set at the traditional 0.05 level. All analyses were performed with SPSS .In total, 644 patients were included in this study. Of these, 343 patients underwent THA and 301 patients underwent TKA. Baseline characteristics are shown in All patients in our database except for one received acetaminophen, so we did not include acetaminophen in our further analysis. Hip surgery was performed in 343 patients. Forty percent of them was male and the median age was 69.0 years. The majority (86%) reported preoperative pain with a median NRS of 7.0 (IQR 2.0). One hundred and eighty-eight participants (56%) received general anesthesia, 150 (44%) spinal anesthesia and no patients reported locoregional anesthesia with or without sedation or general anesthesia.In patients undergoing hip surgery, 28 different combinations of non-opioid pain medications were used . The comOutcome parameters are presented in Table 4. Maximum pain (NRS), time in pain (%), nausea (NRS), itching (NRS) and interference moving in bed (NRS) were not significantly different among the five most commonly used analgesic strategies . Total mOf the patients undergoing knee surgery 40% was male, median age was 69.0 years. The vast majority (91%) experienced preoperative pain and reported a median NRS of 7.0 (IQR 3.0). One hundred and fifty participants (50%) received general anesthesia, 140 (47%) received spinal anesthesia. Locoregional anesthesia was performed in 10 patients (3%), this included femoral nerve block (n = 9) and epidural anesthesia (n = 1).We identified 35 different combinations of non-opioid pain medications and LIA for pain treatment in this group. The most commonly used strategies: NSAID with ketamine, gabapentinoids and LIA; NSAID with LIA; NSAID with gabapentinoids and LIA .Postoperative data are listed in Median postoperative maximum pain (NRS) was not statistically different when using more drugs p = 0,328). Median postoperative pain did not differ when using more medication in patients undergoing hip surgery (p = 0.229) and knee surgery (p = 0.656) Figs  and 2.8. MedianWe performed a post-hoc analysis comparing 43 patients receiving acetaminophen and NSAIDs only did not differ from 174 patients receiving acetaminophen and NSAID and additional pain medications for THA (median maximum pain NRS 7.0 vs 6.0 (p = 0.754), and median time in severe pain 30% vs 30% (p = 0.205)).The aim of this study was to evaluate the differences in perioperative pain management practices for THA and TKA in different hospitals in the Netherlands, and to evaluate the associations between patient- and therapy related factors and pain outcomes. The inclusion of multiple hospitals in the Netherlands provided a clear picture of the different strategies used for treating postoperative pain across the country. We used the PAIN-Out questionnaire, which is internationally validated . Our resWe did not find a significant difference in pain scores between the most commonly used multimodal analgesia strategies. The number of different drugs prescribed was not related to postoperative pain intensity. We found some statistically differences in total morphine equivalents between the multimodal strategies used. Unfortunately the study design does not allow us to confirm causality.Recently, the new PROSPECT guideline for total knee arthroplasty recommends a combination of acetaminophen, NSAID and dexamethasone, together with LIA and single shot adductor canal block for managing postoperative pain. There was conflicting or inconsistent evidence for other intravenous analgesics like gabapentinoids, ketamine and dexmedetomidine . In lineWe found several associations that are well known to predict postoperative pain. Lower age and female gender are associated with higher postoperative pain intensities, and a psychiatric comorbidity was related to pain during mobilization. Furthermore, some relations were found regarding pharmacotherapy. The use of ketamine and the use of NSAIDs were related to less pain during movement following knee surgery. The use of NSAIDs was associated with less nausea following THA and TKA and gabapentin use was associated with less nausea following TKA. These effects might be explained by the opioid sparing properties of these analgesics. Dexamethasone was associated with lower pain intensities and less nausea after THA. Unexpectedly, gabapentinoids were positively related to longer time in pain after TKA. Gabapentinoids were generally provided as part of opioid free rapid recovery programs in which functional recovery and early discharge were the primary goals of therapy. However, contribution of patient and surgery-related factors cannot be ruled out. García-López and colleagues demonstrated in a recent study the following factors associated with moderate to severe postoperative pain after TKA: chronic preoperative pain, general anesthesia, opioid use before or after surgery. There were no protective factors observed . This isIn this database, locoregional anesthesia was rarely used. Previous research shows an increasing popularity of peripheral nerve blocks, however it is still used in only a minority of patients . ClassicOne of the limitations of this study is the fact that postoperative pain was only evaluated once and only on POD 1. Answers could be influenced, not only by the level of pain while filling in the questionnaire, but also by the timing of the analgesics administered by the wards relative to the timing of the questionnaire. Due to the cross-sectional design of this study causality cannot be confirmed. We managed to create a large database containing the different strategies in our country, however, the data contained a lot of different combinations of multimodal drugs. Due to this large diversity of pain strategies, we were only able to study the individual relation between specific drugs and therapy outcome in our regression analysis. To evaluate the effects of specific combinations of analgesics, prospective comparative studies or a large sample size are needed.In conclusion, our study demonstrated a large diversity of analgesic strategies following total joint arthroplasties in the Netherlands. The use of more drug classes does not show lower postoperative pain scores. Although no ideal strategy was identified, the use of NSAID’s, ketamine and dexamethasone were independently associated with less pain and less side effects.S1 Table(XLSX)Click here for additional data file.S2 Table*NRS if not stated otherwise **Kruskal Wallis test.(XLSX)Click here for additional data file.S3 Table*NRS if not stated otherwise; **Kruskal Wallis test.(XLSX)Click here for additional data file.S4 Table* Variables entered on step 1: Sex, Age, BMI, Psychiatric comorbidity, Preoperative opioid use, Dexamethasone, Ketamine, Clonidine. ** Variables entered on step 1: Sex, Age, BMI, Diabetes, Respiratory comorbidity, Spinal anesthesia, Locoregional anesthesia, LIA, Dexamethasone. *** Variables entered on step 1: Sex, Age, BMI, Psychiatric comorbidity, LIA, NSAID, Dexamethasone. **** Variables entered on step 1: Sex, Age, BMI, Addictive disorder, Spinal anesthesia, General anesthesia, Locoregional anesthesia, NSAID, Dexamethasone, Gabapentinoids.(XLSX)Click here for additional data file.S5 Table* Variables entered on step 1: Sex, Preoperative pain, Preoperative opioid use, General anesthesia, Ketamine. ** Variables entered on step 1: Sex, Cardiovascular comorbidity, Preoperative opioid use, Gabapentinoids. *** Variables entered on step 1: Age, NSAID, Ketamine. **** Variables entered on step 1: Sex, BMI, Cardiovascular comorbidity, General Pain syndrome, NSAID, Ketamine, Gabapentinoids, Clonidine.(XLSX)Click here for additional data file.S1 File(XLSX)Click here for additional data file.


Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) may cause pain, impaired ambulation and decreased quality of life (QoL). International guidelines advocate management of FD/MAS in a tertiary multidisciplinary care pathway, but no longitudinal data are available to support this recommendation. This multicenter prospective observational study aimed to evaluate effects of 1 year of treatment in the FD/MAS care pathway in 2 tertiary clinics on QoL and pain, assessed by change in Short Form 36 and Brief Pain Inventory between baseline and follow-up. Patients completing baseline questionnaires < 1 year after intake were classified as new referrals, others as under chronic care.s = − 0.281, p = 0.007). QoL was in all domains lower compared to the general population. New referrals reported clinically important differences (CID) over time in domains Physical Function  0.31, p = 0.020), Role Physical , Social Functioning , and Health Change , chronic patients in Physical Function  and Emotional Wellbeing . New referrals reported a CID of 1 point in maximum pain, average pain and pain interference, chronic patients reported stable scores. Change in pain interference and Role Physical were correlated . Patients with limited disease extent improved more than patients with severe disease. Patients receiving FD-related therapy had lower baseline scores than patients not receiving therapy and reported improvements in QoL after 1 year. Yet also patients without FD-related therapy improved in Physical Function.92 patients were included, 61 females (66%). 22 patients (24%) had monostotic disease, 16 (17%) isolated craniofacial FD, 27 (40%) polyostotic FD and 17 (19%) MAS. 26 were new referrals (28%) and 66 chronic patients (72%). Median age at baseline was 47 years (Q1–Q3 36–56). Skeletal burden correlated with baseline Physical Function (rAll FD-subtypes may induce pain and reduced QoL. A multidisciplinary care pathway for FD/MAS may improve pain and QoL, mainly in new referrals without MAS comorbidities with low baseline scores. Therefore, we recommend referral of patients with all subtypes of FD/MAS to specialized academic centers.The online version contains supplementary material available at 10.1186/s13023-022-02588-z. GNAS gene and subsequent aberrant bone turnover [Fibrous dysplasia (FD), is a rare, congenital bone disease, where fibrous skeletal lesions develop due to postzygotic mutations in the turnover , 2. The turnover . Becauseturnover , 4. Receturnover . This guturnover , 6. Mostturnover –10, or rturnover –13. Howeturnover  and moreturnover , 16. Theturnover –16, but turnover . In additurnover –19, reduturnover , 21, impturnover , 20–23 aturnover . For FD/This study was conducted between January 2018 and August 2021 and was performed within the PROFID-study, an ongoing multicenter prospective observational cohort study into patients with FD/MAS. The PROFID started in 2017 and is conducted on the outpatient clinics of Endocrinology and Orthopaedic Surgery of the LUMC and RUMC. Inclusion criteria are a certain diagnosis of FD/MAS  and at least 1 visit at one of the outpatients clinics. In the current cohort we only presented results of the adult population. Written informed consent is required for inclusion. The study was approved by the Medical Ethics Committee of both centers (protocol number P17.136). Several patients have been included in previous studies , 25, 26,Patients were asked to complete questionnaires upon inclusion in the study and again after 1 year of care in the FD/MAS care pathway. If follow-up visits were not deemed necessary or were planned further ahead than 1 year, questionnaires were send regardless of outpatient clinic visits, 1 year after completion of the baseline questionnaire. The questionnaire set included the Short Form 36 (SF-36)  and EuroFor this study, patients were selected who completed at least one questionnaire at both time points. The primary endpoint was the change in SF-36 and BPI scores during the 1 year of follow-up. This endpoint is assessed in 2 groups: patients were regarded as new referrals if the baseline questionnaire was completed within 1 year after intake in the hospital and all other patients were classified as under chronic care. This distinction was made because in the newly referred group, the baseline scores for QoL and pain can be used as proxy for the level of QoL and pain at the end of the care trajectory elsewhere. In this way the temporal change during follow-up was regarded to reflect the added value of the FD/MAS care pathway in comparison to usual care. Change in QoL and pain in chronic patients was assessed to observe baseline differences between groups and longitudinal change in this subgroup. For the SF-36 the clinically important difference (CID) was expressed as effect size (ES) and a threshold of 0.20 was used , for the18F-NaF PET/CT [Patients are referred to the LUMC or RUMC by general practitioners, non-academic hospitals or academic hospitals. The diagnosis, often established in the referring center, is made on clinical, biochemical, radiographical or pathological parameters. During the 1 year of follow-up in this study, patients were staged and treated in the FD/MAS care pathway according to the guidelines . The FD/F PET/CT  to deterF PET/CT .p-value as dichotomizing instrument [Categorical data are presented as number (percentage), numerical data as mean (± SD) or median (quartile 1-quartile 3). SF-36 scores were compared with the general Dutch population by one-sample t-tests. Numerical data were in case of normality compared between time points with paired t-tests, between 2 groups with independent t-tests, and between the 4 FD subtypes by one-way ANOVA, whereas in absence of normality Wilcoxon Signed rank, Mann–Whitney U and Kruskal Wallis tests were used respectively. Categorical data were compared with Chi Square tests. Analyses concerning pain were conducted in patients with pain (baseline maximum or average pain score ≥ 0) and the subgroup of patients with moderate to severe pain (score ≥ 4/10), because the pain severity in the latter group is an indication for analgesic therapy. Subgroups for FD-related treatment during follow-up were compared on the presence or absence of antiresorptive or surgical treatment during the 1 year in the care pathway. The correlation between SBS and SF-36 domain Physical Function at baseline was assessed by Spearman’s rank-order correlation, as well as the correlation between temporal change in pain interference and in Role Physical. Correction for multiple testing was not performed because of the exploratory nature of the study, because the CID was deemed more important, and to omit the misuse of the strument , 36. Misp = 0.007). Most patients were included in the LUMC  and were referred from a non-academic hospital  or from another academic hospital . Mean follow-up (time between survey completion) was 1.2 (± SD 0.3) years. The majority of patients had received FD-related treatment prior to inclusion in this study, specifically bisphosphonates , denosumab  or surgery . Half of the patients had received FD-related treatment during follow-up: 35 patients (38%) received bisphosphonates, 16 (17%) denosumab and 5 (5%) surgery, whereas 42 patients (46%) did not receive FD-related therapy.92 consecutive patients were included in this study, 26 new referrals (28.3%) and 66 patients under chronic care (72.7%) Table . 85 patip = 0.020) (Table p < 0.001), compared to new referrals, 56 (± 21) to 60 (± 17) (p = 0.275). Social Functioning improved in new referrals from 64 (± 24) to 76 (± 23) (p = 0.054), was in chronic patients higher at baseline but stable over time, and was therefore comparable between groups after 1 year. Role Emotional and General Health were at baseline higher in chronic patients and in both groups stable over time. In contrast, Health Change improved in new referrals from 39 (± 19) to 53 (± 24) (p = 0.016), whereas chronic patients reported no change.New referrals reported clinically important improvements in Physical Function after 1 year of follow-up, from mean 67 ± SD 24) to 74 (± 21) (4 to 74 (p = 0.038), 1 point (0–2.5) in average pain (p = 0.044) and 1 point (- 0.5–3) in interference of pain with general activity, which decreased from median 6 (3.5–7.5) to 3 (1.5–7) (p = 0.090) (Table p = 0.083) although median change was 0 (− 2.5–1) (Table p = 0.099). Chronic patients had better scores at baseline and no temporal change, hence scores were similar in both groups after 1 year. In the total cohort, a moderate correlation was observed between temporal change in pain interference and in SF-36 domain Role Physical .In the combined cohort 62 patients (67%) reported moderate to severe pain at baseline. New referrals in this subgroup reported a decreased of 1 point Q1–Q3 0.5–3) in maximum pain ( 0.5–3 inn p = 0.04 and 1 pp < 0.001), Energy/Fatigue , Role Physical  and General Health . After 1 year, scores improved in several domains but did not reach the level of the general population.In the total cohort, significant and clinically relevant impairments in all domains of QoL were observed compared to the general Dutch population  Additio: Fig. A.p = 0.088. The summary score and all scores for chronic patients remained constant (data not shown).In new referrals, the EQ-5D health state increased from median 68 (Q1–Q3 44–90) to 80 (59–91), p = 0.050) . In other FD subtypes scores remained stable. Emotional Wellbeing was most impaired in patients with MFD (49 ± 29) and MAS (50 ± 29) and improved in both groups to 63 (± 19) (p = 0.05) and to 71 (± 11) (p = 0.017) respectively. Also patients with PFD reported higher scores for Emotional Wellbeing at follow-up. Role Emotional was similar between subtypes and time points. Social Functioning was most impaired in MFD and CFD and improved in all subtypes except MAS. General Health did not differ between FD subtypes and no improvements were observed at follow-up. All patients except for those with MAS reported slightly better health than 1 year ago at follow-up than at baseline.Patients with isolated CFD reported better Physical Function 84 ± SD23) compared to patients with MFD 63 ± 31), PFD (70 ± 19) or MAS (67 ± 24)  and most in MFD . In patients reporting pain with score > 0, patients with PFD reported the highest score for maximum pain of 7 (3–7.5), versus 5 (2.5–8) in patients with MFD, 5.5 (2–7) for CFD and 5 (1–8) for MAS , but improved during follow-up to 71 (± 24) (p = 0.007). Similarly scores for Role Physical were lower in patients receiving treatment, although in this domain remarkably the greatest improvement was observed in patients not receiving therapy . Emotional Wellbeing and Social Functioning were both lower at baseline but improving during follow-up in patients with FD-related therapy.In the entire cohort 50 patients (54.3%) received FD-related therapy during the 1 year of follow-up  , but with median difference of 0. No change was observed in patients without FD-related therapy.Patients receiving FD-related therapy during follow-up had worse scores for maximum pain, average pain and pain interference at baseline compared to patients without therapy  and 6 patients (5%) completed none after 2 reminders. Complete cases were slightly older than excluded patients, but the sex ratio and FD subtype were comparable between groups  completed the first questionnaire before and the second after the national social distancing measures in March 2020, whereas 22 patients (24%) completed both questionnaires before and 21 (23%) both during the pandemic. The major increase in Social Functioning, which we had not expected, may be explained by the fact that patients with low baseline scores for Social Functioning, mainly new referrals, experienced less difficulties in social life during the pandemic because of the absence of social gatherings.A previous cross-sectional study on QoL and pain in FD/MAS has been conducted in our center by Majoor et al.  and showIndeed of all FD subtypes in our cohort, patients with MFD demonstrated most impairments in domains Physical Function, Pain and Role Physical and most interference of pain with general activities. Both QoL and pain responded well to academic care and improved during follow-up. The largest reduction in pain interference with general activity was observed in patients with isolated craniofacial FD. On the contrary, patients with MAS experienced least improvement over time in both SF-36 and BPI scores. A hypothesis for the least severe FD subtypes benefiting most from therapy is that selection bias occurred when MFD or CFD patients with minor complaints were treated in non-academic centers and only those with severe complaints were referred and treated in academic centers, selecting the patients who are more likely to benefit from treatment. Nevertheless, this highlights that even patients with low skeletal burden may experience substantial negative FD-related consequences and may benefit from referral to a specialized center.A secondary aim was to assess illness perceptions. The observed increase in QoL in our cohort could not be supported by a change in Illness Perceptions. The counselling, providing information and treatment in the LUMC care pathway surprisingly did not effectuate better perceived coherence of the disease or a higher perceived control over disease related complaints. The correlation between temporal change in SF-36 domain Role Physical and in pain interference is in line with the finding that QoL in our cohort was not influenced by altered illness perceptions but rather by improved pain management.However QoL may even improve without change in pain scores. This was demonstrated by patients who had not received FD-related therapy during follow-up but still experienced a major improvement in Role Physical with an ES of 0.47 after 1 year, despite constant pain severity or interference. We hypothesize that the rise in QoL in our cohort may not only be explained by the effect of antiresorptive therapy or pain management but also by other factors, possibly multidisciplinary care, recognition of FD-related complaints, lifestyle advice or disease acceptance.The COVID-19 pandemic could comprise a limitation of our study, as several negative consequences of the pandemic have been established in the general population including stress or worry , less phWe have established that patients with all subtypes of FD/MAS may suffer from negative consequences of their disease, and that the multidisciplinary coordinated care pathway for FD/MAS may improve QoL, pain and in particular pain interference, even though illness perceptions are unchanged. Patients who seem to benefit most from this care pathway are symptomatic new referrals without MAS comorbidities with low baseline performance. We recommend referral of patients with all subtypes of FD/MAS to tertiary academic centers and the implementation of the multidisciplinary care pathway for FD/MAS in those centers. Future studies should aim to determine the effect of the FD/MAS care pathway on time to diagnosis or therapy initiation, adherence to guidelines and uniformity of care. Lastly, attention is required for risk factors for an impaired QoL, for considerable pain interference, and for treatment-resistance in patients with FD/MAS.Additional file 1. Supplementary tables A–G.Additional file 2. Figure A SF-36 at baseline and follow-up in patients with FD/MAS versus general Dutch populationAdditional file 3. Figure B SF-36 domains at baseline and follow-up for FD-subtypesAdditional file 4. Figure C Pain scores in patients with moderate to severe pain over time across FD subtypesAdditional file 5. Figure D Pain scores in patients with pain score > 0 over time across FD subtypesAdditional file 6. Figure E SF-36 scores at baseline and follow-up across treatment during follow-upAdditional file 7. Figure F Pain scores at baseline and follow-up across treatment during follow-up


Background and Objectives. Antibiotic regimen optimization is a major concern in post extraction sequelae management following third molar surgery, mostly owing to the absence of universal guidelines. Hence, this study aimed to determine the effect of antibiotic prophylaxis using three different doses of clindamycin on the prevention of infection and other complications following mandibular third molar disimpaction. The secondary outcome was testing whether clindamycin exhibits activity in acute or chronic models of pain using the visual analog scale of pain and the necessity for post-operative rescue analgesia. The tertiary outcome was to assess clindamycin penetration into the saliva by measuring its concentration using liquid chromatography/electrospray ionization tandem mass spectrometry. Materials and Methods. A randomized, two-center, triple-blind, controlled clinical trial was conducted, in which the patients were randomly allocated to three groups: I, receiving 150 mg clindamycin every 8 h; II, receiving 300 mg clindamycin every 8 h; and III, receiving 600 mg clindamycin every 12 h. Each group continued the therapy for five days. Results. An overall decrease in the risk of infection and other post-operative complications, such as trismus, edema, dysphagia, and lymphadenopathy, was achieved, with the best results in group I. Conclusion. As no statistical association was observed between clindamycin concentration in saliva and degree of post-operative inflammation, clindamycin concentration, or pain intensity, smaller doses of clindamycin administered over shorter time periods is recommended. Most oral surgeons recommend the administration of antibiotics following third molar surgery; however, despite various studies, no consistent guidelines on the optimization of antibiotic regimens exist; thus, prophylactic antibiotic therapy remains debatable ,2. CertaSince surgical extraction for impacted mandibular third molars remains the most common procedure in the field of oral surgery, post-operative complications are anticipated to pose a clinical challenge. Although current surgical techniques allow for aseptic procedures and handling of tissues, post-operative infections still occur. Peptostreptococcus, Veillonella, Prevotella, and Actinomyces species. The rate of infection following surgical extraction of impacted mandibular third molars varies from 0 to 16%  based onSince the results of microbiological examination are rarely available in a short time frame owing to the lengthy incubation process, confirmation of the exact microorganisms and their antimicrobial susceptibility is seldom obtained. The polymicrobial nature of odontogenic infections requires the use of pharmaceuticals that show activity towards both anaerobic and aerobic bacteria; hence, clinicians decide between penicillin, amoxicillin, and clindamycin administration. Streptococcus pyogenes, a significant majority of exotoxins produced by Staphylococcus aureus , and extracellular lipase produced by Propionibacterium acnes and granulosum. A decrease in exotoxin synthesis results in reduced bacterial virulence, ultimately facilitating the elimination of microorganisms by the immune system. Clindamycin, a lincosamide antibiotic, is an effective antimicrobial agent that is used in the treatment of specific mixed-flora infections. It is mostly absorbed upon oral administration, with peak concentrations within one hour, and concomitant administration of food does not visibly modify serum concentrations . It has Clindamycin is the antibiotic of choice in patients with penicillin hypersensitivity  and its Hence, this study aimed to determine the effect of antibiotic prophylaxis on the prevention of infection and other complications following surgical extraction of impacted mandibular third molars using three different doses of clindamycin hydrochloride. The secondary outcome was testing whether clindamycin exhibits activity in acute or chronic pain models using the visual analog scale (VAS) of pain and evaluating the need for post-operative rescue analgesia. The tertiary outcome was to assess the penetration of clindamycin into saliva by measuring the clindamycin concentration using reverse-phase high-performance liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS).A triple-blind, parallel, randomized, two-center clinical trial was conducted in the Department of Oral Surgery, Medical University of Lodz, Poland, and the Shanxi Oral Disease Prevention and Treatment Center, Shanxi Provincial People’s Hospital, China, over a period of 12 months from February 2021 to February 2022. The study was approved by the Bioethical Committee of the Medical University of Lodz and the Medical Ethics Committee of the Shanxi Provincial People’s Hospital, in compliance with the Helsinki Declaration, following the acquisition of informed consent from the participants. In order to ensure the highest possible reproducibility of the results, only patients with mandibular third molars with complete root development, retained vertically or mesioangularly (according to Winter’s classification), and belonging to class II B or C (Pell and Gregory classification), and extracted for orthodontic reasons, were included in this study.Since the study followed a triple-blind, randomized protocol, the patient, evaluator, and laboratory personnel were blinded to the group assignment. The surgeon, who was not involved in the evaluation process, was responsible for randomization, delivery, and guidance concerning the administration of the drugs. Randomization was performed using Research Randomizer (randomizer.org), with an allocation ratio of 1:1:1, and the code was unknown to the rest of the investigators until the collection of clinical data was terminated. A total of 285 blocks, with three random numbers in each block (corresponding to the three dose regimens), were generated. These random numbers were categorized into sequences of 1–95 for 150 mg (I), 95–190 for 300 mg (II), and 190–285 for 600 mg (III) of clindamycin. The sealed envelopes were labeled with appropriate codes and included in the administration protocol. Following surgery and randomization, the patient received two sealed boxes, one containing clindamycin and the rescue drug . Identical, non-marked capsules containing 150, 300, or 600 mg of clindamycin hydrochloride were prepared and coded in the hospital pharmacy. Patients were randomly allocated to three groups: I, receiving 150 mg clindamycin every 8 h; II, receiving 300 mg clindamycin every 8 h; and III, receiving 600 mg clindamycin every 12 h after surgery for five days. The inclusion criteria were as follows:Child-bearing potential or non-child-bearing potential, female or male, non-smoker, ≥18 and ≤65 years of age at the time of signing the informed consent, weighing >50 kg.Non-child-bearing potential female participant was defined as follows:Post-menopausal state: absence of menses for 12 months prior to drug administration or history of hysterectomy with bilateral oophorectomy at least 6 months prior to drug administration;Sterile hysterectomy, bilateral oophorectomy, or tubal ligation performed at least 6 months prior to drug administration;Capable of consent;Patients scheduled to undergo disimpaction of bony impacted mandibular molars under short-acting local anesthetic  preoperatively for orthodontic reasons;Patients who signed a written informed consent form prior to any study-related procedures and who were able to understand and comply with the protocol requirements and instructions;Female patients of childbearing potential willing to use a highly efficient birth control method during the study.The following exclusion criteria were applied:A history of clinically significant illnesses or surgeries within four weeks prior to the administration of the study medication;Any clinically significant abnormality detected during the medical screening;Any reason preventing the participation of the individual in the study ascertained by the investigator;Positive testing for hepatitis B, hepatitis C, or human immunodeficiency virus upon screening;Electrocardiographic abnormalities  or vital sign abnormalities  upon screening;2;BMI ≥ 30.0 kg/mHistory of significant alcohol abuse within six months prior to screening or any indication of habitual consumption of more than 14 units of alcohol per week or a positive alcohol breath test upon screening. Alcohol abuse was defined as the consumption of more than 90 mL of liquor or spirit or 530 mL of beer per day for consecutive days during the 6-month period;History of drug abuse or use of illegal drugs. Drug abuse was defined as any recreational drug use for five consecutive days during the 6-month period;Patients with any known history of hypersensitivity to clindamycin or other related drugs  and hypersensitivity reactions, including symptoms of asthma, rhinitis, angioedema, or urticaria;History of heparin allergy;Use of any drugs known to induce or inhibit hepatic drug metabolism  within 30 days prior to the administration of the study medication;Patients with a current or chronic history of liver disease, known hepatic or biliary abnormalities, severe renal impairment, or severe heart failure (New York Heart Association class IV);Patients with a history of gastrointestinal bleeding or perforation related to previous antibiotic or nonsteroidal anti-inflammatory drug (NSAID) therapy, gastrointestinal hemorrhage, cerebrovascular hemorrhage, or other progressive hemorrhage, such as an active or history of recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or bleeding);Patients with inflammation or ulcerative disease of the oral mucosa;Patients with known systemic lupus erythematosus;Indication for extraction of contralateral molar in the same procedure;Participants with very long trans-operative times (>60 min);Patients treated with antibiotics, analgesics, or NSAIDs within 3 days prior to the day of randomization ;Patients who received other antibiotics or analgesics rather than short-acting preoperative or intraoperative local anesthetic agents within 12 h before the start of the surgery or peri-operatively until randomization;Patients with any current dental or medical condition preventing safe participation in this study;Unwillingness or inability to follow the procedures outlined in the protocol;Difficulty in swallowing the medication used in the study;Use of any tobacco products 90 days prior to drug administration;Participants with a clinically significant history of tuberculosis, epilepsy, asthma, diabetes, psychosis, or glaucoma;Clinically significant history of diarrhea subsequent to the administration of antibacterial agents or antibiotics.Additional exclusion criteria for females only:Breast-feeding participants;Positive urine pregnancy test at screening;Female participants of childbearing potential engaging in unprotected sexual intercourse with any non-sterile male partner  within 14 days prior to study drug administration. All surgeries were performed by two dental surgeons specializing in oral and maxillofacial surgery in the same manner. After achieving inferior alveolar and buccal nerve block, surgery was initiated by recording its duration (from the first incision to the last suture). Each surgical procedure consisted of designing and preparing a triangular mucoperiosteal flap, followed by osteotomy with saline irrigation. Following the extraction, the wound was sutured after achieving hemostasis. Post-operative written instructions were clearly provided and were repeated audibly. Patients were instructed to note the exact time of taking the rescue drug if the situation should arise and instructed not to use any other drugs during the trial. In cases of severe post-operative infection, patients were withdrawn from the study and treated adequately. Each patient was scheduled for follow-up on the first, third, and seventh days post-operation. The following parameters were evaluated: trismus, facial edema, lymphadenopathy (submandibular lymph nodes), body temperature, local infection, and dysphagia.Trismus, facial edema, and lymphadenopathy evaluations were performed using a 3-grade scale. Trismus was based on the classification previously used by Kaczmarzyk et al. :Grade 0—possibility of vertical insertion of three of the investigator’s fingers between the dental arches in the maxillary midline;Grade 1—only two fingers;Grade 2—only one finger;Grade 3—inability of inserting even one finger.Facial edema :Grade 0—no visible asymmetry;Grade 1—slight swelling ;Grade 2—medium swelling (visible asymmetry);Grade 3—significant swelling.Lymphadenopathy:Grade 0—lymph nodes not palpable;Grade 1—slight enlargement (not painful);Grade 2—enlargement ;Grade 3—substantial enlargement (highly painful).Dysphagia grade was based on the classification defined by Saeed et al. :Grade 0—unable to swallow;Grade 1—swallows liquids with difficulty but cannot swallow solids;Grade 2—swallows liquids with no difficulty but cannot swallow solids;Grade 3—occasional difficulty in swallowing solids;Grade 4—rarely has difficulty in swallowing, only with solids;Grade 5—swallows normally.Temperature was considered notable if it exceeded 37.5 °C, taking into consideration the mechanisms of psychological stress. Local infection, defined as a dry socket, was diagnosed based on the clinical findings  and evaluated as presence (1) or absence (0).To address the second objective, post-operative pain relief was compared among the three groups. The VAS was used to evaluate the intensity of pain experienced following surgery with respect to the dose of clindamycin. The VAS is a horizontal line with an eleven-point numeric range. It is labelled from zero to 10, with zero indicating no pain and 10 indicating the worst pain possible; therefore, a higher VAS score represents a worse outcome. Patients assessed their pain using the VAS once, 60 min after surgery, and three times afterwards .All the adverse events, such as (but not limited to) nausea, vomiting, diarrhea, skin rash, itching, chest pain, abdominal or stomach cramps, pain or tenderness, were self-reported by the patients.18 3.5 µg silica reversed particles . The mobile phase was a mixture of methanol–trifluoroacetic acid 0.01% . Separation was achieved using isocratic solvent elution at a flow rate of 0.6 mL/min. Quantitation was performed in multiple reaction monitoring mode to monitor the precursor-to-product ion transition of m/z 425.1 → 126.1. The lower limit of quantification (LOQ) was 0.1 µg/mL. Values below the LOQ were set to 0.05 µg/mL for the statistical analysis.On days 1, 3, and 7 of clindamycin administration, parotid saliva samples were obtained from the parotid duct using a 22-gauge plastic catheter attached to 1 mL insulin syringes. The samples were then transferred to Eppendorf tubes and stored at <20 °C. All the samples were frozen until the assay. To perform a quantitative analysis of clindamycin in human saliva, an LC/ESI-MS/MS method developed by Catena et al.  was usedIBM SPSS Statistics 25 software was used for calculations and graph preparation. Spearman rank correlation was used to measure any statistically significant association between the variablesThe effect of time lapse, study group allocation, and the interaction of these variables with clindamycin concentrations and post-operative pain levels were evaluated using the analysis of variance in the mixed model (with repeated measures). Statistically significant interaction of the variables was examined by the analysis of the simple main effects. The size of the effect was measured using the Eta-squared value. In case of a lack of sphericity, Greenhouse–Geisser correction was applied.The chi-square test was used to check whether the compared groups were equipotential and assess the presence of statistically significant correlations between the nominal variables. The Eta coefficient was used to evaluate the correlations between the quantitative and nominal variables. For nominal variables, the strength of association was measured using Cramer’s V.p-value of 0.05 or less was considered statistically significant.Mean, median, standard deviation, minimum, maximum, and the first and third quartiles were used for the analysis. A The sample size calculation was based on the data obtained from our pilot study, in which the infection rate was evaluated based on the results of 20 patients who received conventional antimicrobial treatment (300 mg of clindamycin hydrochloride every 8 h for 5 days). Assuming a two-tailed alpha error of 0.05, a statistical power of 90%, a mean of 6.5 points with a standard deviation of 3, expecting to detect a clinically significant difference of 2 points, 90 patients were required for each treatment arm. Assuming a 5% withdrawal rate, 95 patients per treatment arm were selected. The research was conducted in a group of 278 patients, since 6 patients were lost to follow-up; 92 (33.1%), 92 (33.1%), and 94 (33.8%) patients were included in groups I, II, and III, respectively, as presented in the Consolidated Standards of Reporting Trials (CONSORT) flowchart .2(2) = 0.03, p = 0.99) and evenly split considering sex and body mass index (BMI) (The comparison groups were equinumerous (χex (BMI) .p = 0.02). There were no statistically significant differences in age between the groups.Statistically significant differences in BMI were observed in the three groups; however, the strength of the effect was low. The BMI of the patients receiving a higher dose of clindamycin (600 mg) was slightly lower than that of the patients in the second group  and III (p < 0.001). In the case of other time frames, the groups differed significantly from one another (p < 0.001). Interestingly, the lowest values were observed among patients in group I, while the highest values were observed in group III, as shown in The statistically significant difference between each group in terms of intensity of post-operative pain was especially relevant in the first, third, and seventh day (strong effect measured with eta-squared). Pairwise comparisons revealed that at 60 min following the administration of the first dose, the level of pain in group I was lower than in groups II , as presented in Stomach and abdominal pain, nausea, and vomiting were the most common adverse effects reported by patients. Interestingly, there were no reports of any adverse effects in group I and only four cases of stomach pain in group II. The situation was much worse in the patients belonging to group III, for which 23 cases of stomach and abdominal pain were reported, along with 7 cases of nausea, 3 cases of vomiting, and 1 case of chest pain.p < 0.001), with the only exception being group I in relation to group II on the seventh day (p = 0.29), as presented in The achieved effect size indicated significant differences in clindamycin concentrations between the study groups. The highest value was observed in group III, which was expected. Each cluster differed statistically significantly from one another  on the first and third days in group III.By conducting an analysis of the simple main effects, we observed a higher concentration of clindamycin in women than in men  did not exhibit a statistically significant association with clindamycin concentration. The value of the coefficient (which can vary between 0 and 1) with respect to the association between the concentration in the three time frames and the grade of each parameter was calculated as zero, which indicated that there was no relationship between clindamycin concentration in saliva and degree of post-operative inflammation.Despite many controversies surrounding antibiotic therapy in the case of third molar surgery, the debate is still ongoing, with emphasis on ascertaining the specific indications, as some authors highlight the risks of adverse reactions and the development of resistant bacteria ,19. AlthOur study demonstrates that a post-operative course of clindamycin is beneficial in terms of alleviating pain and decreasing complications and infection, defined here as the incidence of dry socket, especially with lower doses administered over shorter time periods. We conducted a clinical trial under the usual working conditions of two public hospitals in different countries and the results were consistent. The study was carefully designed to avoid the risk of bias as far as possible, and to further limit such risks, the classification of the resulting inflammatory and infectious complications was conducted based on the clinical symptoms described in other studies ,22,24. OWe do take into consideration the fact that a long duration and multiple courses of antibiotics are associated with bacterial resistance; however, our research clearly demonstrates that a course of 150 mg clindamycin every 8 h for 5 days not only alleviates pain but also decreases the severity of post-operative sequelae, providing relief for patients. A similar finding was reported by conducted by Kaczmarzyk et al. with 600 mg clindamycin administered preoperatively , whose oAlthough clindamycin is considered to be well tolerated and safe, its administration may cause unpleasant adverse effects, especially in the gastrointestinal tract, with diarrhea being the most commonly reported side effect . AlthougEvery tissue injury triggers the immune system and results in an inflammatory response that activates the pain pathways. Even though pain is handled by the nervous system, the immune cells and glia interact with neurons, which results in the remodeling of pain levels and the alteration of pain from acute to chronic pain . AntibioOur study suggests that lower doses of clindamycin administered over shorter time periods are beneficial in relieving pain and reducing post-operative complications following third molar surgery; hence, clinicians should consider prescribing clindamycin at a dose of 150 mg in cases of bony impacted third molars.


Patient-reported outcome measures (PROMs) were developed to examine patients’ perceptions of functional health. Most studies compare the responsiveness of each type of questionnaire. However, reports of patient preferences among PROMs commonly used with patients with hand/wrist injuries or disorders are limited. This study aimed to compare patient preferences, factors associated with those preferences and responsiveness among the Disability of the Arm, Shoulder, and Hand (DASH), Michigan Hand Outcomes Questionnaire (MHQ), Patient-Rated Wrist/Hand Evaluation (PRWHE) and EQ-5D in patients with hand/wrist injuries or disorders.This retrospective cohort study collected data on 183 patients with hand/wrist injuries or diseases who had visited a hand/wrist outpatient clinic or were hospitalized for surgery between 2017 and 2020. Patients had to be at least 18 years old and able to complete the four questionnaires included in the study. The four PROMs  were administered to the patients prior to treatment. After completing the questionnaires, patients were asked to answer two open-ended questions regarding their preferences. Multinomial logistic regression was used to identify factors related to patient preferences. Results are presented as the relative risk ratio (RRR). The standardized response mean (SRM) was used to evaluate questionnaire responsiveness.n = 74, 41%), with the main reasons cited being “specific to injuries/diseases and reflects hand/wrist function ” and “easy to complete .” Sex was found to be associated with patient preference after adjusting for demographic data and reasons for choosing a PROM as confounders . The PRWHE had the highest SRM, followed by DASH .Of the 183 patients, most preferred the PRWHE questionnaire (The PRWHE is the most preferred by patients and is the most responsive questionnaire. It is recommended for use in clinical practice in situations where a clinician would like to use only one PROM for evaluating patients with various types of hand/wrist problems.Level of evidence: Prognostic III. An adjunct to physical examination and radiography after therapy, patient-reported outcome measures (PROMs) were developed to examine patients' perceptions regarding functional health, which represents the true success of treatment , 2. CurrIn the past, many studies have focused on a comparison of the responsiveness of different types of questionnaires to aid in identifying the best outcome measurements for detecting clinical change and to determine the smallest difference in the score of an outcome instrument that patients perceive as important in cases of a specific type of injury or disorder –16. In aThe decision regarding which PROM to use to assess a patient’s hand/wrist symptoms or function depends on the judgement of the clinician and may not reflect the patient’s symptoms or the severity of the injury. A better understanding of patient preferences in terms of performance, ease of completion and precision of evaluation of hand/wrist function can assist in the selection of the most appropriate questionnaire , 23.Identifying a specific PROM for a patient with hand/wrist injuries or disorders that provides both a high ability to detect clinical change over time and which is preferred by patients for describing their symptoms and the severity of their injury in actual clinical practice could potentially provide significant benefits, especially when a clinician would like to use only one PROM to evaluate patients with various types of hand/wrist problems. The aim of this study was to compare patient preferences, factors associated with preferences and responsiveness among four commonly used PROMs .This retrospective study was conducted at a university hospital and was approved by the institutional ethics committee . We collected data on 183 patients with hand/wrist injuries or diseases who had visited a hand/wrist outpatient clinic or were admitted for surgery between 2017 and 2020. Inclusion criteria were aged at least 18 years old and able to complete the four PROMs. Demographic data, including age, sex, dominant hand, injured hand, diagnosis, education level and employment status, were recorded. The Thai versions of the PRWHE, MHQ, DASH and EQ-5D were given to all the patients prior to treatment –27. AfteThe PRWHE questionnaire comprises 15 items grouped into three subscales: pain, specific activities, and usual activities. Response options range from 0 to 10, with lower scores indicating less pain or disability. The total score for the PRWHE ranges from 0 to 100, with lower scores indicating better functional hand use .The MHQ questionnaire consists of 37 items to assess six subscales: overall hand function, activities of daily living, pain, work performance, aesthetics, and patient satisfaction with hand function. Four of these six sections inquire separately about how the right and left hands are impacted. Scores are normalized and summed for a total of between 0 and 100, with 100 representing excellent perceived hand function .The DASH questionnaire contains 30 items in five subscales: common activities; self-care activities; pain symptoms; other symptoms including numbness, joint stiffness, weakness, and sleep problems and psychological effects; and optional sports and work modules, each with five response options (1–5). Lower scores indicate better functional hand use. Total scores range from 0 to 100, with 0 representing no difficulty in the performance of daily tasks , 18.The EQ-5D questionnaire is a two-part outcome measurement which is extensively used to evaluate health status , 30. TheAll four PROMs had previously been translated into Thai and cross-culturally adapted following standard guidelines, and were shown to have adequate internal consistency in all subscales as well as good construct validity and reliability with Thai patients , 31–33.https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-standard-value-sets/crosswalk-index-value-calculator/).The Thai PRWHE, MHQ and DASH were scored manually, following the original scoring algorithms , 19, 21,P < 0.05.For demographic data, categorical variables are reported as frequencies and percentages. Continuous variables are reported as means and standard deviations. Statistical significance was set at Patient questionnaire preferences and reasons for selecting a particular questionnaire are reported as percentages of participants.Univariable and multivariable analysis  were performed to identify factors related to patient preference. Potential factors were chosen from the demographic data and from reasons given by patients for selecting a particular questionnaire. Factors associated with patient preferences are reported as the relative risk ratio (RRR) with the 95% confidence interval (95% CI).Responsiveness is defined as the ability of a measurement to detect clinically significant changes over time . ResponsFloor or ceiling effects were considered to be present if more than 15% of patients reported the lowest or highest possible scores . In thesn = 122, 67%). Most were right-hand dominant . The ratio of injured hand between right and left was comparable . The three most frequent diagnoses were tendon entrapment , hand/wrist fracture  and nerve entrapment . The majority of the patients had a secondary/high school education or equivalent  followed by a bachelor’s degree . Most patients were employed  (Table The mean age of the 183 patients involved in this study was 45 years (SD 17), with females predominant , citing as the main reasons that the PRWHE is “specific to injuries/diseases and reflects hand/wrist function”  and that it is “easy to complete” . The second most preferred questionnaire was the MHQ . The main reasons patients preferred the MHQ were that it “provides high detail”  and that it is “easy to complete”  , adjusting for age ≥ 65 years, diagnosis, education level of at least a bachelor’s degree, employment status and reason for patient preference as confounders. Age ≥ 65 years, diagnosis, education level of at least a bachelor’s degree, being employed and reason for patient preference were not statistically significantly associated with the patient’s choice of preferred questionnaire   Table .Table 3FMore than half the patients in the study received surgical treatment (57%). Fifty-one patients were followed up, at which time they completed each of the questionnaires, including the evaluation of the perceived responsiveness. The mean time to follow-up was 2 months. No floor or ceiling effects were found in the total scores of any of the four PROMs. The results show that the PRWHE was rated as the most responsive questionnaire, with the highest SRM (0.92) and ES (1.0), followed by the DASH questionnaire, with SRM = 0.88 and ES = 0.76 Table .Table 4SThis study found that patients with hand/wrist injuries or disorders preferred the PRWHE and felt it was the most responsive questionnaire among the four commonly used PROMs . This study compares both patient preferences and responsiveness among commonly used PROMs, while previous studies have focused primarily on comparing the responsiveness of various PROMs. This suggests that the PRWHE is appropriate for use by clinicians to evaluate clinical outcomes in a general hand/wrist clinic.In terms of patient preference, the two top questionnaires were the PRWHE and MHQ, both of which are specific to patients with hand/wrist problems. Each questionnaire has its own special advantages. The PRWHE has only 15 items which are specific to pain and function, while the MHQ addresses 37 items in 6 subscales and requires specifying the right or left hand, which increases the time taken to complete the MHQ. DASH is a more general questionnaire which focuses on symptoms and the functional status of the upper extremities with 30 items, and EQ-5D has only 5 items, which are used to evaluate general health. A previous study of 59 patients with hand fractures which described patient PROM preferences in terms of ease of completion and measurement of ability to use the hand reported that the PRWHE was easiest to complete and that the MHQ best reflected ability to use the hand . HoweverThe questionnaire which participants found to be most responsive in our study was the PRWHE, followed by the DASH and MHQ, in that order. The PRWHE, MHQ and DASH have all been previously reported to be commonly used PROMs for the hand/wrist region. Most studies have compared responsiveness between either the MHQ and DASH , 11, 16 The population in the present study would be expected to focus on pain and hand function, which suggests why the PRWHE demonstrated a higher responsiveness compared to the MHQ and EQ-5D, which include evaluations of aspects of aesthetics and mobility, respectively.In our cohort, the three most common hand/wrist problems, in descending order, were tendon entrapment , hand/wrist fracture and nerve entrapment. In previous studies, tendon entrapment and nerve entrapment have been reported to be commonly found in stable populations in Greece and the United Kingdom , 40. HowThere were several strengths of our study. First, we focused on patients’ preferences as well as on their perception of the responsiveness of PROMs commonly used with patients who have hand/wrist problems, unlike prior studies, which have focused primarily on responsiveness. Second, the number of PROMs evaluated and the size of the population in our cohort were relatively high.A limitation of this study is that only one-third of the patients in the study evaluated the responsiveness of all four common PROMs. Eighty-nine patients were lost to follow-up after receiving the treatment, and 43 patients did not complete all four common PROMs when they came to follow-up. However, evaluating responsiveness with 51 patients is roughly comparable to previous studies , 16, 21.Among four common PROMs  for the evaluation of patients with hand/wrist injuries or disorders, the PRWHE is the most preferred by patients and the most responsive questionnaire. The PRWHE is recommended for use in situations where clinicians would like to use only one PROM for evaluating patients with various types of hand/wrist problems.


Chronic pain is common after burn injuries, and post-burn neuropathic pain is the most important complication that is difficult to treat. Scrambler therapy (ST) is a non-invasive modality that uses patient-specific electrocutaneous nerve stimulation and is an effective treatment for many chronic pain disorders. This study used magnetic resonance imaging (MRI) to evaluate the pain network-related mechanisms that underlie the clinical effect of ST in patients with chronic burn-related pain. This prospective, double-blinded, randomized controlled trial  enrolled 43 patients who were experiencing chronic neuropathic pain after unilateral burn injuries. The patients had moderate or greater chronic pain  score of ≥5), despite treatment using gabapentin and other physical modalities, and were randomized 1:1 to receive real or sham ST sessions. The ST was performed using the MC5-A Calmare device for ten 45 min sessions (Monday to Friday for 2 weeks). Baseline and post-treatment parameters were evaluated subjectively using the VAS score for pain and the Hamilton Depression Rating Scale; MRI was performed to identify objective central nervous system changes by measuring the cerebral blood volume (CBV). After 10 ST sessions (two weeks), the treatment group exhibited a significant reduction in pain relative to the sham group. Furthermore, relative to the pre-ST findings, the post-ST MRI evaluations revealed significantly decreased CBV in the orbito-frontal gyrus, middle frontal gyrus, superior frontal gyrus, and gyrus rectus. In addition, the CBV was increased in the precentral gyrus and postcentral gyrus of the hemisphere associated with the burned limb in the ST group, as compared with the CBV of the sham group. Thus, a clinical effect from ST on burn pain was observed after 2 weeks, and a potential mechanism for the treatment effect was identified. These findings suggest that ST may be an alternative strategy for managing chronic pain in burn patients. Up to one-third of patients suffer from chronic pain after burns ,2. ManagChronic pain in burn patients can be treated using pharmacological strategies  and non-pharmacological modalities  ,5. Many It has been suggested that burn injuries trigger the peripheral nerves and cause sensitization of the nociceptive fibers ,13; chroThis prospective, double-blind, randomized controlled trial enrolled 36 male and 7 female patients at the Department of Rehabilitation Medicine at Hangang Sacred Heart Hospital in Korea between March 2018 and October 2020. All patients provided written informed consent. The trial protocol was registered at ClinicalTrials.gov (NCT03865693) and was approved by the ethics committee of Hangang Sacred Heart Hospital (HG2017-088). This study was conducted according to the CONSORT guidelines.To be included in the study, patients had to (i) be 18 years of age or older; (ii) have burn scars that had re-epithelialized after aseptic care or skin grafting; (iii) have complained of moderate or greater chronic neuropathic pain with reduced sensation in the burned area ) lasting for >3 months after the burn injury, despite receiving pharmaceutical treatment and/or physical therapy ,23; (iv)The study used an MC-5A Pain Scrambler Therapy device  with electrode patches applied to a 20–25 mm area surrounding the site of the most painful burn scar. In the ST group, the stimulus intensity was treated as the maximum intensity that the patient could tolerate without discomfort (≤70 U) . In the Only the therapist had access to the allocation schedule, and all participants and evaluators were blinded to the treatment details. Depressive mood was assessed using the Korean version of the Hamilton Depression Rating Scale (HDRS) . Patienthttps://www.fil.ion.ucl.ac.uk/spm/software/spm12/, accessed on 8 May 2022), as previously described [All MRIs were performed using a 3.0 T magnetic resonance scanner  and an established steady-state gadolinium-enhanced MRI technique ,29. Two escribed ,30. The escribed  that impAll statistical analyses were performed using SPSS software . Non-parametric measurements between the two groups were analyzed using the Mann–Whitney test. After testing for data normality, Mann–Whitney U tests were performed to compare pretreatment homogeneity between the groups for total body surface area, days between the burn injury and MRI acquisition, VAS score, BPI score, and HDRS score. Fisher’s exact test was used to assess differences in the sexes and the sites of burn injury between the groups.p-value < 0.05 were considered statistically significant [Pain scores from before and after treatment within each group were compared using the Wilcoxon signed rank sum test. The comparison between the VAS scores of the two groups after 2 weeks of treatment was performed using the Mann–Whitney test. After correction for multiple comparisons with threshold-free cluster enhancement, group differences and VAS correlations with a nificant . p > 0.05). Relative to the baseline value, the ST group showed a significant reduction in the pain score after ST (p = 0.004); the sham group also had a significant reduction in the pain score after 2 weeks of therapy (p = 0.001). After 2 weeks of treatment, it was found that the VAS scores of the ST group were significantly decreased compared with the VAS scores of the sham group (p < 0.001)  . p > 0.05). In the ST group, the CBVs of the right orbito-frontal gyrus (p = 0.004), right middle frontal gyrus (p = 0.004), right superior frontal gyrus (p = 0.004), right gyrus rectus (p = 0.004), left orbito-frontal gyrus (p = 0.004), and left superior frontal gyrus (p = 0.004) were decreased after 2 weeks of ST (There was no difference in baseline CBV before ST between the two groups (ks of ST .p = 0.002) and postcentral gyrus (p = 0.004) of the hemisphere associated with the burned limb in the ST group, as compared with the CBV of the sham group (After 2 weeks of treatment, it was observed that the CBV had increased in the precentral gyrus (am group . No seriThis study aimed to evaluate the clinical usefulness of ST and identify the pain network alterations associated with ST for chronic neuropathic pain in burn patients. The ST group experienced pain reduction from ST and a hypersensitization mechanism potentially related to treatment was observed. These results suggest that ST may demonstrate an alternative strategy to manage chronic pain in burn patients.Pain perception is affected by alterations in the cerebral pain network ; chronicWe collected CBV maps from before ST and after 10 therapy sessions. After 2 weeks of ST, a decrease was observed in the CBVs of the bilateral orbito-frontal gyrus, right middle frontal gyrus, bilateral superior frontal gyrus, and right gyrus rectus in the ST group. In addition, the CBV was increased in the precentral gyrus and postcentral gyrus of the hemisphere associated with the burned limb in the ST group, as compared with that of the sham group. Burn patients may suffer from chronic pain, which is characterized by neuroanatomical plasticity, including central sensitization. Many studies of non-invasive brain-modulatory therapy have demonstrated a relationship between changes in the cerebral pain network and pain intensity. This pain network consists of the primary and secondary somatosensory cortex, the prefrontal lobe, dorsolateral prefrontal cortex, and medial prefrontal cortex . NeuroimThis study explored the effects of ST based on subjective and objective parameters, including cerebral activity in patients with chronic neuropathic pain after burn injury. This study had some limitations, including a small sample size and a short follow-up period. Due to the small sample size, the effects of individual differences in the side of the injuries could not be fully taken into account. The majority of patients with severe burns admitted to this burn center, and consequently enrolled in this study, were male. Thus, it would be inappropriate to generalize the study results to both sexes. For ethical reasons, the patients’ pharmacological and non-pharmacological treatments were maintained the same as before the start of the study; therefore, further study that excludes these aspects is needed. Further studies are needed to develop advanced strategies for controlling neuropathic pain caused by thermal injury, including cranial magnetic stimulation or transcranial direct current stimulation. Future research should also assess the effects of ST on central neurotransmitters, which play a major role in the endogenous pain facilitatory and inhibitory pathways. In order to confirm the therapeutic effect, it is thought that more research is needed on clinical parameters, including not only the pain level, but also sleep disturbances and changes in daily living activities due to pain.This study found that burn patients with chronic neuropathic pain had CBV changes in regions of the cerebral pain network that are associated with the frontal lobe, precentral gyrus, and postcentral gyrus. Thus, a clinical effect from ST on burn pain was observed after 2 weeks, and a potential mechanism for the treatment effect was identified. These findings suggest that ST may be an alternative strategy for managing chronic pain in burn patients.