Laparoscopic surgery has become the preferred surgical approach due to a reduction in postoperative pain, better recovery, shorter hospitalization, and improved esthetic outcomes. Laparoscopic surgery with single-port laparoscopy (SPL) is a laparoscopic surgery technique that is based on making a single parietal incision using a single trocar specifically designed to allow introduction of several instruments. The level of evidence regarding the advantages of SPL in terms of postoperative pain has remained low despite several randomized studies. Adult patients exhibiting a surgical indication for an a priori benign ovarian pathology or for prophylactic purposes that can be performed by laparoscopy will be randomized to receive conventional laparoscopy (CL) or SPL. The aim of our study is to evaluate whether SPL offers advantages over CL in benign adnexal surgery.The patients will be evaluated preoperatively to confirm their eligibility. The perioperative data up to 24 h after the intervention, as well as the postoperative data at day 7 and at one month from the intervention will be collected. The primary outcome for the study will be the postoperative pain at 24 h ± 2 h after the intervention. The pain will be assessed by a numeric rating scale of 0–10.Other outcomes will also be assessed, such as pain at other times, the consumption of analgesics, the operative time, perioperative bleeding, the number of additional trocars in the two groups, the incidence of laparoconversion, the esthetic criteria of the scar at one month, the incidence of complications, and the quality of life at one month.If our hypothesis is confirmed, this study will provide evidence that the use of SPL can decrease postoperative pain in adnexal surgery. The standard surgical treatment of this condition would thus be modified.NCT02739724. Registered on 12 April 2016.ClinicalTrials.gov, The online version of this article (doi:10.1186/s13063-017-2429-y) contains supplementary material, which is available to authorized users. Surgical techniques have evolved significantly in recent years in light of developments in terms of minimally invasive surgery and laparoscopy in particular. Compared to laparotomy, laparoscopy provides better cosmesis, a decrease in the rate of complications at the abdominal wall, shorter hospitalization, faster resumption of daily life activities, lower cost, and less pain . Single-The feasibility of SPL has been evaluated in different surgical specialties such as gynecology, urology, and visceral surgery –12. SeveThere have been six comparative randomized studies of the postoperative benefits regarding adnexal surgery  by SPL vs CL –21. We pAlthough some of these studies found significant differences, this meta-analysis concluded that postoperative pain, perioperative blood loss, cosmetic outcomes, and rates of postoperative complications were comparable between the two techniques, with the exception of operative time, which was longer for the SPL group.These six studies obtained discordant results, since the study by Fagotti et al.  found thIn light of the potential advantages of the SPL technique, further randomized studies with a more appropriate methodology are warranted to confirm or refute the superiority of this technique relative to CL.The aim of our study is to evaluate the postoperative consequences of SPL relative to CL in benign adnexal surgery.Figure The criteria for inclusion are that the patients are aged at least 18 years and that they exhibit a surgical indication for an a priori benign ovarian pathology according to the guidelines of the College National de Gynecologie et Obstétrique (CNGOF) of 2013 or for prophylactic purposes according to the Institut National du Cancer (INCA) guidelines of 2009 that can be performed by laparoscopy , 24. In The criteria for exclusion are patients harboring endometriotic cysts or a prior history of severe endometriosis, patients for whom laparoscopy is contraindicated by the surgeon  or the anesthetist (e.g. prior issues or pathologies that counterindicate the Trendelenburg position), patients requiring emergency surgery for a complicated ovarian pathology , and patients who cannot be adequately informed in regard to providing informed consent. The patients will be treated as outpatients, except in case of an anesthesia counterindication .The participants will receive the assigned intervention, i.e. either SPL or CL. The surgical interventions will be undertaken or supervised by a surgeon who has expertise in the specific area of the intervention. There will be four participating surgeons who have appropriate training for the two techniques . Further details regarding the interventions are provided below.A single vertical subumbilical incision of 2 cm will be made, allowing for insertion of the monotrocar . This monotrocar has an insufflation channel that allows insufflation of carbon dioxide at a pressure of 12 mmHg. An endoscope of 10 mm with an angulation of 0° will be used to visualize the abdominopelvic cavity.Conventional laparoscopy instruments will be used for the procedure with bipolar forceps and monopolar scissors .At the end of the surgical procedure a correct exsufflation will be performed after withdrawal of the monotrocar, and a suture of the abdominal aponeurosis will be made with polysorb 1. The cutaneous suture will be made with inverted intradermal stitches using monocryl 3.0.For the CL group, the abdominal cavity will be accessed by the open laparoscopy technique with a vertical subumbilical incision of 1 cm. A trocar of 10 mm will be placed in this orifice . The carbon dioxide will be insufflated at a pressure of 12 mmHg. Two additional trocars of 5 mm will be added to the right and the left iliac fossa . The same 10-mm lens with an angulation of 0° and the same conventional instruments with bipolar forceps and monopolar scissors as for the SPL group will be used. Removal of the trocars will be done visually with correct exsufflation at the end of the procedure. The aponeurosis of the subumbilical orifice will be closed by a purse-string stitch with polysorb 1 and the cutaneous closure will be with separate inverted stitches using monocryl 3.0.Aside from the laparoscopic approach, for which a single trocar will be used in the “SPL” arm, there is no difference compared to the usual treatment of patients.The surgical techniques will be the same for the two groups. These comprise the intraperitoneal cystectomy laparoscopic surgery technique and the laparoscopic adnexal surgery technique , 27.The cystectomy will be performed by the divergent traction technique between cyst and ovarian wall after aspiration evacuation of the cyst. If necessary, hemostasis of the wall will be performed with bipolar energy. No suture will be performed on the ovarian at the end of the cystectomy. The adnexectomy will be performed by coagulation/sectioning of the infundibulopelvic ligament. The appendage will be connected to the uterine horn by sectioning the peritoneum of the anterior and posterior sides of the broad ligament. The connection of the uterine horn will then be able to be controlled by coagulation/sectioning of the utero-ovarian connection and of the Fallopian tube.After a cystectomy or an adnexectomy, the surgical items are withdrawn with bag through the subumbilical orifice.The patients in both groups will be under general anesthesia, placed in the Trendelenburg position, and a gynecological surgical site is prepared.The perioperative and postoperative analgesia will be the same for all of the patients participating in the study. There will be no premedication for analgesic purposes.The general anesthesia will comprise 0.2 mcg/kg of Sufentanil, 3 mg/kg of Propofol, a non-depolarizing neuromuscular blocking drug, and oro-tracheal intubation. The patients will undergo ventilation with a mixture of air/oxygen, Sevoflurane, Sufentanil (+5 mcg for pneumoperitoneum + 5 mcg before closing for procedures lasting > 1 h). The analgesia 1 h before waking up will comprise 1 g of paracetamol, 20 mg of nefopam, 1.25 mg of droleptan, 4 mg of dexamethasone, and 100 mg of profenid.For both of the groups, the procedure will start with the cutaneous incision and it will end with the closing of the trocar orifices. There will be no local infiltration of the trocar orifices with analgesics as this procedure is not a standard of care in our department.In case pain occurs in the first 2 h after the surgery, the patient will receive a 100 mg intravenous dose of tramadol (associated with a slow injection of 4 mg of intravenous ondansetron in case of nausea).The patients will systematically receive two tablets containing 37.5 mg of tramadol/325 mg of paracetamol and a 100-mg tablet of ketoprofen at 6 h after the intervention per os. The analgesic treatment for the following days will comprise 37.5 mg of tramadol/325 mg of paracetamol: two tablets in the morning, at noon, and in the evening with one 100-mg tablet of ketoprofen in the morning and in the evening before meals . This treatment is taken systematically the day after the intervention and then if the pain continues. A per os rescue analgesia will be prescribed that is a combination of 25 mg opium/500 mg paracetamol in case of intense pain, to be renewed, if need be, every 4–6 h, without exceeding three capsules per day.All of the eligible patients will be informed of the study protocol at the end of the scheduled consultation and the doctor will provide the patients with an information sheet. The doctor will set out the aims of the study, how it will take place, as well as the benefits and the drawbacks associated with their potential participation. They will verify whether the patient meets the inclusion or non-inclusion criteria detailed above. They will provide an information sheet regarding the study. The patient will be given until the day of the intervention to decide whether to participate. In case the patient agrees to be included in the study, written consent will be obtained before they are taken into the operating theatre.The patients will be recruited in a single center by the gynecological consultants in the Gynecology-Obstetrics unit of the CHU of the Conception Hospital of Marseille.Once the patient has agreed to participate in the study, the doctor involved in the investigation will carry out the randomization  and they will inform the patient.The randomization will take place upon entry into the intervention room, and it will allow assignment of the patients to either the SPL group or the CL group; the comparison of these two groups constitutes the methodological framework of the research.The randomization list will be established before the implementation of the study. It will be devised with guidance from the Public Health and Medical Information Unit . The adopted method is based on patient blocks permuted by stratum. The retained stratum is represented by the procedure . The mode of allocation concealment is two packs of numbered envelopes for the stratification.The calculation of the number of individuals required was performed based on the primary outcome, that is to say the pain at 24 h evaluated using a numeric rating scale. We performed a pilot study of 100 files of patients who had undergone an adnexal surgery with CL. The average pain at 24 h was 3 points ± 2.5. In order to reveal a difference of 2 points between the two strategies, a difference that we defined as clinically acceptable, if the standard deviation (SD) is set at 3 , for a power of 90% and first order risk of 0.05 for the study, the number of participants required for each group is 48 patients. The stratification by procedure allows for an equivalent number for each treatment arm. Since we estimate that the loss to follow-up or exclusion will be 10%, a total of 54 patients will be required per group. The total number of patients to be included will therefore be 108.The collection of the data regarding pain will be performed blinded by an independent doctor who has no prior knowledge of the group assignment. The participants will in the first instance be evaluated in the hospitalization unit and subsequently contacted by phone.They will then be evaluated at one month at the end of the postoperative consultation.A case report form (CRF) will be specifically devised for the study. It will be a handwritten log. Prospective collection of data will be performed on the day of the intervention and subsequently also for the after-effects of the intervention.The participants will be evaluated preoperatively to confirm their eligibility. The perioperative data up to 24 h after the intervention, as well as the data at day 7 and at one month from the intervention will be collected. The results provided by the patients will be added to the CRF at 2, 4, and 6 h following the intervention, as well as those obtained by phone at 24 h, at seven days after the surgery, and during the postoperative consultation at one month. The follow-up items for the participants are presented in Table The primary outcome for the study will be the postoperative pain at 24 h ± 2 h after the intervention. The end of the intervention will be defined by the closing of the trocar orifices. The pain will be assessed by a numeric rating scale of 0–10; the collecting caregiver will be blinded to the technique used on the individual and they will be independent of the surgeon. When evaluating the pain, we will take care to do so well after the patient has been bandaged (i.e. at least 1 h later if the care took place within a 24-h time slot). The parietal pain will be dissociated from scapular pain caused by the insufflation gases by a thorough examination and by a numeric rating scale for each site. The evaluation of the pain at other times will be reported based on the secondary assessment criteria.The choice to evaluate pain from a numeric rating scale is based on the fact that this evaluation method remains consensual in the literature even though this evaluation, especially by phone, is subjective.The evaluation of postoperative pain will be achieved by determination of the pain at other times by a numeric rating scale assessment at 2, 4, and 6 h, as well as at day 7 and at one month after the intervention. The parietal pain will be dissociated from scapular pain caused by the insufflation gases by a thorough examination and by a numeric rating scale for each site.The surgical characteristics will be noted: perioperatively, there will be an evaluation of operative time, defined as the time between the start of the incision up to the cutaneous closing of the trocar orifices; evaluation of perioperative bleeding by the Entry/Exit balance between perioperative lavage and aspiration (in mL); evaluation of the need for conversion to laparotomy in the two groups; evaluation of the need to add an additional trocar in the two groups; and evaluation of the perioperative rate of complications .For the surgical aftermath, we will note the consumption of analgesics, the number of days that they are taken, and the number of tablets consumed by a phone call seven days after the intervention; and we will evaluate the esthetic criteria by the patient based on a numerical scale of 0–10 at one month from the intervention, as well as the postoperative quality of life by an SF-12 questionnaire of the quality of life at one month from the intervention. The number of days before resuming normal physical activity according to the patient, the number of days off work, the rate of postoperative complications , and the rate of reintervention and of rehospitalization in the first three postoperative weeks will also be evaluated.The chart of the observations will be kept by the doctor involved in the investigation until the end of the follow-up of the participants. A clinical research associate (CRA coordinator) will be in charge of performing the quality control of the case report logs before the information is digitally entered and they will verify that informed consent has been properly obtained from the patients according to the regulatory guidelines. Particular attention will be paid to the main evaluation criteria, i.e. the pain at 24 h. The analysis plan is drafted according to the criteria devised by the Consolidated Standards of Reporting Trials (CONSORT) group. The statistical processing will not start until after verification of the validity of the database . The database will then be locked. After the database is locked, the consolidated data are processed by the statistician. Analysis of the data will be performed using SPSS version 17.0 software. There will be a procedure and an algorithm for anonymization of the data that assigns a number to each individual. A correlation table is available that is separate from the operations base. Only this number will be taken from the digital data.The statistical analysis will in regard to the intention to treat population , while excluding the patients for whom a major violation of the protocol is observed (e.g. no objective post-inclusion data). A complementary analysis will be performed on the population based on the protocol .In the first instance, a descriptive analysis of the entire sample will be carried out. The qualitative variables will be presented as proportions and the number of participants, the quantitative variables as averages and SDs, or medians and quartiles. For each variable, the proportion of missing data will be specified. The normality of these will be evaluated using frequency histograms and Shapiro tests; straightforward mathematical transformations may be used in order to normalize the non-normal data. The comparability of the two groups will be determined based on the entire set of the available variables at the inclusion so as to ensure the initial compatibility, using the Chi-squared test for qualitative variables and the ANOVA or Kruskall–Wallis tests for quantitative variables. The comparative analyses will be carried out blinded, i.e. neither the statistician nor the coordinating investigator will have knowledge of the identification of the groups. Once the analysis has been completed, the identification of the groups will be made available.The average values of pain at 24 h will be compared between the two groups using a Student’s t-test or a Mann–Whitney test, as appropriate. The average values of pain for the other evaluation times will also be compared between the two groups. This analysis will be carried out through use of a mixed model for the longitudinal data that takes the different times of the pain evaluation into consideration.This ordinal scale is treated as a continuous dependent variable in all comparative studies of the same type, such as the Hoyer Sorensen study .The criteria will also be compared between the two groups: the proportions with the Chi-squared test ; and the quantitative variables using the t-test and Mann–Whitney test .The intended duration of the study is 24 months.The study obtained approval from the “Comité de Protection des Personnes” (CPP) Sud Méditerranée I (no. 15109) (CPP) on 16 December 2015 and the National Agency for the Safety of Medications (ANSM) on 6 October 2015.This study will be conducted in accordance with the declaration of Helsinki Additional file The sponsor for this project is represented by the Marseille Public Hospital system and will provide insurance for the duration of the study in this capacity.This project is classified as interventional biomedical research as defined by article L.1121-1 and it does not involve a product mentioned in the medications section of article L.5311-1 of the Public Health Regulations; it is subject to the new regulatory conditions that apply to research “organized and carried out on human beings with the aim of developing biological and medical knowledge,” namely Public Health Law no. 2004-806 of 9 August 2004 regarding public health policies, and its decrees for application of 27 August 2006, aimed at getting French regulations to conform with European laws. For this reason, it will be the object of a request for advice from the Committee for the Protection People and a request for authorization from the relevant authority represented by the National Agency for the Safety of Medications. This research will be conducted according to Good Clinical Practice guidelines, which comprise a set of quality requirements in the area of ethics and science, that need to be heeded during the planning, implementation, execution, follow-up, quality control, audit, collection of data, as well as the analysis and presentation of the results. Observance of Good Clinical Practice guidelines guarantees the protection of the individuals who avail themselves to this research and the preservation of their anonymity as well as the credibility  and the accuracy of the data and the results of such research. Informed consent needs to be collected from each participant.In light of the processing of digital data for this health-related project, it is subject to the relevant legislative requirements, in particular the law of 9 August 2004. This will apply exclusively to the data to preclude direct or indirect identification of the individuals participating in the study. It will be carried out in keeping with the reference methodology certified by the French Data Protection Authority and established in concert with the advisory committee for the treatment of research information in the areas of health devised with the aim of streamlining the formalities (decision of 5 January 2006. Reference methodology RM-001).This study involves laparoscopic surgical procedures for adnexal surgery. The possible complications and after-effects are below.All operations carried out under general anesthesia involve a risk of death, muscle paralysis, and technical problems, as well as adverse and allergic reactions.All abdominopelvic operations involve a risk of death and morbidity. The latter comprises infection of the lesion, hernias, visceral abdominal lesions, peri- and postoperative bleeding, intestinal occlusion, respiratory infections, pulmonary atelectasis, thromboembolic complications, and complications secondary to co-morbidities (e.g. ischemic cardiopathy and diabetes).The specific complications linked to the laparoscopic approach include an inadvertent injury to the abdominal viscera due to the restraints associated with laparoscopy, inability to appreciate the extent of the pathology, possible suboptimal repair of the intraoperative injuries, and inadequate closure of the trocar orifices with a delayed hernia that can lead to intestinal occlusion. With single-port endoscopic access, the loss of instrument triangulation, generally considered to be necessary in laparoscopic surgery, limits access and handling by the surgeon.The likely serious adverse events (SAE) in the setting of this protocol that will be considered to be AEs and that will be recorded in the CRFs are as follows: postoperative complications: hemorrhaging and abscess of the abdominal wall; perioperative complications: risk of laparoconversion or of conversion to “conventional” laparoscopy; and blood transfusion.The investigator will evaluate every AE in terms of its seriousness.The investigator must notify the sponsor within 24 h of the time that they become aware of any SAEs that occur during the trial.The investigator must, as thoroughly as possible, document the event by providing the medical diagnosis and they should seek to establish a causal link between the SAE and the research protocol. This statement is forwarded to the sponsor using a dated and signed form for reporting SAEs that is appended to the CRF, in addition to copies of the laboratory results or reports of examinations or hospitalizations informing of the SAE, including relevant negative results. These items need to be rendered anonymous and the number and the code for the patient need to be indicated.The investigator needs to ensure that the relevant information for the follow-up is communicated to the sponsor within eight days after the event is noted. The investigator needs to monitor the patients who have exhibited an SAE until it resolves, stabilizes to a level that the investigator deems to be acceptable, or returns to the prior status. This needs to be done even if the patient has left the trial and they need to inform the sponsor of the progression of the SAE.The benefit for the individuals participating in the trial is a chance to receive a less invasive treatment for their adnexal surgery. We believe that this study does not pose any specific risk for the participants beyond those of laparoscopic surgery in general, provided that the surgeon does not hesitate to convert to multitrocar or conventional surgery should this become necessary.According to our hypotheses, SPL should allow for a reduction in postoperative pain, a shorter duration of the hospitalization, and an improvement in the quality of life. The literature does not provide evidence for a decrease in complications of the abdominal wall , 29.The patient information sheet provides the participants with information regarding the known risks. The patients will undergo surgery whether or not they are included in the study. We do not foresee any additional risk for those who are randomized. The patients who cannot be admitted, or who decline to participate in the study, will have conventional laparoscopic surgery.This study is a randomized controlled single-blind trial. A double-blind design was not possible because the two branches of the study correspond to surgical procedures.The validity and reliability of the data collection procedures used in the trial could be called into question as it is expected that follow-up will involve telephone conversations or questionnaires. However, we took into account a 10% loss of follow-up rate when determining the sample size.Concerning subjectivity of pain evaluation, today, the numeric rating scale is the main tool used in the literature. The second criteria which is often used is painkiller consumption. We used this criterion as the second measure in this study. The choice to evaluate pain from a numeric rating scale is based on the fact that this evaluation method remains consensual in the literature even though this evaluation, especially by phone, is subjective.The collection of pain data and the statistical analysis of the results will be done blindly. The stratification on the type of procedure will allow to have two comparable and balanced groups on the distribution of the type of procedure .If our hypothesis is confirmed, this study will provide evidence that the use of SPL can decrease postoperative pain in adnexal surgery. The standard surgical treatment of this condition would thus be modified.The randomization started on 9 June 2016 and 60 patients have been randomized to date (5 November 2017).


To determine quality of life (QoL) outcomes after palliation of pain from bone metastases using magnetic resonance-guided high intensity focused ultrasound (MR-guided HIFU), measured using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL and the QLQ-BM22 questionnaires.Twenty patients undergoing MR-guided HIFU in an international multicentre trial self-completed the QLQ-C15-PAL and QLQ-BM22 questionnaires before and on days 7, 14, 30, 60 and 90 post-treatment. Descriptive statistics were used to represent changes in symptom and functional scales over time and to determine their clinical significance. QoL changes were compared in pain responders and non-responders .Eighteen patients had analysable QoL data. Clinically significant improvements were seen in the QoL scales of physical functioning, fatigue, appetite loss, nausea and vomiting, constipation and pain in the 53% of patients who were classified as responders at day 30. No significant changes were seen in the 47% of patients who were non-responders at this time point.Local treatment of pain from bone metastases with MR-guided HIFU, even in the presence of disseminated malignancy, has a substantial positive effect on physical functioning, and improves other symptomatic QoL measures. This indicated a greater response to treatment over and above pain control alone. MR-guided HIFU is non-invasive and should be considered for patients with localised metastatic bone pain and poor QoL. •High intensity focused ultrasound (HIFU) palliates localised metastatic bone pain.•Quality of life (QoL) after HIFU improved in pain responders more than in non-responders.•Systemic QoL improved after HIFU to a single painful site, even in those with disseminated disease.•Physical functioning was improved after HIFU, even in patients with end-stage disease. Patients at all sites provided written informed consent, following approval from an Institutional Review Board . The study was conducted in accordance to the principles of the Declaration of Helsinki, Good Clinical Practice and the study protocol. Treatments were carried out using the Philips Sonalleve MR-guided HIFU device. Participants were followed-up on days 7, 14, 30, 60 and 90 days after treatment. All patients included in this QoL analysis had previously received radiotherapy to their painful bone metastases and had experienced differing levels of response. Baseline patient characteristics are presented in Participants were recruited to an international, prospective, single-arm study, designed to determine the efficacy of MR-guided HIFU for the palliation of painful skeletal metastases (NCT01586273) Assessment of baseline QoL occurred on the day of MR-guided HIFU treatment before treatment was administered. A further QoL assessment was completed at each follow-up time point. The QoL questionnaires were self-completed by patients during their hospital visits at baseline, 30, 60 and 90 days, and at home at the 7 and 14 day time points.The QLQ-C15-PAL The QLQ-BM22 Items on both the QLQ-C15-PAL and QLQ-BM22 questionnaires were rated on a four-point Likert scale and were rated from 1  to 4 (very much), with the exception of the overall QoL status item, which was rated from 1 (very poor) to 7 (excellent). A higher score for the symptom scales represents a higher level of symptomatology and, therefore, a decreased QoL. By contrast, a higher score for the functional scales represents a higher level of functionality and, therefore, an increased QoL. Each scale was transformed to a score ranging from 0 to 100, according to their respective scoring manual.Patients were categorised as responders to MR-guided HIFU treatment if they experienced a complete response or a partial response at day 30 after treatment, and non-responders if they experienced no response or pain progression at day 30. This was determined using the international consensus for clinical trial end points on bone pain palliation with radiotherapy criteria www.graphpad.com).All analyses were conducted on GraphPad Prism  n = 17. The same patient did not complete the BPI-SF at the day 30 time point and therefore their response to treatment could not be assessed. One patient had not completed the psychosocial aspects scale from the QLQ-BM22 at day 14, and another patient had not completed the second side of the QLQ-C15-PAL questionnaire at baseline and so their data were not available for the constipation, fatigue, emotional functioning and overall QoL scales at this time point, and was not included in the determination of clinical significance.Eighteen patients completed the QoL assessment at baseline and at least two other follow-up time points at days 7, 14 or 30, and so were included in this QoL analysis. Two patients were excluded as they withdrew from the study before day 30 due to progression of underlying disease. Multi-item scales were included in analyses if at least 50% of the items included in the scale were answered. One patient who had not completed the QLQ-BM22 at day 14 completed all other questionnaires at all other time points. Additionally, another patient had not completed either questionnaire at day 30. Therefore, the number of participants at the day 30 follow-up was n = 13 at the day 60 follow-up and n = 11 at the day 90 follow-up.The number of patients remaining in the study decreased to n = 18), 61.1% (n = 18), 53% (n = 17), 61.5% (n = 13) and 63.6% (n = 11), respectively. There was a significant, positive correlation between the QLQ-C15-PAL pain symptom scale and the BPI-SF worst pain score at baseline  and day 30 , meaning pain was reported consistently across the two measures.Pain response rates  to MR-guided HIFU at days 7, 14, 30, 60 and 90 were 38.9%  and the painful characteristics scale (>29%) in responders. The functional interference scale of QLQ-BM22 followed a similar pattern to the physical functioning scale from the QLQ-C15-PAL by showing a persistent and gradually increasing improvement across time points, with a slight dip in scores at day 30. Psychosocial aspect scores remained relatively stable throughout the study.The QLQ-C15-PAL showed that non-responders had little improvement in physical functioning across any of the time points, and a worsening of physical functioning at day 30 by 20%. The mean scores for the insomnia, appetite loss and nausea and vomiting scales had improved by ≥10 points by the study end, equating to a 29%, 40% and 100% reduction in symptoms, respectively. However, scores were consistently worse than those of the responders at each follow-up time point, with the exception of the nausea and vomiting response scale at day 7. The fatigue scale remained relatively constant throughout the study, with a small worsening of 9% by day 90. There was also a substantial (40%) worsening in constipation scores at study end. Emotional functioning saw a 6% worsening in scores by day 90, compared with a 9% improvement seen in responders. In terms of overall QoL there were no notable changes, with a small decrease (7%) by study end. Although pain scores remained relatively constant for non-responders up to day 60, there was an improvement at day 90 by 33%. Using the QLQ-BM22, non-responders saw a 15% worsening in painful sites scores by day 90. The 22% improvement in painful characteristics scores at study end was preceded by a consistent worsening of scores by an average of 27%. The functional interference and psychosocial aspects scales remained relatively constant throughout, reflecting similar trends as in the physical and emotional functioning scales seen in the QLQ-C15-PAL for non-responders.Our study shows that beneficial QoL changes occur after MR-guided HIFU treatment, in addition to improvements in pain, which indicate even greater responses to treatment than when assessed using pain criteria alone. Physical function and symptoms, including appetite loss, fatigue, insomnia and constipation, were improved across the whole cohort, reflecting the importance of monitoring the individual elements that constitute QoL when considering patient outcome. With an increasing number of cancer survivors, the control of metastatic bone pain is critical in maintaining QoL, making interventions that achieve this (such as MR-guided HIFU) of paramount importance.The reduction in pain scores measured by the BPI-SF and the QLQ-C15-PAL were associated with an increase in physical functionality as assessed by the QLQ-C15-PAL, and further corroborated by the functional interference scale in the QLQ-BM22. Improved physical functioning may improve the patients' ability to complete activities that are a part of daily life. The slight worsening of scores in the physical functioning scale for both responders and non-responders at day 30 (compared with later post-treatment time points) was unexpected. These patterns remained even when accounting for patients who withdrew from the study before day 90. It is hard to draw firm conclusions on the reason for this from our small cohort. However, one theory relates to bone weakness, which, pre-clinical studies have shown to occur after MR-guided HIFU, predominantly 4–6 weeks after treatment, returning to normal levels at 3 months Although the clinically significant reductions in fatigue, appetite loss and nausea and vomiting may be as a direct result of improvement in pain scores, there could also be an indirect effect through a reduction in analgesic intake as a result of reduced pain. Also, although the initial low score of ∼26 for constipation may be subject to floor effects, the mean changes show responders consistently experienced at least a 57% improvement in constipation symptoms from day 14 onwards, indicating that a reduction in opioid analgesic consumption caused this improvement Interestingly both the emotional functioning and psychosocial aspects scales remained relatively stable, suggesting that improvement in other aspects of QoL was insufficient to constitute an improvement in emotional functioning. This is to be expected in end-stage patients with extensive metastatic disease. In fact, the end-stage nature of this cohort needs to be considered; 17% of patients died during the study. It is therefore reassuring that at a time when QoL would usually be worsening a priori as the primary end point for measuring pain response. However, this did not reflect the changing responses some patients experienced throughout the study. In fact, 27% of patients who remained in the study until day 90 would have been classified differently then, compared with their classification at day 30. This may explain why the pain scale of the QLQ-C15-PAL and the painful characteristics scale of the QLQ-BM22 decreased to a similar level in responders and non-responders by the study end. In our small cohort, the assessment of pain and QoL may have been better classified later than 30 days after treatment. Although this observation might not be generalisable, it does indicate a need for longer-term follow-up. In our experience, the duration of improvements in pain and QoL in all participants after a single treatment was highly encouraging.The response for the purposes of this QoL assessment was based on classification at day 30, as this was determined As in some other studies By using the QLQ-C15-PAL, a palliative-specific questionnaire, we have been able to determine a variety of symptom and functional changes that can be easily interpreted from a clinical perspective. In addition, using the QLQ-BM22, a bone metastasis-specific questionnaire, we have been able to reliably assess a range of QoL issues that are the most pertinent for patients with bone metastases. However, both questionnaires have limitations. Neither questionnaire measures spiritual components, which have been found to be equally important to physical symptoms for QoL Our data show that patients with disseminated malignancy and focal metastatic bone pain, refractory to palliative radiotherapy, can experience substantial QoL improvements after a single MR-guided HIFU treatment. We observed improvements in both pain and physical functioning, which may have been related to decreased reliance on analgesics, with subsequent reduction in their side-effects. We did not observe any treatment-related serious adverse effects. Further studies that will evaluate QoL outcomes in treatment-naïve patients undergoing either EBRT or MR-guided HIFU will be important in determining the optimal treatment pathways for patients with painful bone metastases.


Pain is a subjective feeling and one of the defense and alerting mechanisms of the body, which is distinguished from the body senses, including touch sensation and perception of heat, cold, pressure, etc.Pain, discomfort, and edema are very common after dental procedures, especially after periodontal surgeries, usually occurring during the first 24 hours after surgery; such pains are classified as medium to severe pains. Generally, medications are used to manage patients’ pain and discomfort. One of the most commonly used medications for pain control is Ibuprofen, which is one of the NSAIDs and is a simple derivative of phenylpropionic acid.There is evidence that caffeine alone or in association with Acetaminophen, Ibuprofen, or Aspirin can increase their analgesic effects. Novafen is a new drug which consists of Acetaminophens, Ibuprofen and caffeine and has been marketed in Iran in recent years.70 subjects referring to the Department of Oral and Maxillofacial Surgery, Tabriz Faculty of Dentistry, who were candidates for crown lengthening procedure, were randomly selected and included in the present study, based on inclusion and exclusion criteria.No significant differences were detected in pain severity between the two groups either clinically or statistically at 30-minutes postoperative interval.Pain, discomfort, and edema are very common after dental procedures, especially after periodontal surgeries. Such conditions usually occur during the first 24-hours postoperative interval and are considered moderate to severe pains.Although in the present study, the administration of Novafen before periodontal surgery resulted in the relief of postoperative pain, further studies are recommended on the subject,The administration of Novafen before periodontal surgeries resulted in pain relief after surgery. Generally, medications are used to manage patients’ pain and discomfort. One of the most commonly used medications for pain control is Ibuprofen, which is one of the NSAIDs and is a simple derivative of phenylpropionic acid. It exhibits anti-inflammatory and analgesic effects through inhibition of the biosynthesis of prostaglandins . Some side effects have been reported for Ibuprofen, including alimentary tract irritation, hemorrhage, skin eruptions, itching, ear whizzing, confusion, headache, aseptic meningitis, etc. .Pain, discomfort, and edema are very common after dental procedures, especially after periodontal surgeries, usually occurring during the first 24 hours after surgery; such pains are classified as medium to severe pains .Another analgesic is Acetaminophen. It is a safe medication even in its maximum dose, which is 4 g/ daily. However, it is always effective in inhibiting severe pain and can be used in association with Ibuprofen as an analgesic of choice [7-9]. Novafen is a new drug which consists of Acetaminophens, Ibuprofen and caffeine and has been marketed in Iran in recent years . Merry et al. carried out a study on the effect of Novafen and Ibuprofen on pain after extraction of wisdom teeth in adults and concluded that the effect of Novafen was much higher [3]. Mehrvarzfar et al. carried out a study (2012) and reported that the administration of Naproxen, Novafen and Tramadol, as three analgesic agents, was effective in preventing pain after endodontic treatment [9]. Hungund et al. carried out a study to evaluate the effect of administration of Ketorolac tromethamine before periodontal surgeries and concluded that the severity of pain in patients receiving Ketorolac was significantly less than that in the control group [11]. Moreover, Arsalen et al. evaluated the effect of prophylactic administration of Tenoxicam on postoperative pain in periodontal procedures and reported that the administration of analgesics before surgery is a useful technique to mange pain [12]. Based on what was discussed above and the importance of managing the patients’ pain after periodontal surgeries, the present study was undertaken to evaluate the effect of the administration of Novafen before periodontal surgeries on pain relief after periodontal surgery.There is evidence that caffeine alone or in association with Acetaminophen, Ibuprofen, or Aspirin can increase their analgesic effects . The subjects were randomly assigned to two equal groups (n=35) by using the website at www.randomizer.org. The subjects in group 1 received a Novafen capsule  immediately after surgery, the subjects in group 2 received placebo. The medications were the product of Alhavi Pharmaceutical Company  in packages with no names. Novafen capsules were used in one group and, in another, placebo tablets consisting of starch. The surgical procedures were carried out by senior periodontics postgraduate students in the Department of Postgraduate Studies. Considering the effect of duration of surgery on postoperative pain severity, patients whose surgery lasted for more than 45‒60 minutes were excluded from the study. 1‒2 lidocaine cartridges were used to achieve local anesthesia. All the subjects took ibuprofen tablets only after surgery. On the other hand, the subjects did not receive any analgesics for at least 4 hours before undergoing the surgical procedure. The patients’ pain severity was determined at 30-minute and 1- and 3-hours postoperative intervals [10] by using VAS. To this end, a checklist was submitted to all the patients who were asked to score their pain severity from zero to 5 based on the images provided; pain severities were determined at 1-, 2- and 3-days postoperative intervals by using VRS. To this end, the subjects were called on the phone and asked to score their pain based on the following scoring system: Inclusion criteria consisted of the following: signing an informed consent form, an age range of 16‒40 years, and being a candidate for crown lengthening procedure. The exclusion criteria consisted of systemic or mental diseases, alcohol abuse, or use of any psychotropic agents, and known allergy to NSAIDs, caffeine or Acetaminophen. The sample size was determined at n=70 using the ratio estimate formula by considering pain relief of 40% and 10% in groups receiving and not receiving Novafen, respectively, and a 10% difference in pain relief . Novafen is a new medication, consisting of Acetaminophen, Ibuprofen and caffeine, which has been marketed in Iran in recent years . The present study was designed and undertaken to evaluate the effect of administration of Novafen, before periodontal surgeries, on pain relief in patients after such procedures. The results showed that the prophylactic administration of Novafen in periodontal surgeries resulted in pain relief after surgery. However, half an hour after surgery, there was no significant difference in pain severity between the two groups, but the pain was more severe in the control group over time. Moreover, Mehrvarz et al. reported that the administration of three analgesics, Naproxen, Novafen and Tramdol, was very effective in preventing pain after the endodontic treatment [9]. Dejkam et al. (2015) administrated prophylactic Novafen and Gelofen before root canal therapy and reported that Novafen was more effective than Gelofen in relieving postoperative pain [13]. Hungund et al. evaluated the effect of the prophylactic administration of Ketorolac tromethamine before periodontal surgeries and concluded that pain severity in patients receiving Ketorolac was significantly less than that in the control group [11]. Even more, Arsalan et al. evaluated the effect of the prophylactic administration of Tenoxicam on postoperative pain in periodontal procedures and reported that the administration of analgesics before surgery is a useful technique to manage the patients’ pain [12].Pain, discomfort, and edema are very common after dental procedures, especially after periodontal surgeries. Such conditions usually occur during the first 24-hours postoperative interval and are considered moderate to severe pains [Although in the present study, the administration of Novafen before periodontal surgery resulted in the relief of postoperative pain, further studies are recommended on the subject, with a larger sample size and by taking into account other confounding factors, considering the importance of pain control in patients and the limited number of studies in this field. In addition, since the postoperative pain severity was the same in both groups, it is suggested, that in order to manage the patients’ pain more effectively, the injection of the local anesthetic agent should be repeated in the surgical area immediately after the completion of surgery, so that the patients would experience less pain and discomfort during the early postoperative period. The administration of Novafen before periodontal surgeries resulted in pain relief after surgery.Sources of fundingNot Applicable.DisclosuresNot Applicable.


The aim of the present study was to adapt the Foot Function Index-Revised Short Form (FFI-RS) questionnaire into Polish and verify its reliability and validity in a group of patients with rheumatoid arthritis (RA). The study included 211 patients suffering from RA. The FFI-RS questionnaire underwent standard linguistic adaptation and its psychometric parameters were investigated. The enrolled participants had been recruited for seven months as a convenient sample from the rheumatological hospital in Śrem (Poland). They represented different sociodemographic characteristics and were characterized as rural and city environments residents. The mean age of the patients was 58.9 ± 10.2 years. The majority of patients (85%) were female. The average final FFI-RS score was 62.9 ± 15.3. The internal consistency was achieved at a high level of 0.95 in Cronbach's alpha test, with an interclass correlation coefficient ranging between 0.78 and 0.84. A strong correlation was observed between the FFI-RS and Health Assessment Questionnaire-Disability Index (HAQ-DI) questionnaires. The Polish version of FFI-RS-PL indicator is an important tool for evaluating the functional condition of patients' feet and can be applied in the diagnosis and treatment of Polish-speaking patients suffering from RA. Foot disorders are currently very common; they significantly limit patients' activity and worsen their quality of life (QoL). It is assumed that the incidence of these disorders varies between 10% and 24% and in most cases concerns older people –5. AboutQuestionnaires evaluating the QOL, mobility (or daily living activity), and disease progression are clinically significant . There aOne such questionnaire is the Foot Function Index (FFI). It was established in 1991 based on clinical observations and experiments by three American authors: Budiman-Mak, Conrad, and Roach [The aim of this study was to translate the original short form of the FFI-RS questionnaire into Polish and to verify its reliability and validity in a group of Polish-speaking patients suffering from RA.The study involved 211 patients. Participant inclusion criteria were adults with RA diagnosed according to ACR criteria from 2010 [Each participant was coached to correctly fill the questionnaire.Ethical Considerations. This study was approved by the Research Ethics Committee at Poznan University of Medical Sciences, under protocol number 183/14, and all the participants were informed and signed the free consent statement. The permission to translate was also granted by Dr. Elly Budiman-Mak, the primary author of the original FFI-R short form.The FFI-RS questionnaire consists of 34 questions grouped into 5 subcategories: pain (7 questions), stiffness (7 questions), difficulty (11 questions), activity limitation (3 questions), and social issues (6 questions). The answers are represented by a 4-level Likert scale. The numerical 5 is not a Likert scale; it is an option that the particular question is not applicable. The scoring of the FFI-R is based on the assumption that the severity of impairment in foot function is determined by the combination of pain, stiffness, difficulty, activity limitation, and psychosocial scales. A score is derived for each item by marking the patient experience on the choices displayed on a Likert scale. For example, on the pain subscale, grade 1 corresponds to no pain and 4 corresponds to worst pain imaginable. The numerical 5 is not used as a score but is used to indicate that the subscale question is not applicable for the study subject (participant). To obtain a subscale score, the item scores for a subscale are added and divided by the maximum total possible for the subscale items that the patient indicated were applicable, after which they are multiplied by 100.This method of scoring was applied to all subscales.The FFI-R short form score will be the average of the five subscale scores.The total scores of each subscale, pain, stiffness, difficulty, activity limitation, and psychosocial, will be summed and then divided by 5 .The translation process started after obtaining the permission from the authors of the original FFI-R short form to translate FFI-RS into Polish. The process is depicted in N = 211), whose native language was Polish, with the minimum basic educational level of primary school level. During the test, each participant could write a comment about the experience in using FFI-RS-PL. Participants had no difficulty in understanding or answering the questionnaires. The average time needed to complete the test was 10 minutes. The test was rated positively regarding the transparency of all of the questions and their appropriateness, clarity, length, and usefulness. A final Polish version of the Foot Function Index-Revised Short Form-Polish Version (FFI-RS-PL) was accepted  and assess the pain level using the visual analogue scale . Moreover, the duration of the disease and the number of swollen and tender joints were recorded for each participant individually.To examine physical function, the Health Assessment Questionnaire-Disability Index (HAQ-DI) was used. This questionnaire evaluates patients' health functional status and correlates it with other biochemical and clinical measures, comorbidities, healthcare resource utilization and cost estimations, and mortality. The HAQ-DI is composed of 20 detailed questions about daily activities, divided into 8 categories: dressing and taking care of appearance, arising, eating, walking, hygiene, reaching, gripping, and daily life activities. All respondents assessed their own difficulty in carrying out each of the activities on a scale from 0 to 3 (0 means no difficulty in performing the task and 3 means the task was impossible to perform) .DAS 28 is an important and very often used outcome for clinical practice and research all over the world in patients with rheumatoid arthritis. Published thresholds define absolute DAS 28 scores representing remission (<2.6), mild (≤3.2), moderate (>3.2), or severe (>5.1) disease activity , 15.The VAS pain scale results were obtained by measuring the distance in millimeters from the beginning of the scale to the position selected by the patient from 0 to 100 mm where 0 is “no pain” and 100 is “the worst possible pain” . StructuClass I. They were completely able to perform usual activities of daily living . Class II. They were able to perform usual self-care and vocational activities, but limited avocational activities. Class III. They were able to perform usual self-care activities, but limited vocational and avocational activities. Class IV. They had limited ability to perform usual self-care, vocational, and avocational activities [ tivities .For the evaluation of the functional assessment of both feet, each patient defined the number of swollen and tender metatarsophalangeal (MTP) joints . Each suThe reliability of the FFI-RS questionnaire was assessed by analyzing its internal consistency using Cronbach's alpha coefficient and the test-retest reliability method. Subsequently, the diagnostic, convergent, and divergent validity were assessed. Diagnostic validity, that is, the coherence of the test with external criteria, was evaluated by checking the association between the FFI-RS scores and functional condition, duration of RA, and pain location within the MTP joints. It was assumed that patients with a higher FFI-RS score would be characterized by worse functional condition and longer duration of the disease. It was also assumed that there would be a statistically significant difference in pain scale score between patients with pain located within the MTP and patients with pain in another location. Convergent validity was assessed by checking the correlation between scores of FFI-RS and HAQ-DI scale, VAS pain scale, and HAQ-DI subscale concerning walking, the latter having the strongest association with foot function. Divergent validity, that is, the lack of or weak correlation between the test's score and variables, which in assumption have no impact on foot function, was verified by checking the correlation between FFI-RS outcome and DAS 28 (number of swollen and tender joints) from the questionnaire.We chose DAS 28 for this purpose because it does not take into account the number of swollen and tender joints in the feet.We also examined our research participants for the presence or absence of floor and ceiling effects. These effects show the proportion of patients who gain the lowest or highest possible scores and are considered to be present when more than 15% of the examined individuals achieve these scores.p < 0.05.Statistical calculations were conducted using SPSS v14. software. Statistical significance was established at the level of The study involved 211 patients, 179 female and 32 male. The average age of patients was 58.9 ± 10.2 years. The characteristics of the research participants are shown in The average scores in the FFI-RS subscales were as follows: pain subscale 56.6 ± 16.8, stiffness subscale 59.1 ± 17.3, activity limitation subscale 54 ± 22.9, and social issues subscale 57.4 ± 22. The highest score (75.2 ± 17.7) was observed in difficulty subscale.Internal consistency was achieved at the high level of 0.95 using Cronbach's alpha test. The lowest score was achieved in activity limitation subscale (0.58). In the test-retest study, an interclass correlation coefficient (ICC) score of 0.81 was achieved for the whole questionnaire .p = 0.002). Analysis of the relation between FFI-RS total score and duration of RA showed the following: the longer the duration of RA, the higher the score obtained in FFI-RS, suggesting worse foot function. Moreover, the relation between pain location within the MTP joints and pain subscale of FFI-RS was analyzed. A statistically significant difference (p = 0.048) was observed between participants with and without MTP joint pain  and FFI-RS (short form). Both forms were shown to be equally qualified as measurement tools .Considering economic issues and practicality in the patient care management process, we decided to adapt and validate the FFI-RS questionnaire into Polish.Our results confirmed the accuracy of the FFI-RS questionnaire in terms of achieving a high level of 0.95 in Cronbach's alpha test. The highest score was achieved in the difficulty subscale (0.93) and the lowest score in the activity limitation subscale (0.58) .A lower score in the activity limitation subscale compared to other subscales may be due to the fact that this subscale has only three questions. Moreover, two of the questions were answered as “not applicable” , which means that participants had not performed those particular activities. This observation was taken into consideration while summing up the final result of the subscale.In the diagnostic validity examination, statistically higher results were obtained in patients with pain located within the MTP joints, long-lasting duration of the disease, and worse functional condition, indicating impaired foot function.The outcomes obtained during convergent and divergent validity checks were in line with the authors' assumptions.The DAS 28 scale, which assesses the wrist, hand, elbow, shoulder, and knee, but not foot and ankle , 23 joinA significant finding from previous studies was that 15% of patients suffering from RA developed the first symptoms of the disease in their feet . As the The limitation of the present study is the fact that the responsiveness to the changes in the FFI-RS questionnaire was not checked. An ongoing study of our group on the usefulness of FFI-RS (short form) will evaluate the physiotherapeutic procedures among patients with rheumatological disorders located within feet. Another limitation was the fact that the FFI-RS PL was studied in patients among older RA patients, drawn from a single hospital (monocentric). It is possible that the outcomes of the DAS 28 and FFI-RS subscales may be different in a younger population, who have more acute/active joint swelling. Also patients without RA may present different results in FFI-RS scores. Next limitation is the fact that we do not know accurate target population of the hospital . The study should be continued with consideration of cultural, socioeconomic, and language differences in Polish population.The Polish version of FFI-RS-PL is an important evaluating tool and can be applied in clinical and epidemiological studies among Polish-speaking patients suffering from RA. FFI-RS-PL research process should be conducted in other patient groups.


Patients with chronic orofacial pain due to temporomandibular disorders (TMD) display alterations in somatosensory processing at the jaw, such as amplified perception of tactile stimuli, but the underlying mechanisms remain unclear. This study investigated one possible explanation, namely hypervigilance, and tested if TMD patients with unilateral pain showed increased attending to somatosensory input at the painful side of the jaw.n = 20) and matched healthy volunteers (n = 20) performed a temporal order judgment (TOJ) task indicated which one of two tactile stimuli, presented on each side of the jaw, they had perceived first. TOJ methodology allows examining spatial bias in somatosensory processing speed. Furthermore, after each block of trials, the participants rated the perceived intensity of tactile stimuli separately for both sides of the jaw. Finally, questionnaires assessing pain catastrophizing, fear-avoidance beliefs, and pain vigilance, were completed.TMD patients with chronic unilateral orofacial pain (p = .07). In the control group, tactile stimuli were perceived as occurring simultaneously. Secondary analyses indicated that the magnitude of spatial bias in the TMD group is positively associated with the extent of fear-avoidance beliefs. Overall, intensity ratings of tactile stimuli were significantly higher in the TMD group than in the control group, but there was no significant difference between the painful and non-painful jaw side in the TMD patients.TMD patients tended to perceive tactile stimuli at the painful jaw side as occurring earlier in time than stimuli at the non-painful side but this effect did not reach conventional levels of significance (The hypothesis that TMD patients with chronic unilateral orofacial pain preferentially attend to somatosensory information at the painful side of the jaw was not statistically supported, although lack of power could not be ruled out as a reason for this. The findings are discussed within recent theories of pain-related attention. Temporomandibular disorders (TMD) represent a group of highly prevalent and disabling conditions characterized by problems and dysfunctions in the jaw muscles and/or in the temporomandibular joint, with chronic orofacial pain as one of the typical features . TMD arespecifically at the painful side of the jaw. However, studies investigating location-specific attention biases in clinical samples, including TMD, are currently lacking. Understanding the presence and nature of somatosensory hypervigilance in TMD may help us determine new treatment for these patients.One possible source of amplified somatosensory perception in chronic pain patients is hypervigilance, that is, the process of habitually attending to pain-related information such as bodily cues . HyperviThe present study aimed to investigate whether TMD patients with unilateral orofacial pain show a bias in somatosensory attending to the painful jaw side. For this purpose, we used a Temporal Order Judgment (TOJ) paradigm , assessiTMD patients were a convenience sample recruited in the Department of Dentistry at the Ghent University Hospital. Inclusion criteria included having chronic (longer than three months) unilateral orofacial pain due to a temporomandibular disorder assessed by the dentist, having an age between 18 and 65 years, and being Dutch speaking. Exclusion criteria were the presence of a severe psychiatric/neurological condition, and the presence of non-TMD related chronic pain problems. Based upon power calculations (see further), we recruited 20 TMD patients and 20 healthy controls. Potential participants were informed about the possibility of participating by means of a flyer and information given by the clinician. When they agreed to participate, they received a phone call from the researcher providing more detailed information about the study. Twenty-one patients agreed to participate in the experiment. It was not registered if they had participated in previous studies. One woman  had to be excluded because she reported chronic widespread pain . The age of the remaining 20 TMD patients  was 36.8 years . Mean duration of pain was about 14 months . Ten patients reported pain at the left jaw, the other ten had pain at the right jaw. The majority of the sample (70%) had not received treatment for their TMD at the time of testing. An overview of the demographic characteristics is provided in χ2(1) = 0.23, p = .633, mean age, t(38) =  − 0.03, p = .980, and educational level, χ2(3) = 0.69, p = .877.The control group was recruited from an existing database, consisting of individuals from the general population who had expressed interest to participate in scientific studies of the Ghent Health Psychology Research Group, by registering at a website. Potential participants were selected with the aim of obtaining a control group matched at group level with the TMD group for age, gender and educational level. Inclusion criteria for the control participants were being Dutch speaking and having an age between 18 and 65 years. Exclusion criteria were presence of chronic pain complaints, presence of current orofacial pain, and presence of neurological/psychiatric conditions. Eligible participants were contacted and provided with information about the study. Twenty-one healthy volunteers were willing to participate. One man  was excluded for further analysis due to not attaining the requested performance criteria during the task (see TOJ data handling). The age of the remaining 20 participants  was 36.9 years . An overview of the demographic characteristics is provided in The study was approved by the Medical Ethical Committee of the Ghent University Hospital (B670201213538). At the end of the experiment, all participants received 25 Euro as reimbursement for their expenses. The experimental session lasted for approximately 1 h and a half.http://www.eaiinfo.com/) consisting of a housing of 3.05 cm diameter and 0.79 cm high, and a skin contactor of 0.76 cm diameter. In order to control for differences in tactile sensitivity between both sides of the jaw, subjective stimulus intensity was individually calibrated and matched between jaw sides before the experiment using a double random staircase procedure  on a laptop (Dell Vostro 3550).The task was programmed and controlled by the INQUISIT Millisecond software package , presence of medical/psychological problems, and use of pain medication. In the TMD group, this questionnaire also assessed which side of the jaw was painful, duration of the TMD problem, current treatment status (whether they had received treatment for their TMD or not), and presence of other chronic pain complaints. Several validated self-report questionnaires measuring pain and pain-related cognitions were used. Internal consistency  was acceptable for all these instruments see .Pain severity and pain interference were assessed by means of the Dutch version of the Multidimensional Pain Inventory MPI-DV; . This quThe Tampa Scale for Kinesiophobia for Temporomandibular Disorders TSK-TMD;  consistsThe Pain Catastrophizing Scale PCS;  is a 13-The Pain Vigilance and Awareness Questionnaire PVAQ;  containsAfter each test phase, the participants were asked to rate the perceived intensity of the tactile stimuli (‘How intense did you experience the stimuli on your left/right jaw?’) on an eleven-point numerical rating scale . This was included to check for potential sensitization or habituation effects.Upon arrival at the laboratory, participants were informed about the experimental procedures and provided written informed consent. After this, they completed a series of questionnaires (see self-report measures) in the following order: general questionnaire, MPI-DV, TSK-TMD (only TMD patients), PCS, and PVAQ. Next, they were seated in front of the experimental apparatus. Their forearms were positioned symmetrically on the table. The tactors were placed in the middle of the superficial head of the masseter muscle of each side of the jaw. The participants were informed that they had to decide on each trial which stimulus had been presented first. The accuracy of participants’ responses was emphasized, rather than the speed. Participants wore noise-cancelling headphones (PXC 350 Sennheiser) to prevent any interference from environment noise. Following this, the session began with a practice block of twenty trials . Next, four blocks of 70 trials  were presented. The participants were not given any feedback about their performance. After each block, they were asked to rate perceived intensity of tactile stimuli at both jaws. These data were not used to adapt stimulus intensity in case of left–right differences. The participants also completed several single rating scales gauging concentration, effort, attention, and fatigue (not reported).The analyses were based upon procedures that have been commonly described in the literature . The protest stimulus was presented before the reference stimulus. In the TMD sample, we regard stimuli at the painful jaw side as test stimuli, while stimuli at the non-painful jaw side are labeled as reference stimuli. In the remainder of the manuscript, positive SOAs refer to trials in which the stimulus at the non-painful jaw side preceded the stimulus at the painful jaw side. When interpreting effects on the PSS measurement, it is thus important to keep in mind that positive values indicate that stimuli stemming from the non-painful jaw side should be presented before stimuli originating from the painful jaw side for both to be perceived as simultaneously occurring. Correspondingly, positive PSS values indicate that tactile input at the painful jaw side is prioritized over tactile input at the non-painful jaw side. In the control group, we made the (arbitrary) choice to consider stimuli at the right jaw side as test stimuli, while stimuli at the left jaw side were reference stimuli. Here, positive values indicate that stimuli stemming from the left jaw side should be presented before stimuli originating from the right jaw side for both to be perceived as simultaneously occurring. Correspondingly, positive PSS values indicate that tactile input at the right jaw side is prioritized over tactile input at the left jaw side.PSS refers to the  SOA at which participants report the two events (in this case: right jaw first and left jaw first) equally often. The PSS is computed as the opposite of the intercept divided by the slope from the best-fitting straight line. It is customary to code SOAs so that negative values indicate that the In line with t-tests. Based upon the study by t-test. As a result, at least 19 patients were needed. As an additional analysis, we compared the mean PSS between the TMD group and the control group. However, it should be noted that the meaning of these values is different for these groups (see TOJ data handling). In the control group a positive PSS simply means that tactile input at the right jaw side is prioritized over tactile input at the left jaw side. In the TMD sample a positive PSS means that tactile input at the painful jaw side (irrespective of whether this is left or right) is prioritized over tactile input at the non-painful jaw side. As a secondary, exploratory, analysis, we tested within the TMD group whether the PSS was different between those that had pain at the left jaw side (N = 10) and those that had pain at the right jaw side (N = 10), using an independent-samples t-test. We had no specific hypotheses regarding the JND.We tested in each group whether the obtained mean PSS value was significantly different from the actual point of simultaneity  using one-sample t-tests. As an exploratory analysis, we also compared average perceived tactile intensity between the TMD and the control groups, using an independent samples t-test.As a validity check, to prevent explanations of TOJ effects in terms of differences in subjective tactile intensity, we compared perceived intensity (average across the four blocks) between the painful and the non-painful side of the jaw in the TMD group, and between the left and the right side of the jaw in the control group, using paired-samples t-tests. As a secondary analysis, we calculated Pearson correlations in the TMD group only, to examine possible associations between questionnaire scores and the behavior measure of spatial bias (PSS).For the TSK-TMD we only provide descriptive statistics for the TMD group. For all other questionnaires  we compared scores between TMD patients and controls, using independent-samples p <.05. For ease of comparison with the norms of In all analyses significance level was set at N = 491) sample of TMD patients  was similar as the score obtained in a large sample of TMD patients   .t-tests revealed that the TMD group had significantly higher scores as compared to the control group (pain severity: t(38) = 3.33, p = .002; pain interference: t(38) = 2.67, p = .011). For the PVAQ, independent samples t- tests revealed that the TMD group had significantly higher scores as compared to the control group, t(38) = 2.62, p = .01). No significant differences between both groups were found on the Pain Catastrophizing Scale (t(38) = 0.55, p = 0.58).With regard to the MPI, independent samples M = 5.56, SD = 2.02) and tactile stimuli presented on the non-painful side  was found in TMD patients, t(19) = 0.80, p = 0.44. Perceived intensity of tactile stimuli (across sides and blocks) was significantly higher in the TMD group  than in the control group , t(38) = 2.29, p = .028 (d = 0.71 (95% CI [0.07–1.35]). When considering the results on perceived tactile intensity it is important to note that the actual intensity of administered tactile stimuli was not different between the TMD group  and the control group , t(38) = 0.82, p = .419, and that in the TMD group there was no significant difference in actual tactile intensity between the painful  and the non-painful side of the jaw , t(19) = 0.46, p = 0.651. Possible TOJ effects in TMD patients thus could not be due to differences in tactile stimulation between the painful and non-painful side of the jaw.No significant difference in perceived intensity between tactile stimuli presented on the painful side , but the mean difference with the actual point of simultaneity (0 ms) was not significant, t(19) = 1.90, p = .07 ). There was no significant difference in PSS values between patients with left jaw pain  and patients with right jaw pain , t(18) = 1.13, p = .27. In the control group, the PSS was close to zero , and did not differ from the actual point of simultaneity (zero), t(19) =  − 0.02, p = 0.98. Note that the mean PSS was not significantly larger in the TMD group than in the healthy control group, despite a medium effect size, t(38) = 1.59, p = 0.12, d = 0.50, 95% CI [−0.13–1.13].Analysis of the PSS values in the TMD group showed that tactile stimuli delivered to the non-painful side of the jaw had to be delivered before tactile stimuli at the painful side, for both stimuli to be perceived as occurring at the same time  and the control group , t(38) = 1.63, p = .11.The JND (about which no hypothesis was formulated) was not significantly different between the TMD group , suggesting that higher scores on this scale were associated with a tactile processing bias toward the painful side of the jaw.Pearson Correlations in the TMD group are shown in p = .07), and there was also no significant difference with the control group. Strong interpretation of these results is difficult, given that confidence intervals were large, and that the study was only sufficiently powered to detect a medium effect size. It is possible that true effects are smaller than what was expected based on the study of This study investigated hypervigilance for somatosensory information in TMD patients with chronic unilateral orofacial pain. Specifically, we tested the hypothesis that processing of tactile stimuli would be biased towards the painful side of the jaw in TMD patients. While the average PSS in healthy controls was approximately zero, it was positive (about 18 ms) in the TMD group, but the difference with the actual point of simultaneity (0 ms) did not reach conventional levels of statistical significance  in the TMD group. Most of the correlations between PSS and self-reported cognitive-affective variables were not significant, but we observed a significant positive association between the PSS and the “somatic focus” subscale of the TSK-TMD, suggesting that those who tend to appraise somatic sensations in their jaw in a threatening way, show a stronger spatial bias in tactile processing to the painful side of the jaw. This finding fits well with previous findings showing that levels of pain-related fear are associated with self-reported jaw activity limitations and disability in TMD patients  and fastIt is interesting to compare our results with previous findings in patients with other unilateral pain complaints. Studies using tactile TOJ methodology have shown that in patients with both unilateral chronic low back pain and complex regional pain syndrome, tactile processing at the painful side appeared be attenuated . More spSeveral issues deserve further discussion. First, the overall perceived intensity of tactile stimuli (across both sides) was higher in the TMD group than in the control group. This is an intriguing finding, because the objective  intensity was not different between groups, and it was individually calibrated to the same rating  before the start of the experiment. This may suggest some form of sensitization or delayed habituation to somatosensory input in TMD patients. Note that this is not in line with previous findings of elevated tactile thresholds in these patients . BecauseSecond, the spatial bias in TMD patients was small, and individual variability was high, with secondary analyses suggesting stronger bias in those patients characterized by threatening appraisal of bodily signals in the jaw. An interesting avenue for future research would be to investigate the effect of contextual factors, such as anticipation of pain, on spatial bias. It should be noted that in this study, there was no induction of any bodily threat. It might be that situations in which patients actively anticipate pain would increase spatial bias to the painful jaw. It could be recommended that future studies examine somatosensory processing while patients are anticipating a painful dental procedure, or after experimentally inducing pain anticipation by requiring patients to perform certain activities using the jaw muscles. There have been successful attempts to implement pain-related physical activities in somatosensory attention paradigms in healthy volunteers  as well Our main hypothesis, that TMD patients would be characterized by a spatial tactile bias towards the painful side of the jaw, was not statistically confirmed, although the effect was in the expected direction. Given the higher than anticipated variability in PSS, inadequate power could not be ruled out a possible reason for this lack of statistical significance. In addition, the significant positive correlation between the amount of spatial bias and the somatic focus subscale of the TSK-TMD, suggests that somatosensory attending to the painful side of the jaw might be elevated especially in patients who are characterized by fear-avoidance beliefs, but a more adequately powered study would be needed to confirm this.10.7717/peerj.4310/supp-1Data S1The file contains the raw data for all behavioral and self-report variables collected in this study. Also included is a tab in which all variable names are explained.Click here for additional data file.