Myofascial pain in the masticatory region, generally referred to as headache, is a common temporomandibular disorder (TMD) characterized by the hypersensitive regions of the contracted skeletal muscle fibers. A correct clinical treatment of myofascial pain has the potential to modify the functional activation of cerebral networks associated with pain and unconscious teeth clenching, specifically the pain network (PN) and default mode network (DMN). In this study, research is presented as a case series of five patients with myofascial pain: three were diagnosed with intra- and extra-articular disorders, and two were diagnosed with only extra-articular disorders. All five patients received gnathological therapy consisting of passive splints and biofeedback exercises for tongue–palatal vault coordination. Before and after treatment, patients underwent pain assessments , nuclear magnetic resonance of the temporomandibular joint, and functional nuclear magnetic resonance of the brain. In each patient, temporomandibular joint nuclear magnetic resonance results were similar before and after the gnathological treatment. However, the treatment resulted in a considerable reduction in pain for all patients, according to the visual analog scales and the palpation test. Furthermore, functional nuclear magnetic resonance of the brain clearly showed a homogeneous modification in cerebral networks associated with pain , in all patients. In conclusion, gnathological therapy consisting of passive aligners and biofeedback exercises improved myofascial pain in all five patients. Most importantly, this study showed that all five patients had a homogeneous functional modification of pain and default mode networks. Using passive splints in combination with jaw exercises may be an effective treatment option for patients with TMD. This research could be a starting point for future investigations and for clinicians who want to approach similar situations. Temporomandibular disorder (TMD) is a general term used for several clinical issues involving the masticatory muscles and the temporomandibular joint (TMJ), and is one of the most common pathologies of the maxillofacial region in patients between 20 and 40 years. About 33% of the population has at least one symptom of TMD, and between 3.6 and 7.0% require prompt treatment. Furthermore, the concomitant incidence of anxiety and stress in patients exacerbate the TMD symptoms. TMD etiology is related to chronic pain, teeth grinding, and cervical spine problems. Signs and symptoms of TMD include pain, malocclusion, TMJ dysfunction, joint noises, deviation in opening or closing, and restricted jaw movement. Therefore, as an antalgic mechanism, the patient limits their own mandibular movements .Unconscious teeth clenching constitutes a persistent microtrauma of muscles and articulation and is one of the main etiological factors of myofascial pain. It is characterized by regions of contracted motor fibers, defined as “trigger points,” which are the source of constant deep pain and can cause central excitatory effects, commonly referred by patients as headache. The diagnosis of myofascial pain is easily made through medical history and physical examination. The diagnostic suspicion is based on a history of chronic daily headaches and facial pain without evidence of neurological or intracranial abnormalities.The goals of TMD treatment are to alleviate and/or reduce pain to improve mandibular function. Several procedures have been used as treatment methods, such as drug therapies, surgical and non-surgical procedures, dental appliances, physical therapy, and behavioral and psychosocial interventions. The guidelines of the Royal College of Dental Surgeons of Ontario recommend applying irreversible procedures  only after the failure of conservative treatments, if the symptoms are severe and persistent .Functional magnetic resonance imaging (fMRI), by taking the endogenous oxyhemoglobin as a contrast mean, allows inferring functional information on the metabolic activity of different cerebral regions . Several fMRI studies have shown a permanent modification of pain and behavioral-associated cerebral networks following jaw-related therapeutic interventions , 3.fMRI assesses neural functional activity by measuring the level of intra-tissutal oxyhemoglobin and deoxyhemoglobin, indices of regional blood supply and metabolic activity. The blood oxygenation level-dependent (BOLD) signal can be measured during the execution of a task (task-evoked fMRI) or during rest as a measure of brain functional connectivity (fcMRI). In our setting, we evaluated the fcMRI of two networks, the pain network (PN), and the default mode network (DMN). The PN is the cortical network of the physiology of pain, and the DMN is the network used in the processing of the unconscious processes. DMN is also involved in pain perception. These two cortical networks were analyzed in terms of functional connectivity. This study investigated the neural network activity at rest, in the absence of stimuli. Functional network connectivity is defined as the temporal correlation at rest in cortical networks. The resting functional connectivity represents 80% of the oxygen consumed by brain activities .In this research study, a case series of five patients diagnosed with myofascial pain and treated with passive aligners and biofeedback exercises to teach the patient not to clench their teeth is presented. All the patients underwent quantitative pain assessments and fMRI before and after the gnathological treatment.The study was performed in the Oral Sciences Department of the University of Chieti G. D'Annunzio. Ethics approval (number 23) was obtained by the hospital's Independent Ethics Committee of Chieti. The study protocol was drawn in accordance with the European Union Good Practice Rules and with the Helsinki Declaration. The sample consisted of a group of five patients who were treated at the Orthodontics and Orofacial Pain Department for TMD disorders. Each patient signed an informed consent form before the study.The study lasted 1 year: 6 months were used to recruit the patients, 3 months for follow-up of the recruited subjects, and 3 months for data processing.1) At least 18 years of age.2) Diagnosis of chronic myofascial pain syndrome of the masticatory muscles.3) Pain in the jaw muscles at least four times a week and for at least 12 weeks.4) Average pain severity of 4 on a 10-point scale for at least 1 h per day.5) Pain in the jaw, temples, face, pre-auricular area, or in the ear during rest or function.6) Diagnosis of TMDs using MR imaging of the TMJ to evaluate the articular disk, or meniscus, in terms of its morphologic features and its location related to the condyle in both closed- and open-mouth positions.1) Pregnancy.2) Current opioid use.3) Claustrophobia.4) Moderate or severe psychiatric disorder or current use of psychiatric medications.5) Presence of fibromyalgia or other chronic pain disorder.6) Diagnosis of metabolic disease, coagulopathy, neurological disorder, vascular disease, or neoplasia.7) Family history of arthritis or gout.Also, participants taking non-steroidal anti-inflammatory drugs or paracetamol (acetaminophen) stopped those medications at least 1 day prior to their study appointment.The pain intensity ratio was estimated by using a visual analog scale (VAS), which consisted of a graphic representation of the patient's face. The patient had to highlight painful areas, specifying the intensity  and frequency of the disturbance, and how it affected everyday life .Palpation of the temporal, masseter, sternocleidomastoid, digastric, and pterygoid muscles and TMJ was made bilaterally with constant pressure. It consisted of searching for trigger points in the masticatory muscles. Accordingly, these trigger points, once stimulated, tend to produce and provoke headaches through central excitatory effects.The sensations of pain were classified on a scale from 0 to 3:- 0: the absence of pain;- 1: mild pain or apparent discomfort with muscle contraction;- 2: moderate pain or discomfort with muscle contraction;- 3: severe pain; the patient “draws back” or “drops in tears” .MRI evaluated the integrity of the temporomandibular joint, disc dislocations, and condyle positions to diagnose intra-articular or extra-articular disorders and to assess changes in the condyle–disc relationship associated with clinical treatment. Each patient underwent TMJ MRI procedures with open-mouth and closed-mouth postures, before and after the treatment.fMRI of the brain analyzed the functional resting connectivity of the pain network (PN) and default mode network (DMN). The PN represents the cortical network of the physiology of pain, whereas the DMN is the system that processes the unconscious mechanisms involved in pain perception.The DMN areas that were studied:Right occipital lobe (DMN-RIGHT-OCC);Left occipital lobe (DMN-LEFT-OCC);Right temporal lobe (DMN-RIGHT-TEMP);Left temporal lobe (DMN-LEFT-TEMP);Posterior cingulate cortex (DMN-PCC);Precuneus (DMN-PRECUNEUS);Medial pre-frontal cortex (DMN-MPFC).The PN areas that were studied:Anterior cingulate cortex (PAIN-ACC);Right insula (PAIN-RIGHT-INSULA);Left insula (PAIN-LEFT-INSULA);Right somatosensory cortex 1 (PAIN-RIGHT-S1);Left somatosensory cortex (PAIN-LEFT-S1);Right somatosensory cortex 2 (PAIN-RIGHT-S2);Left somatosensory cortex 2 (PAIN-LEFT-S2).average functional connectivity concerning PN and DMN networks from the different functional connectivity matrices, obtained from the difference between the connectivity matrix at T2 (posttreatment) and the connectivity matrix at T1 (baseline), for each subject. In the matrices, each node corresponds to the numerical value of the interaction of two specific ROIs (regions of interest): the ROI of the row with the ROI of the column. In the difference matrix of each patient, the algebraic sum of all the nodes in each network was calculated. A positive value of average functional connectivity corresponds to a greater functional connectivity at rest in that network after treatment. A negative value corresponds to a lower functional connectivity at rest after treatment.The fMRI of the brain allowed assessment of the The MRI data were collected using a GE Medical Systems 3.0 Tesla system with an eight-channel brain-receiving coil.The protocol used a fast 3D-SPGR sequence with the following parameters:- TR = 6.9 ms,- TE = 1.6 ms,- TI = 450 ms,- flip angle = 15°,- matrix = 256 × 256,- field of view = 25.6 × 25.6 cm,- 156 axial slices with 1 mm thickness, yielding a voxel size of 1 × 1 × 1 mm.The scanning parameters provided complete coverage of the brain, midbrain, pons, and cerebellum regions.CNS abnormalities associated with M-TMD were assessed using several MRI tools.The first step was the brain extraction and parcellation by using FreeSurfer . Then, tEach patient received two passive splints made of hard polycarbonate that covers all the teeth without pre-established mandibular positions  Figure . There wWhile wearing the LPAS, patients performed a biofeedback exercise for 2 min, three times a day , with a minimum of 3 h between each exercise, 7 days a week. Biofeedback exercises of the tongue serve to enhance patient awareness of the palatal arches' spatial positioning associated with jaw clenching so that patients can learn to stop or refrain from doing this maladaptive behavior.During the exercise, patients assumed an upright position or reclined on a hard, flat surface, and were required to follow the accorded three steps:In the first phase, the patient clenched their teeth to fully contract the masseter bilaterally. A light touch with the forefinger on the contracted masseter was applied during maximum contraction. The patient visualized the muscle's volume in a mirror as a swollen tennis ball for 5 s.In the second phase, the patient clenched their teeth to partially contract (~50%) the masseter bilaterally; a light touch with the forefinger was applied during the contraction force, which is about halfway. The patient visualized the muscle's volume in a mirror as a semi-deflated tennis ball for 5 s.In the third phase, the patient was instructed to fully relax their jaw by opening it ~1 mm and applying a light touch with the forefinger on the utterly relaxed masseter. The patient visualized the muscle's volume in a mirror as a completely deflated tennis ball for 5 s.In the fourth phase, the patient touched the tip of the tongue on the top of the palatine vault, approximately between the palatine wrinkles and the flat palate for 5 s.Then, the patient removed the LPAS for breakfast.The same exercise was repeated before lunch and before dinner with the LPAS inserted. Biofeedback was timed to occur immediately prior to meals because masseter activation during meals typically causes pain levels to worsen.The treatment lasted ~3 months. In the 6 months follow-up, a new assessment was made using the VAS and palpation test of temporal, masseter, sternocleidomastoid, digastric, pterygoid muscles, and TMJ MRI, and fMRI of the brain was repeated to evaluate the treatment effect.Throughout the entire study duration, every patient continued to record in their diaries the extent and intensity of their pain during headaches and treatment sessions/compliance.The study included five patients, three with intra-articular and extra-articular disorders and two with only extra-articular disorders, who were diagnosed by magnetic resonance imaging of the TMJ. All patients were treated using gnathological therapy consisting of passive aligners and biofeedback exercises. The study's patient selection was founded on the diagnosis of TMD based on a standardized and complete clinical examination that fulfills the Research Diagnostic Criteria (RDC TMDs) .In the first phase of the study, all the patients underwent the palpation test and VAS to diagnose myofascial pain disorders. After recruitment in the study, the patients underwent TMJ MRI to assess the TMJ condition and fMRI of the brain to assess functional response.During the second phase of the study, lasting 6 months, all five patients were treated by gnathological therapy consisting of passive aligners and biofeedback exercises for 2 min, three times a day , with a minimum of 3 h between each exercise, 7 days a week.Patients underwent follow-up appointments once a month, in which the VAS and the palpation test were repeated.After 3 months, all patients underwent a second TMJ MRI and fMRI of the brain.All the clinical examinations, splint fitting, and follow-up appointments were performed by the same examiner.Paired Student t-tests  were used to understand the impact of the treatment protocol on VAS scores and PN and DMN average connectivity. The significance threshold for all tests was set at 0.05.All five patients exhibited forms of tension headaches but no sort of migraines, diagnosed according to the criteria of the International Classification of Headache Disorders 3rd edition (ICHD-III beta) .In p = 0.0013] (Table 4).The improvements were independent of age and gender but dependent on symptom intensity and chronicity at T1. Patient 1, patient 2, and patient 4 had intra-articular and extra-articular disorder; patient 3 and patient 5 had only extra articular disorder. Patient 1 exhibited, after treatment only, residual symptomatology (VAS 4) on the neck and shoulder region, but had a long-standing spinal disc herniation detected by MRI of the spine. In patients 2 and 3, the symptomatology almost disappeared in each painful area (VAS 1). In patient 4, there was only residual symptomatology on the TMJ (VAS 4). In patient 5, the symptomatology completely disappeared in each painful area (VAS 0). There was a significant effect for VAS , temporalis , sternocleidomastoid , digastric , and pterygoid  (Table 4).Pain on palpation in the digastric muscle region disappeared in all patients (PALPATION TEST 0). Pain on palpation in the pterygoid muscle region was relevant only in patient 4 (PALPATION TEST 2) with residual TMJ pain. There was a significant effect for palpation of the masseter  and for the PN average connectivity  . If there are substantial loads , slight flexion in the mandible causes tension in the discal ligaments and intracapsular disorders. The unconscious clenching and bruxism cause microtrauma against the teeth, muscles, and joints.The most frequent TMD associated with unconscious clenching is myofascial pain syndrome, the fourth stage of muscular pathology in TMD . Tooth cBiofeedback has been used for over 50 years in muscle rehabilitation to facilitate standard movement patterns after injury. This technique provides biological information, which would not otherwise be known by the patient in real-time . A systeThe study outlined a significant decrease in the symptomatology , 2.2, 4,Our finding of lower functional connectivity of the DMN, associated with a greater functional connectivity of the PN after the treatment, is consistent with the results of a recent study showing that DMN and the PN are functionally connected but show an inverse temporal modulation . It is iThis study research outlines limits concerning low sample sizes; therefore, the aim for the future is to increase the sample size; furthermore, another limit is the no use of EMG, on which inclusion in future studies will be relevant. Based on our qualitative and quantitative clinical and fcMRI evaluation of five patients, our data suggest that a gnathological treatment protocol based on a splint and associated biofeedback exercises is effective and repeatable in future studies. Moreover, we showed the neurophysiological impact of the gnathological therapy, assessed as qualitative clinical/quantitative fMRI PN and DMN measurements of improvement. After the treatment was completed, the functional connectivity of the brain networks showed homogeneous changes in all the five patients.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by University of Chieti Ethics Committee. The patients/participants provided their written informed consent to participate in this study.MM and CR submitted the study protocol to the ethics committee and wrote the manuscript. FF, MM, and CR selected the sample. MC and RN performed the fMRI and analyzed the radiological data. FF, MM, AS, and CR analyzed the clinical data. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Here, we report our initial experience with subxifoid video‐assisted thoracoscopic surgery (SVATS) lobectomy for the management of primary lung cancer, and compared the outcomes of SVATS with those of conventional transthoracic VATS (CVATS) lobectomies to validate its feasibility and usefulness.The clinical data of consecutive patients undergoing VATS lobectomy via SVATS or CVATS for lung cancer were retrospectively compared. The endpoints were to evaluate the statistical differences in surgical results, postoperative pain  and paresthesia . The two groups were compared before and after matching analysis.P = 0.001), preoperative comorbidity as cardiopathy (P = 0.007), BMI value (P = 0.003), left‐sided procedure (P = 0.04), tumor stage (P = 0.04), and tumor size (P = 0.002). These differences were overcome by propensity score matching (PSM) analysis that yielded two well‐matched groups which included 61 patients in each group. Surgical outcomes including blood loss, hospital stay and complications were similar before and after matching analysis, but SVATS compared to CVATS was associated with longer operative time before , and after matching analysis  and significant reduction of postoperative pain during the different time‐points (P < 0.001), and paresthesia at one (P = 0.001), and three months (P < 0.0001).Our study population included 223 patients: 84 in the SVATS and 139 in the CVATS group. The two groups were not comparable for sex (SVATS lobectomy is a feasible and safe strategy with surgical outcomes similar to CVATS lobectomy but with less postoperative pain and paresthesia.Subxifoid thoracoscopic lobectomy is a feasible and safe procedure, with potential benefits in terms of postoperative pain and paresthesia compared to conventional thoracoscopic lobectomyOur results showed that surgical outcomes including blood loss, hospital stay, morbidity and mortality are similar but subxifoid thoracoscopy was associated with significant reduction of postoperative pain and paresthesia.Subxifoid thoracoscopy is a safe procedure; compared to conventional transthoracic thoracoscopy, it avoids intercostal incisions, and spares nerve trauma, resulting in a reduction of postoperative pain and paresthesia. Subxifoid thoracoscopy is a safe procedure compared to conventional transthoracic thoracoscopy. It avoids intercostal incision and spares nerve trauma, resulting in a reduction of postoperative pain and paresthesia. Since its introduction in the early 1990s, video‐assisted thoracoscopic surgery (VATS) has become the preferred approach for the management of early stage lung cancer. Compared to standard thoracotomy, VATS is associated with a significant reduction in postoperative pain, morbidity and mortality, and hospitalization.In this study, we report our initial experience with SVATS lobectomy for the management of lung cancer. We evaluated the validity of this approach by comparison of surgical outcomes, postoperative pain and paresthesia of SVATS lobectomies with those of CVATS lobectomies. This article is presented in accordance with the STROBE reporting checklist which is provided as an additional file.This was a retrospective comparative study of patients who underwent lobectomy for management of lung cancer via either the SVTAS or CVATS approaches between January 2015 and January 2020. The patients were not randomized, but underwent SVATS or CVATS at the surgeons' discretion. The end‐points of the study were to evaluate: (i) the feasibility and safety of the SVATS approach by comparison of the surgical outcomes of SVATS with those of CVATS lobectomies; and (ii) whether SVATS was associated with potential benefits over CVATS with regard to postoperative pain and paresthesia.The study design was approved by the Local Ethics Committees of University of Campania Luigi Vanvitelli (code number: 326‐20); all patients gave their written informed consent for the surgery, and were aware that all their data could be used anonymously for scientific purposes only.The clinical data of all patients undergoing lobectomy for lung cancer via SVATS or CVATS approach and with complete follow‐up regarding surgical outcomes, postoperative pain and paresthesia were included in the study. We excluded: (i) patients undergoing open lobectomy; (ii) patients undergoing VATS resection different from lobectomy  or undergoing lobectomy with concomitant decortication and/or chest wall injury or resection; (iii) patients with a history of previous thoracic surgical procedures and/or of chronic pain, or taking regular analgesics; and (iv) patients with incomplete follow‐up.2, and cardiac diseases including cardiomegaly and arrhythmia were not evaluated for SVATS.The choice of approach (CVATS or SVATS) was made by surgeons based on tumor and patient characteristics. Since 2016, with increasing experience in VATS, lobectomy has been performed using a SVATS approach in selected patients. Indications for SVATS were peripheral small tumors, without lymph node involvement. Patients with pleural adhesions, BMI >30 kg/mAll patients received the same preoperative workup including computed tomographic (CT) scanning, integrated with positron emission tomographic (PET‐CT) scanning, and standard cardiopulmonary functional tests. Invasive mediastinal procedures were carried out only in cases of suspicion of mediastinal involvement on radiological examination. For each patient, demographic data, ie, age at operation, gender, body mass index (BMI); preoperative comorbidity; pulmonary function status; tumor characteristics ; operative outcomes ; postoperative results ; and postoperative pain and paresthesia were recorded.CVATS and SVATS were performed under general anesthesia, and single‐lung ventilation. Surgical equipment included endoscopic articulating linear cutters, long curved endoscopic surgical instruments, curved suction, and a 10 mm 30 grade thoracoscope. Energy‐based devices and surgical endoclips were also used to divide small vessels and/or thin portions of the fissures, and for lymphadenectomy.CVATS lobectomy was performed exclusively via a standard three‐port approach. The patient was positioned in lateral decubitus and the surgeon was positioned in front of the patient. A 4 cm incision was carried out within the fourth intercostal space on the anterior axillary line, and protected by a wound retractor. This access was used for working instruments, staplers, and for retrieving specimens. A 10 mm incision for the camera was performed within the seventh intercostal space in the mid‐axillary line, and a 20 mm incision for grasping the lung, dissection and for stapling was made within the sixth or seventh intercostal space in the posterior axillary line.SVATS was performed using a single incision in the subxiphoid space. The patient was placed in a lateral decubitus position with a 30 degree lateral inclination Fig . Both thBoth procedures (CVATS and SVATS) followed the classic principles of pulmonary resections. The first step was to explore the pleural cavity for any unexpected disease and to resect adhesions. Next, the lobectomy was performed. The target pulmonary veins Fig , arterieAfter surgery, the patient was usually transferred to an intensive care unit and the next day to the postoperative ward. The drain was removed when there was no air leakage, and the daily output was less than 300 mL.Surgical outcome was assessed by collecting operative and postoperative data. Operative data included operative time (minutes), intraoperative blood loss (mL), and complications . Postoperative data included output drainage, length of chest drainage, length of hospital stay and morbidity and mortality.The protocol for postoperative pain management was the same for each group. Pre‐emptive wound analgesia with ropivacaine was performed before incisions. At the end of the operation, a multilevel intercostal nerve block using ropivacaine , 4 mL for each intercostal space, was performed including the intercostal level of the incision and one level above and below. During the postoperative course, oral paracetamol (1 g), and oral Ketorolac (20 mg) was administered every 6 hours. If the visual analog scale (VAS) score was higher than 4, intravenous injection of morphine (0.1 mg/kg) was administered.Maximum pain scores were evaluated using the VAS with 11‐point levels, ranging from 0 (no pain) to 10 (the worst pain experienced). Pain was evaluated postoperatively at eight hours, on days 1, 2, and 3 and at discharge. All patients were subsequently followed‐up in the outpatient department by general enquiry at the time of the first and third months to evaluate any residual pain.Paresthesia was assessed using data from previously reported studies.We calculated our sample size based on the primary outcome measure as the VAS score. Based on previous studies,t‐test for normally distributed variables to compare means, the Mann‐Whitney test to compare non‐normally distributed variables, and a chi‐square test to compare categorical data. Repeated measures analysis of variance (ANOVA) test, corrected with Bonferroni post‐hoc test, if indicated, was used for comparison of symmetric continuous variables measured at different time‐points.The Kolmogorov‐Smirnov test and graphic histograms were used to check the normality/skewness of continuous variables data in subgroups before further analysis, and appropriate statistical tests were chosen accordingly. Data are summarized as mean and standard deviation (SD) for continuous variables, and absolute number and percentage for categorical variables. We used a Student's P‐value < 0.05 was considered statistically significant. MedCalc statistical software  and PASS 11  were used for the analysis.To minimize the influence of clinical confounders on outcomes, PSM analysis between the two groups was performed to create comparable groups of patients. A 1–1 ratio was used and the propensity score was constructed by using the following covariates: age (<70 or ≥70 year‐old); BMI (< 25 or ≥25); ppoFEV1% (≤40% or >40%); cardiac disease (yes or no); involved side and type of resection ; tumor size (≤30 mm or >30 mm); stage (stage I–II or stage III–IV); and major postoperative complications (yes or no). Specifically, we sought to match each SVATS patient to CVATS patient who had a propensity score that was identical to nine digits. If this match could not be found, the algorithm then proceeded sequentially to the next highest digit match on propensity score to make “next best” matches, in a hierarchical sequence until no more matches could be made. Once a match was made, previous matches were not reconsidered before making the next match. More detailed information is reported as a supplementary file. A n = 2) or bronchial lesion (n = 1). Five patients presented with chronic postoperative pain, and one had previous chest surgery. In the SVATS group, three patients were excluded as they were converted to thoracotomy for vessel injury (n = 1), for technical difficulties and bleeding (n = 1), and for arrhythmia and hypotension (n = 1). Thus, our study population included a total of 223 patients for final analysis: 84 in the SVATS group, and 139 in the CVATS group. The flow chart of the study is summarized in Fig In the study period, 570 patients underwent lobectomy for cancer, and 236 of these were performed via CVATS or SVATS. In the CVATS group, 10 patients were excluded. In one case lobectomy was associated with the resection of parietal pleura, while in three there was a conversion to thoracotomy due to a vascular (P = 0.001); patients with cardiopathy ; and with a higher BMI  (Table P = 0.0003), and left lower lobectomies ; patients with larger tumors  and those at an advanced stage  , and matched populations . The incidence of overall postoperative complications was 4% and 6% in unmatched and matched populations, respectively. The SVATS group compared to the CVATS group showed no statistical differences before (P = 0.99) and after matching analysis (P = 0.69). There were no perioperative deaths, with 30‐ and 90‐day survival of 100% in both groups.The data are summarized in Table P = 0.54), while significant differences were found at day 1 , day 2 , day 3 , at discharge , one month  and three months  after surgery . Similar results were observed in the matched analysis population  who needed morphine to manage their pain at a comfortable level (VAS ≤4).The data are summarized in Table gery Fig . ANOVA ttion Fig . AdditioP = 0.001) one month after surgery, and 6% vs. 34% (P < 0.0001) three months after surgery. After matching analysis, paresthesia was also significantly lower in the SVATS than in the CVATS groups one month  and three months  after surgery. In all cases, the paresthesia level did not limit the patients' daily activities.Before matching analysis, the incidence of paresthesia in the SVATS compared to the CVATS groups was 20% vs. 42%  from Shanghai Pulmonary Hospital, Shanghai, China is planning to compare postoperative pain, and quality of life between SVATS and CVATS for lung cancer management.Postoperative pain and chest wall paresthesia remain unsolved issues for thoracic surgeons. They also still occur when surgical resection is performed using CVATS. The reduction in the number of ports does not affect postoperative pain, confirming that port location could be more important than numbers.et al. et al. et al.et al.First, our surgical outcomes related to SVATS which included operative time, length of hospital stay (LHOS), postoperative morbidity and mortality were similar to those reported by other authors Table . No caseet al.Second, SVATS compared to CVATS was associated with a significant reduction in acute postoperative pain during the entire postoperative course. Although a trend was seen during the first eight postoperative hours, the difference become more evident in the following days, and at discharge. In theory, the residual effects of general anesthesia still influenced the pain perception in the immediate postoperative period. Our results were in line with all previous authors but Pfeuty and Lenot2 remains the main contraindication for SVATSThird, from a technical point of view, SVATS remains a more challenging procedure compared to CVATS as shown by the longer operative time observed in our study and other series.The present study had several limitations; thus, our results should be evaluated with caution before drawing any definitive conclusions. The small sample size, and selection bias due to the retrospective nature of the study were the main limitations, despite PSM being performed to reduce the intergroup differences. Yet, we compared a single technique incision using SVATS versus a multiport technique incision using CVATS. In theory, the number of incisions rather than their location could affect the results. However, several reportsIn conclusion, this study confirmed that SVATS lobectomy is a feasible and safe procedure with surgical outcomes similar to those of CVATS lobectomy, but with significant advantages in controlling postoperative pain and paresthesia. However, SVATS remains a complex procedure that needs particular skills, and appropriate endoscopic instruments. Thus, it should be performed in a high volume center and by surgeons with considerable experience using the VATS procedure. Furthermore, patient selection is crucial for the success of the procedure. Obviously, our results should be corroborated by further and larger studies to establish the potential and promising outcomes of this strategy.All authors disclose no conflict of interest and no funding for this study.Appendix S1: Supporting InformationClick here for additional data file.


Background: Fibromyalgia (FM) is a chronic primary pain condition, associated with widespread musculoskeletal pain, disturbed sleep, fatigue, cognitive dysfunction, and a range of comorbid conditions such as irritable bowel syndrome, and depression. Despite its high prevalence of 2% in the general population, FM continues to pose scientific and clinical challenges in definition, etiology, and day-to-day management. In terms of treatment, FM can be treated with selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs).Objective: Patients with FM and other chronic primary pain syndromes are known to experience substantial and clinically relevant placebo effects. An update of the placebo responses for various outcomes in the FM population and especially a discussion about clinical implications is therefore needed.Methods: We used data from a large data pool that includes randomized controlled trials (RCTs) examining within-placebo mean change scores of baseline vs. follow-up assessments in FM trials of SSRIs and SNRIs. The primary outcomes were pain, functional disability, and depression and using different scales. We assessed heterogeneity of included trials.Results: A total of 29 RCTs with N = 8,453 patients suffering from FM were included in our analysis. Within-placebo mean change scores of baseline vs. follow-up assessments were large for pain , functional disability , and depression . Heterogeneity was found to be large for all outcomes.Impact: Our results provide preliminary evidence that placebo responses, which also consist of non-specific effects, might play a role in the treatment of FM. Furthermore, we highlight limitations of our analyses and make suggestions for future studies. Fibromyalgia (FM) is a Chronic Primary Pain condition classified under MG30.01 Chronic Widespread Pain in the ICD-11. The cardinal markers of FM include non-specific musculoskeletal pain, fatigue, chronically disturbed sleep, and mild cognitive dysfunction , and a mIt remains undetermined what causes FM but separate mechanisms have been suggested for the individual symptoms. Chronic pain, for example, has been linked to central sensitization, a physiological process, in which nociceptive input is abnormally amplified in dorsal horn neurons . This leThere are several options for pain management through pharmacotherapy in FM. The most common include non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) and gabapentinoids . None ofThe placebo response is well-established effect across various pharmacological interventions . The plapost-hoc analyses or secondary analyses, and results reported solely on clinical trials were excluded. RCTs had to be either in English or German. Patients of both sexes from the age of 18 up, with a primary diagnosis of FM diagnosed by the American College of Rheumatology (ACR) 1990, 2010, or 2016 were included.A systematic literature search of RCTs was undertaken in the following electronic databases: MEDLINE, Embase, PsycINFO, Cochrane Central, and Web of Science, without applying restrictions to language or date of publication. A first search was conducted until April 5, 2018 and was updated in October 2019. The search revealed a total of 72215 records. After removing 9,800 duplicates, 62,415 records remained. Note that the search strategy also included all other categories of CPP , as this analysis is part of a larger project . See AppN), means (M), standard deviations (SD), CIs, and changes from baseline were noted for each extracted treatment arm of the respective study. If the study reported different doses of either an SSRI or an SNRI, Ms, SDs, and changes were averaged, and N was merged. If N was reported as a total of all treatment arms, it was divided through the number of treatment arms. Additionally, intention to treat was prioritized over the completer analysis.The following information was extracted from all included studies: study characteristics , participant characteristics , study design , special inclusion criteria, special exclusion criteria, emergency medicine, co-intervention), intervention details . If several assessments were reported, we chose the one with the longest timeframe since randomization . For the continuous outcomes, sample sizes  > Fibromyalgia Impact Questionnaire (FIQ)  > NumeriQ statistic . In total, 5,126  participants were randomly assigned to pharmacological treatments and 3,327  were randomly assigned to placebo. Weighted mean age was 49.15 years. In those studies that reported sex, 94.40% of patients were female. Seventeen of 29 trials (58.62%) recruited patients from the USA, eight from Europe (27.59%), three recruited patients cross continental (10.34%), and one from Asia (3.45%). On average 21.91% of patients suffered from Major Depressive Disorder (MDD). Mean treatment duration was 12.5 weeks (range 4–28 weeks). More detailed information and individual characteristics of the included studies can be found in A total of p = 2.31, 95% CI: 0.42 to 4.21, p = 0.017; see 2 = 25.49, I2 = 99.9%, and Q = 23,728.42 (p < 0.000).The mean change score for pain reduction in the placebo group was large and statistically significant .For functional disability, the mean reduction was large and statistically significant with a mean change score of baseline vs. follow-up = 3.31, 95% CI: 2.37–4.26, 0001 see . Heterogp < 0.0001 .Finally, for depression, the mean change score of baseline vs. follow-up assessment was large and statistically significant again, with a mean change = 1.55, 95% CI: 0.92–2.18, 0001 see . HeterogThe present meta-analysis intended to examine the placebo response in the baseline vs. follow-up comparison in pain, functional disability, and depression in trials examining SSRIs and SNRIs in patients with FM. In total, 29 RCTs were included with a mean treatment duration of 12.5 weeks, which is longer than in previous meta-analyses on antidepressants for FMS . We founp < 0.0001). In the included studies, functional disability measures assessed the impact of FM on a broad range of activities: from mundane everyday tasks, such as self-care and mobility, to general well-being, and engagement in vocational tasks. It has been long-recognized that FM can disrupt these common actions and thus considerably disable patients : P4P4PS_194536. HK is sponsored by the Swiss National Science Foundation (SNSF) fellowship P400PS_186658. AK received funding from the EPIC  project, which was in part funded by the University of Plymouth and the European Regional Development Fund (ERDF), Grant Number [05R18P02814]. The funding bodies have no role in the design of the study and collection, analysis, and interpretation of data and manuscript writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To explore the effects of an anterior quadratus lumborum block (QLB) on opioid consumption, pain, nausea, and vomiting (PONV) after ambulatory laparoscopic cholecystectomy.This randomized controlled study recruited 70 patients scheduled for ambulatory laparoscopic cholecystectomy from January 2018 to March 2019. The participants were randomly allocated to one of the following groups: 1) anterior QLB (n = 25) with preoperative ropivacaine 3.75 mg/mL, 20 mL bilaterally; 2) placebo QLB (n = 22) with preoperative isotonic saline, 20 mL bilaterally; and 3) controls (n = 23) given only standard intravenous and oral analgesia. The primary endpoint was opioid analgesic consumption. The secondary endpoints were pain  and PONV . Assessments were made up to 48 hours postoperatively.The groups did not significantly differ in opioids consumption and reported pain at 1, 2, 24, and 48 hours postoperatively. PONV in the QLB group was lower than in the placebo and control groups.Preoperative anterior QLB for laparoscopic cholecystectomy did not affect postoperative opioid requirements and pain. However, anterior QLB may decrease PONV.NCT03437187; January 22, 2018. Inadequate post-operative pain control may lead to adverse outcomes, such as prolonged hospitalization, higher incidence of re-operation, re-admission, and higher treatment costs -3. AfterThe evolution of nerve stimulation techniques and ultrasound-guided regional anesthesia have greatly enhanced the success and quality of peripheral nerve blocks ,6. In thQLB provides early and rapid pain relief and allows early ambulation in certain patient populations. Multiple case studies also confirmed the QLB to be a rescue block after different surgical procedures ,15,16. CThe primary aim of this study was to evaluate the effect of using the anterior QLB in ambulatory, laparoscopic cholecystectomy, as measured by opioid consumption (primary outcome), experienced pain, and postoperative nausea and vomiting (PONV) (secondary outcomes). The anterior approach to the QLB was chosen since studies have shown that the spread of local anesthesia to the thoracic paravertebral space reduces visceral pain ,18-22, a2, and being scheduled for ambulatory laparoscopic cholecystectomy. The exclusion criteria were allergy to local anesthetics, chronic pain requiring opioid analgesics, atrioventricular block II, treatment with class III antiarrhytmics, severe renal and/or hepatic disease, coagulation disorders, or infection injection site .randomization.com.” We used a sequentially numbered opaque sealed envelope system. Seventy-six patients scheduled for ambulatory laparoscopic cholecystectomy were randomly allocated to one of the following groups: 1) group QLB; preoperative: ropivacaine 3.75 mg/mL, 20 mL bilaterally; 2) placebo group; preoperative: isotonic saline, 20 mL bilaterally; and 3) control group: intravenous and oral analgesics only.Random allocation was performed with block randomization (random block sizes) using the online tool “The patients, the nurses in the postoperative anesthesia care unit (PACU), and the researcher who conducted the postoperative telephone interviews with the patients at home, were blinded to the group assignments, except randomization to the control group.The sample size was calculated based on clinical evaluation of opioid consumption at 1 hour postoperatively, and a 20% reduction was assumed significant (1-beta set to 0.80). The chosen critical alpha level was set at 0.05. The calculations showed that the required sample size was 69 patients (23 in each group). When adjusting for potential drop-outs and patients lost to follow-up, we determined that the adequate sample size would be 75 patients.The bilateral QLBs were performed before the induction of general anesthesia by two staff anesthesiologists (KIS and BS) experienced in the ultrasound-guided QLB technique, who were aware of the type of injected solution. The patients were transferred to the PACU before the operation and underwent standard monitoring with a three-lead EKG, pulse oximetry, and non- invasive blood pressure monitoring. They were then positioned in the lateral decubitus position, and the transmuscular QLB was performed bilaterally using an ultrasound unit  with either a curvilinear transducer (5-2 MHz C60XP) or a curved transducer (8-3 MHZ C35xp). The skin was prepared with two applications of 5% chlorhexidine-added phenol red, and the probe was covered with sterile covering. The probe was positioned superior to the iliac crest, in the transverse orientation, at the posterior axillary line. The Shamrock sign  was idenAll participants followed a standardized perioperative procedure: premedication with paracetamol 2 g per os (po) and diclofenac 100 mg po at least 1 hour before surgery; general anesthesia using a target-controlled infusion of propofol and remifentanil; ondansetron 4 mg and dexamethasone 8 mg iv preoperatively; endotracheal intubation performed after topical spray with lidocaine 50 mg. No muscle relaxant was used throughout the procedure. The surgical approach involved applying two 5-mm ports and two 12-mm ports umbilically and supra-umbilically. The pneumoperitoneum was established and maintained at 12 mm Hg. All ports were closed with resorbable sutures. Intravenous (iv) oxycodone 5 mg was given when the laparoscopic instruments were removed from the patient. Subcutaneous port hole infiltration at the end of surgery was performed with ropivacaine 2 mg/mL, 20 mL.Postoperatively, oral paracetamol and codeine-fixed combination up to 1000 mg and 60 mg, respectively, was administered every 6 hours. In the case of insufficient analgesia as experienced by the patient, oxycodone 1-5 mg iv was given to achieve a NRS<4. If PONV occurred, ondansetron 4 mg iv was administered and followed by droperidol 0.625 mg iv if PONV persisted. Analgesics consumed at home were tramadol and paracetamol/codeine po. Oral morphine equivalents were calculated according to The primary outcome was opioid consumption in the first 48 hours postoperatively. In hospital, this information was collected from patients’ medical journals. The consumption at home was self-reported by the patients. The secondary outcomes were self-reported pain at the incision site, deep pain (during coughing), and PONV.The outcome measures were assessed during the recovery room stay, as well as postoperatively through telephone contact after approximately 24 and 48 hours. The outcome measures were as follows:• postoperative pain at the incision site and deep pain (when coughing) was self-reported on NRS (where 0 = no pain and 10 = severe pain) 1 and 2 h postoperatively, as well as 5-24 h and 25-48 h postoperatively;• postoperative pain during mobilization 5-24 h and 25-48 h postoperatively (NRS 0-10);• opioid analgesic consumption during three time intervals: 0-4 h, 5-24 h, and 25-48 h postoperatively;• PONV self-reported on a 4-point scale, where 0 = no nausea/vomiting and 3 = severe nausea/vomiting, 0-4 h, 5-24 h, and 25-48 h postoperatively.Continuous data were tested for normality by the Kolmogorov-Smirnov test. Descriptive data are expressed as mean and standard deviation (SD). The Kruskal-Wallis test was used to test for significant differences between the groups in surgery duration and peroperative dose of propofol/remifentanil, as well as to assess the differences in outcome measures. In addition, the Mann-Whitney U tests were used to compare 1) QLB vs placebo group, 2) QLB vs control group, and 3) placebo vs control group regarding pain, PONV, and opioid consumption. The significance level was set to <0.05. The statistical analysis was performed with the software IBM SPSS Statistics for Windows, version 25.0  .In total, 76 patients were recruited. Seventy participants were included: 22 in the control group; 25 in the QLB group, and 23 in the placebo group . The groThe three groups did not significantly differ in the primary outcome measure. Even though most patients received 5 mg oxycodone peroperatively, 8 of 22 (36%) patients in the control group received approximately 2 mg more than this, compared with 3 of 24 patients (13%) in the QLB group and 6 of 22 patients (27%) in the placebo group .P = 0.012) and 3 h (P < 0.001), but lower at 5-24 h (P = 0.002), and significantly lower pain at incision site at 5-24 h vs the QLB group . Placebo group had a significantly higher PONV score at 2 h , 3 h (P = 0.001), and 25-48 h (P = 0.001), lower PONV at 5-24 h (P = 0.001), higher deep pain (cough) at 2 h (P = 0.042), and pain at the incision site at 5-24 h (P = 0.012) vs the QLB group.The control group and the placebo group did not differ in outcome measures. The control group had a significantly higher PONV score at 2 h (In this study, the groups did not significantly differ in postoperative opioid consumption at any time point. The lack of differences in analgesic consumption and pain scores is in contrast to previous studies comparing the posterior QLB and a sham block with saline in patients undergoing laparoscopic cholecystectomy. One study demonstrated both lower analgesic consumption and lower pain scores in the posterior QLB group . AnotherWe only used 20 mL ropivacaine. Cadaver studies have examined the spread of insertion of 30 mL dye solution in the QLB ,19. MoreOur study did not identify differences between the control, placebo, and the QLB group regarding analgesics consumption or pain score immediately after surgery. These findings are in line with the study by Ishio et al , who empIn the anterior QLB, the needle tip is introduced through the muscle and the anterior fascia. The spread of the injectate is not always easy to visualize, and accidental intramuscular injection of the QL or psoas muscle has been reported . Future A recent review of postoperative pain management in laparoscopic cholecystectomy recommended multimodal pain management consisting of paracetamol, NSAIDS, or cyclooxygenase-2 specific inhibitors, and local anesthetic infiltration at the surgical site. Opioids are only recommended for rescue analgesia. Moreover, nerve blocks are not recommended as a routine option, but only when there are no other options for pain management . All ourClinical experience indicates that patients with insufficient pain relief experience a great effect of nerve blocks such as the anterior QLB. Nevertheless, when placing “rescue-blocks,” patients have already experienced excessive pain, and any relief will result in an experience of effect. Of course, including patients with insufficient pain relief, and providing them with an anterior QLB could have been more beneficial.We did identify small differences in PONV during 2-48 h postoperatively, with less PONV in the QLB group. The clinical relevance of this finding is unclear.This study has some limitations. We did not test our patients receiving the block by cold sensation or pinprick test; hence, the QLB may have failed in some patients. On the other hand, the lack of changed sensation in the saline control patients may have biased the study because the patients realized they did not receive local anesthetics. The position of the needle tip relative to the transversalis fascia is of the outmost importance as a slight displacement of the needle tip may lead to a failed block. There were no signs of local anesthetics toxicity, hemodynamic instability or urinary retention, and paralysis of the lower limbs was not observed. Moreover, the ultrasound indicated correct placement and distribution of local analgesics. A further limitation is that the study relied on self-report measures. This may represent a bias in the reporting of opioid consumption after discharge.Randomized controlled trials comparing outcomes such as pain or patient experiences when using regional nerve blocks vs traditional intravenous and/or oral analgesia in patients undergoing abdominal surgery are not common. Hence, our randomized study adds information about the effects of QLB vs conventional analgesic approaches.The inclusion of patients from one hospital only, the surgical technique, the anterior placement of the block, as well as the limitations described above may call into question the external validity of our findings. Nevertheless, since we used a sufficient sample size and successfully randomized the patients, the applicability of findings is assumed.In conclusion, the anterior QLB did not alter postoperative opioid consumption in comparison with placebo block and standard oral/parenteral analgesics following laparoscopic cholecystectomy. Due to uncertain effect of preoperative placement of the QLB, this should not be a routine option, but should be used only when there are no other options for pain management.


Helplessness showed no direct or interaction effect for fatigue. Nevertheless, higher rumination and magnification were associated with higher fatigue only in patients who walked. Therefore, to promote adherence to walking and reduce the effects of catastrophizing on fatigue, it seems necessary to manage rumination and magnification among patients who walk.Walking is one of the most beneficial treatments for fibromyalgia patients. However, adherence to walking behavior is low due to the initially associated symptoms (including pain and fatigue). Although the association of catastrophism with greater symptoms is known, the results regarding fatigue have not always been consistent. Nevertheless, it is unknown whether the association between catastrophism and fatigue could, in turn, be conditioned by whether the patients walk or not. Therefore, our goal was to explore the moderating effect of walking on the association between catastrophizing and fatigue in patients with fibromyalgia. A cross-sectional study was carried out with 203 women with fibromyalgia. We used the Multidimensional Fatigue Inventory to assess fatigue and the Pain Catastrophizing Scale to assess pain catastrophizing (differentiating between its three dimensions). An ad hoc item was used to evaluate walking (moderator). Lower scores for fatigue and pain catastrophizing were found among patients who walked versus those who did not. Walking moderated the relationship between rumination and fatigue (Beta = 0.16, t = 1.96,  Fibromyalgia is a disorder characterized by chronic widespread pain and frequent comorbid symptoms, such as sleep disturbances, cognitive impairment, emotional disorders and fatigue. It was not until 2010, however, that the diagnostic criteria were changed and the clinical significance of these comorbid symptoms were clearly recognized .Fatigue is a highly prevalent and persistent symptom among fibromyalgia patients , and it In the context of physical exercise and within models of fear of movement , pain caPain catastrophizing is composed of three elements: magnification is related to the disproportionate perception of pain situations and expectations of negative results. Rumination includes ruminating thoughts, worry and an inability to inhibit thoughts related to pain; and helplessness refers to the ability to control it . This biPast research has shown that the relationship between pain catastrophizing and physical health outcomes in people with chronic musculoskeletal pain might be contextually determined by patient characteristics, for example, by pain severity . This isThe findings might have important repercussions on the design of programs aimed at maintaining walking as a form of physical exercise due to its known benefits ,39, by tIn order to participate, all participants had to have a diagnosis of fibromyalgia, according to the diagnostic criteria for fibromyalgia of the American College of Rheumatology ,42. In aThe sample, initially, included 234 women with fibromyalgia who were between the ages of 30 and 78, with a mean of 57.03 and a standard deviation (SD) of 9.07. Most participants had completed only primary (53.2%) or secondary studies (26.4%). The majority of them were married or in a stable relationship at the time of assessment (53%). The remaining participants were either single (11%) or divorced/widowed (36%). Only a small percentage of the participants were working when the study was conducted (12%). The rest of them were homemakers (33.8%), retired (32%), on sick leave (10%) or unemployed (12.1%). The patients had experienced fibromyalgia for an average of 12.14 years . Their average pain severity score was 7.15 (SD = 1.52) on a scale ranging from 0 to 10, with higher scores indicating more severe pain.General fatigue. The Spanish version of the Multidimensional Fatigue Inventory (MFI)  was usedPain Catastrophizing. The Spanish version of the Pain Catastrophizing Scale (PCS)  has 13 iWalking. The walking behavior proposed by Gusi et al.  for fibrPain: Four items assessing maximum, minimum and the average pain intensity during the last 7 days and pain at that moment in a numerical rating scale were used  ,47. The Disability: To assess disability, the total score of the Spanish adaptation of the Fibromyalgia Impact Questionnaire-Revised (FIQ-R) was used . Items iThis study is part of a larger project PI17/00858) that mainly aims, among patients with fibromyalgia, to identify the role of catastrophism, fear of pain and perception of self-efficacy in the preference and setting of goals related to exercise and walking behavior. This manuscript is part of the first phase of this study. We collected a convenience sample by contacting several patients’ associations of fibromyalgia in various Spanish regions. These associations require members to have been diagnosed with fibromyalgia, although all diagnoses were independently confirmed by the research team 7/00858 t. In totaThe assessment sessions lasted approximately 45 min. First, a structured interview was carried out to assess demographic and clinical variables , pain intensity , medicalThe Statistical Package for Social Sciences IBM SPSS for Windows, version 22.0   was usedBefore performing the analyses, we analyzed the possible outliers through the stem plot. Four cases were excluded since they presented mean scores of less than 8 in general fatigue (dependent variable). The remaining scores were between 9 and 20.Based on our objectives, the main analyses were of the catastrophism and fatigue variables, taking walking as a moderator. To control the effects of the covariables, previous bivariate analyses were carried out in relation to pain, disability and medication used to manage pain, so as to assess their inclusion in the moderation analyses.t tests, and in relation to walking (chi-square test). Effect sizes were calculated.First, descriptive and bivariate Pearson correlation analyses were performed. Then, an analysis of mean differences in catastrophizing (and its dimensions), fatigue, pain intensity and disability was conducted based on adherence to walking. The effect of prescription drugs on pain management was also assessed (opioids and non-opioid painkillers and anti-inflammatory medication), both in relation to the continuous variables  using Student’s Finally, the moderation analyses were conducted with model 1 from the PROCESS Macro version 3.4  . WalkingFour models were tested, one for each catastrophizing dimension . Statistical significance was set at an alpha level of 0.05. In the moderation analyses, we used values in conditional tables, which are the 16th, 50th and 84th percentiles. When a moderation was found to be significant, these cut-offs were used to calculate conditional effects . In the post hoc analyses, non-centered variables were used to facilitate the interpretation of results. Uncentered variables reflect the ‘real’ scores with which readers will be familiar.Regarding the possible covariables, statistically significant correlations were found between pain, disability, fatigue, catastrophizing and its dimensions. The strongest correlations were found between disability and the study variables.More than half of the patients (58.15%) adhered to walking behavior as a way of exercising. Fatigue, rumination, helplessness and pain catastrophism were higher in patients who did not adhere to walking, as shown in In relation to the covariables, disability and pain were higher in patients who did not adhere to walking exercise. The largest effect size was found for disability (moderate effect size).Fatigue, rumination, magnification, helplessness and pain catastrophism were higher in patients who took painkillers, as shown in 2 = 1.135 p = 0.29).Regarding the covariables, disability and pain were higher in patients who took painkillers. The largest effect size was found for disability. Walking was not related to painkillers (xn = 203).The previous bivariate analyses showed the need to control both the intensity of the pain and disability in the moderation analyses. In relation to these variables, given the higher correlation found between disability in relation to the main outcome variables, it was decided to include disability as a covariable in the moderation analysis. This decision was also conceptually backed up, as disability, assessed using the FIQ-R , containp = 0.49), as well as the association between magnification and fatigue . The assessed models predicted significant variance of fatigue , which ranged from 13% to 17%.p < 0.001) of fatigue.In relation to the influence of disability as a covariable, the results showed a direct and positive contribution in all the interaction models  role of adherence to walking in this relationship. Past research has shown that low adherence to exercise, such as walking, imposes a significant physical burden on patients with fibromyalgia, including an increased sense of overall fatigue ,14,15,16To date, pain has been the most studied outcome of catastrophism, and fatigue has been studied less frequently. Additionally, it has been assumed that the relationship between pain catastrophizing and outcomes  is linear, that is to say, it is not influenced by other personal, behavioral or contextual variables. The results of the present study show that while a modest bivariate association exists between pain catastrophism and fatigue, this association is no longer significant when adherence to walking and its interactions with catastrophizing are considered. This suggests that the relationship between rumination, magnification and fatigue is largely explained by adherence to walking, which was confirmed in the post hoc analyses of conditional effects after the moderation analyses.In contrast to rumination and magnification, helplessness had no significant associations (direct or indirectly) with walking in relation to fatigue. This component of catastrophism has been especially studied in relation to pain. Specifically, previous studies have shown the relevance of helplessness as the best predictor of the affective dimension of pain  and diseAs noted above, pain catastrophism has been widely and consistently associated with various symptoms in patients with fibromyalgia, including pain, depression, distress or cognitive and functional impairments ,62,63,64Thus, the present study provides further support for this contextual relationship between psychological processes and outcomes in chronic pain. Our results have also shown a contribution of (adequate) adherence to walking to reduced fatigue, which is consistent with the findings of previous studies ,12. The This study has some limitations. First, the associations must be interpreted according to the observational nature of the design, which does not allow causality inferences. Second, this study is based on self-reported data; in this sense, a relevant limitation is presented by the walking having been assessed using self-reports. It should be noted in this regard that the current study is part of a larger project that previously assessed this same behavior by means of self-administered questionnaires and pedometers, and a high consistency was found between measures ,68,69. AWhile this study has some shortcomings, the findings could have important clinical implications for practices in the field of psychological and interdisciplinary treatments and personalization in chronic pain  and in fIn relation to personalized treatments, our findings suggest that slightly different recommendations should be provided to reduce fatigue according to the walking pattern of individuals. In particular, among patients who walk, when attempting to regulate fatigue by reducing catastrophizing, tapping into the rumination and magnification components might be adequate according to our findings. In this regard, cognitive-behavioral therapy has proven to be effective in reducing these catastrophizing dimensions , and speAs described in previous literature, walking is one of the most effective treatments in reducing the symptoms of patients with fibromyalgia. Nevertheless, the patients consistently show low adherence to walking, given that at the beginning patients frequently feel more pain and fatigue. The latter has scarcely been studied despite it being one of the more disturbing symptoms. Our results, in agreement with the cognitive flexibility models, suggest that interventions aimed at improving rumination and magnification could contribute to reducing fatigue among the patients who do walk and would therefore increase adherence to walking as a form of treatment and management of fatigue .


No association between the sociodemographic and clinical variables and the PAINAD scale was found (p > 0.05). Between 97.3% and 96.2% of patients with pain on the PAINAD scale also showed pain based on the sTNF-RII levels; in all of them, sIgA levels did not fit the logistic models. Therefore, the correlation highlights the usefulness of this scale and confirms the usefulness of sTNF-RII and sIgA as biomarkers of pain.The pain assessment in advanced dementia (PAINAD) appears to be a clinically useful tool. However, the salivary determination of tumor necrosis factor receptor type II (sTNF-RII) and secretory IgA (sIgA) as pain biomarkers is still incipient. The aim was to correlate the PAINAD score with sTNF-RII and sIgA biomarker levels in the saliva of patients with advanced dementia. In this regard, a cross-sectional study was conducted. The sample consisted of 75 elderly patients with a clinical diagnosis of dementia and a global deterioration scale (GDS) score of 5 to 7. The PAINAD scale was determined by a previously trained professional and the collection of salivary samples was performed using the passive secretion method. Human sTNF-RII and sIgA using ELISA kits. The results showed a correlation between the PAINAD scale  and sTNF-RII and sIgA ( Pain has been defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” . TherefoPain is common in older people because of the many chronic diseases that often affect this population group, such as osteoporosis, depression, cancer, or cardiovascular diseases . It is eTherefore, tools such as self-reports can be used to assess the presence and intensity of pain in early and even moderate stages of dementia, when the person still can abstract reasoning. In contrast, these pain assessment tools may yield biased results in patients with advanced dementia due to patients’ lack of ability to understand the concepts assessed through these tools and, in some cases, even to communicate this pain ,15. ConsThe determination of pain biomarkers is an innovative and useful way of assessing pain, especially in saliva, as a non-invasive and cost-effective test. Specifically, some biomarkers of pain, such as salivary cortisol, salivary amylase, testosterone, secretory IgA (sIgA), or tumor necrosis factor receptor type II (sTNF-RII), have been determined in previous studies ,23,24,25In this context, the potential correlation between the levels of biomarkers (sIgA and sTNF-RII) and the levels of pain reported by the PAINAD scale could be used in two directions: On the one hand, to reinforce the usefulness of this scale as a valid tool in the healthcare setting; and on the other hand, to suggest the determination of these biomarkers as a complementary method for the evaluation of pain in these patients.Correlate the scores of the PAINAD scale with the levels of pain biomarkers sTNF-RII and sIgA in saliva samples from patients with cognitive impairment.This has been a cross-sectional study performed between May 2018 and June 2020.The Andalusian network of Primary Healthcare centers , four nursing homes and a center specifically dedicated to the care of dementia patients participated in the study.The sample size was calculated for a correlation magnitude of r = 0.3, a statistical confidence interval (CI) of 95%, a statistical power of 80%, a unilateral approach, and 10% losses. The result sample size was 75 subjects.Being 65 or older.Having a medical diagnosis of dementia or Alzheimer’s disease-like dementia (AD) with a global deterioration scale (GDS) score between 5 and 7. Those patients who met DSM-V clinical criteria were diagnosed with dementia, and those who met the NINCDS/ADRDA  criteria were classified as probable or possible AD patients.Being unable to communicate verbally.Having received health care at the community level for at least three months because of the dementia process. In the center dedicated to the care of patients suffering from AD, the included patients were those who have used this service for at least three months.Having an informed consent signed by a relative or legal representative for the patient’s inclusion in the study.The following inclusion criteria was required for participants:All subjects participating in the study were recruited consecutively by the interventional nursing, selecting those who met the previously mentioned criteria from among the subjects they care for in their health care institutions.Subjects were not allowed to practice physical exercise or to eat, ingest any drinks (except for water), chew gum, brush their teeth, or consume caffeine during the previous hour preceding the sample collection process.Five minutes before the collection of the sample, as a way to reduce the contamination of saliva with food debris, the subjects were asked to rinse their mouth with clean water.Right before starting the sample collection, any saliva present in the mouth at that time should be swallowed.Afterwards, the saliva accumulated in their mouths for 5 min was deposited in a collection tube, 1 mL being the minimum volume required. In the case of the 5 mL collection tube being filled before those 5 min, the corresponding amount of time elapsed was recorded.The main variables were the scores of the Spanish version of PAINAD and the values in saliva of the sTNF-RII and sIgA biomarkers. To assess the level of pain through the PAINAD scale, a researcher completed a book for data collection, having previously received training to ensure the reliability and reproducibility of the data. Likewise, the researchers received training with regard to how to perform the collection of the saliva sampler by using the passive secretion method : SubjectSaliva samples were collected under supervision in a clinical setting, between 09:00 am and 10:00 am and ensuring it always was done before the intake of the morning medication. After collection, the samples were put under refrigeration and subsequently frozen  and kept in that state until the analysis was carried out.In addition, sociodemographic variables  and clinical variables related to pain were collected from the patient’s medical records. Furthermore, the GDS and the level of autonomy in basic activities of day-to-day life, measured by the Barthel index, were determined by the research team at data collection or, in the cases in which that information was available (and not older than three months), it was collected from the clinical record.ELISA kits were used to determine sTNF-RII and sIgA levels in saliva. Specifically, sTNF-RII levels were measured through the Human sTNF-RII Quantikine ELISA kit  and sIgA values were determined utilizing the sIgA ELISA kit . In addition, Bradford’s method was the one used for the determination of total protein levels in saliva, in order to standardize the data. Descriptive statistics were used to characterize the sample. In this sense, for quantitative variables, the following metrics were calculated: mean and its corresponding 95% CI, standard deviation (SD), minimum, maximum, interquartile range (IQR), median, and the number of observations. On the other hand, regarding qualitative variables, the corresponding frequency distributions were determined (both absolute and relative frequencies).The matrix of polyserial correlations and the appropriate hypothesis contrasts were the tools of choice to evaluate the association between the levels of the biomarkers under study and the PAINAD scale.2 coefficient with their corresponding significance levels were obtained to evaluate the potential relationships of demographic and clinical variables with biomarkers and PAINAD scores. Then, polyserial correlations and the χFinally, in the case of detecting some kind of relationship between these variables, they were included in all logit and logistic multinomial models, in order to evaluate their relative influence on the fact that pain appears or not, and its corresponding degree.This logit model was utilized with the goal of stablishing which saliva biomarker affects more the pain condition, and multinomial logistic models were considered to evaluate which of the biomarkers had the biggest influence on pain levels. The statistical package SPSS  was employed for the majority of calculations mentioned previously, and the R software to determine the coefficients of polyserial correlations. Through all this statistical analysis, a significance of 5% was assumed.The study was carried out following the principles stablished in the Belmont report and the Helsinki Declaration (updated at the Seoul Assembly in 2008) for biomedical research. A Patient Information Sheet (PIS) was handed over to all family members or legal representatives of the candidates to offer them information regarding the general aspects of the study. Written informed consents were obtained and voluntarily signed by the patient’s relative or legal representative. All participants were allowed to withdraw consent to participate at any time during the development of the process.Data confidentiality was always guaranteed, and so was the subject’s anonymity. In this sense, the study received the permission of all participating centers, as well as the approval of the Ethics Committee for Research of Andalusia .A total of 75 participants were studied, of whom 59 (78.7%) were women. The overall mean age was 84.41 (7.44) years, 95% CI (82.70–86.13), and the range was 65–95 years. Regarding the marital status, a total of 68% of the sample were surviving spouses. Concerning the place of residence, 64 subjects lived in a rural area. In addition, 69.3% were institutionalized. Regarding the diagnosis of dementia, 69.33% had AD, which is, therefore, the most frequent type of dementia. Similarly, regarding the level of cognitive impairment, 34 subjects had a GDS 7. Furthermore, as for the level of independence for performing basic activities of daily living, the median Barthel index score was 10 (max = 80 and min = 0). Only 34 subjects of the total sample were prescribed analgesic treatment for their pain. The median of the PAINAD scale was 0 (max = 8 and min = 0), 95% CI (0.96–1.95). Furthermore, the median sTNF-RII (pg/mg protein) was 2.56 (max = 684.28 and min = 0.0162) 95% CI (5.84–49.28), whereas the median sIgA (ng/mg protein) determination in 54 of the participants was 5285.60 (max = 157440.83 and min = 6.49), 95% CI (4439.82–18905.34). p > 0.05).Concerning the possible association between the PAINAD variable  and the rest of the sociodemographic variables of the categorical type, no correlation was found in any case (p = 0.20), time consuming analgesics (p = 0.94), and Barthel index score (p = 0.21).The degree of relationship between PAINAD (numeric) and the rest of the sociodemographic and clinical numerical variables, measured through the polyserial correlation coefficient, demonstrated a lack of relationship between the variables considered. Specifically, the results showed no relationship between PAINAD and age (p = 0.11), time consuming analgesics (p = 0.44), and level of dependence for basic activities of daily living according to the score of the Barthel index (p = 0.21), based on the calculation of the polyserial correlation coefficient.Similarly, no relationship has been found between PAINAD (in its binary recoding) and age (p = 0.13), time consuming analgesics (p = 0.50), and Barthel index score (p = 0.37).Similarly, the polyserial correlation coefficient showed no association between recoded PAINAD  and age  is independent of sex, age, marital status, area , institutionalization, type of dementia, time consuming analgesics, GDS, and degree of dependence according to the Barthel index. p < 0.001) and 0.56 (p < 0.001), respectively; whereas the value based on maximum likelihood estimation was 0.99 (p < 0.001) for sTNF-RII and 0.58 (p < 0.001) for sIgA.The polyserial correlation coefficient, both following a simple two-step method and based on the maximum likelihood estimates method, was used to measure the degree of correlation between the PAINAD variables  and the levels of sTNF-RII and sIgA. In the two-step method, the value of the association between PAINAD (numeric) and sTNF-RII and sIgA was 0.76 (p < 0.001) and 0.72 (p < 0.001), respectively. Additionally, according to the likelihood estimation, this ratio was 0.99 (p < 0.001) for sTNF-RII and 0.94 (p < 0.001) for sIgA.In addition, in the two-step method, the associations between the binary-coded PAINAD scale score and the sTNF-RII and sIgA levels were 0.85 (p < 0.001), whereas it was 0.99 (p < 0.0001) in the maximum likelihood estimation. In turn, the correlation between recoded PAINAD and sIgA was 0.70 (p < 0.001) in the two-step model and 0.95 (p < 0.001) according with the maximum likelihood estimate.Moreover, in the simple two-step method, the relationship between the recoded PAINAD variable and sTNF-RII was 0.79  and the sTNF-RII biomarker.A binary logistic model was applied using a conditional step-by-step forward procedure to assess which of the two biomarkers had the largest influence on determining the presence of pain (no pain) in study subjects. In this model, the dependent variable was the binary PAINAD variable , and the sTNFR-II and sIgA levels were considered independent variables. The procedure excluded sIgA as a predictor variable in the model. Thus sTNF-RII was determined as the most influential variable for the prognosis of pain. Data obtained in the analysis are shown in The PAINAD variable was then recoded into three categories . In this case, a multivariate logistic model was applied to again determine the most influential indicator. In relation to the original PAINAD variable, Our results support the usefulness of the PAINAD scale for assessing pain in patients with advanced dementia, given the correlation between the sTNF-RII and sIgA measurements and the score on the PAINAD scale. Therefore, the PAINAD scale was confirmed as a simple and feasible tool, but with remarkable precision, that allows to assess pain in people with dementia and inability to communicate and thus to mitigate the characteristic underdiagnosis and undertreatment in these patients ,30. HoweSimilarly, the determination of pain biomarkers in fluids such as the saliva is a promising strategy , especiaRegarding the correlation between both biomarkers (sTNF-RII and sIgA) and the PAINAD scale, based on the results achieved, both should be considered as biomarkers of pain. Specifically, regarding sTNF-RII levels, it has been shown that between 97.3% and 96.2% of patients with pain on the scale would also have pain according to sTNF-RII. This result would probably be related to the pain-modulating function of some cytokines , includiThe results, therefore, confirm the usefulness of the PAINAD scale for pain assessment in patients with advanced dementia. Moreover, our results point to the determination of sTNF-RII in saliva as an effective method by itself and complementary to the PAINAD scale, if it is desired to objectify the assessment.Furthermore, the correlation found in our study between the PAINAD scale values and the sIgA levels has also previously been reported by Sobas et al. (2016) in healthy patients, which would allow us to establish a link between pain and the pain biomarker sIgA . HoweverThe absence of a relationship between pain and sociodemographic characteristics  could be conditioned by the characteristics of our sample (patients with advanced dementia). The associations found in previous studies seem to be related, at least in part, to the psychological component of pain (the thoughts the person has about what happens to him/her and what he/she feels) ,46.The lack of association with clinical characteristics may be because our study subjects represent a very homogeneous population (with significant cognitive impairment and a significant level of dependence for basic activities of daily living). This would have made it difficult to recognize such an association.Finally, the lack of association between analgesic use and the PAINAD scale could be related to the scarce and limited analgesic treatment of the study subjects due to the frequent underdiagnosis and undertreatment of pain in this group that, often, is constricted to the first step of analgesia in the World Health Organization (WHO) classification ,48. Thern = 54) in the measurement of sIgA. However, statistical analysis has shown that the number of subjects was sufficient to achieve significant results.The xerostomia present in some subjects has hindered the collection of enough salivary sample volume for measuring both biomarkers in some subjects. Therefore, the sample size was relatively lower (The correlation between the PAINAD scale and the sTNF-RII and sIgA pain biomarkers reinforce the usefulness of this scale in assessing pain in people with dementia and inability to communicate. Similarly, the sTNF-RII and sIgA salivary biomarkers are suggested as efficient and complementary tools of utmost applicability for pain assessment, and sTNF-RII is most accurately predicting pain in people with advanced dementia, according to the PAINAD scores.