Numerous neuroimaging studies have demonstrated that the brain plasticity is associated with chronic low back pain (cLBP). However, there is a lack of knowledge regarding the underlying mechanisms of thalamic pathways for chronic pain and psychological effects in cLBP caused by lumbar disc herniation (LDH). Combining psychophysics and magnetic resonance imaging (MRI), we investigated the structural and functional brain plasticity in 36 patients with LDH compared with 38 age- and gender-matched healthy controls. We found that (1) LDH patients had increased psychophysical disturbs , and depression  was found to be an outstanding significant factor to predict chronic pain ; (2) the LDH group showed significantly smaller fractional anisotropy values in the region of posterior corona radiate while gray matter volumes were comparable in both groups; (3) resting state functional connectivity analysis revealed that LDH patients exhibited increased temporal coupling between the thalamus and dorsolateral prefrontal cortex (DLPFC), which further mediate the relationship from chronic pain to depression. Our results emphasized that thalamic pathways underlying prefrontal cortex might play a key role in regulating chronic pain and depression of the pathophysiology of LDH. Chronic low back pain (cLBP) is one of the most common reasons for adults to visit the clinic , 2. ClinNeuroimaging studies have concluded that central nervous system is engaged in the development of cLBP, and the brain of chronic pain patients is continuously processing spontaneous pain by integrating information between multiple brain regions, mainly including primary somatosensory cortex (S1), anterior cingulate cortex (ACC), thalamus, insula, and periaqueductal gray (PAG) –8. In paNotably, among the thalamocortical linkage, some researchers emphasized the functional connectivity of the thalamus with prefrontal cortex (PFC), possibly reflecting individual differences in pain modulation. It is well documented that the mediodorsal thalamus employs a role in the affective dimension of pain, and deficits of the thalamus and PFC coupling have been well documented in some psychiatric conditions, including depression disorder and schizophrenia . ChronicIn the current study, combining psychophysics with MRI techniques, we investigated the structural and functional brain alterations in patients with LDH compared with age- and gender-matched healthy controls (HCs). We related these brain alternations with pain intensity as well as pain-related emotional comorbidities in the patient group. We hypothesized that LDH patients (1) exhibited increased psychophysical problems and (2) had structural and functional thalamic abnormalities, which is significantly related to its pain intensity and pain-related emotional comorbidities.t-tests, and differences in gender were assessed using chi-square test.A total of 36 right-handed LDH patients  and 38 age- and gender-matched right-handed HCs  participated in the study. All patients met the following inclusion criteria: (1) diagnostic and radiological evidence (CT or MRI) for LDH was confirmed by 3 experienced clinicians, (2) radiating pain > 3 score ); and (3) duration of pain > 3 months. All enrolled patients did not take any painkillers at least one week before the MRI scan. None of the participants had a past or current diagnosis of any psychiatric or major neurological illness. Participants signed the informed consent prior to the experiment on the premise of fully understanding the content of the experiment. The local ethics committee at the Third Affiliated Hospital of Henan University of Chinese Medicine approved the study. All participants were recruited from 2018 to 2019. For the demographic data, group differences in age and education level were evaluated using independent-sample Pain characteristics were assessed using the short form of the McGill Pain Questionnaire (SF-MPQ)  and paint-tests. For LDH patients, Pearson's correlation analyses were adopted to assess the relationship between pain intensity, psychological variables, and thalamus-based functional connectivity.All participants completed psychological questionnaires to assess depression  as well as state and trait anxiety  . In addip < 0.05). Then, the procedure adjusts by repeatedly adding other explanatory variable (if any) that could significantly improve the fitting of the model (p < 0.05), until no one could improve the model. Before performing multiple linear regression analysis, all variables were examined on deviation from normality using Kolmogorov-Smirnov test , and no serious deviation from the normality was observed for any variable (p > 0.05).In order to assess the joint influence psychophysical factors on chronic pain, a multiple linear regression analysis based on a forward stepwise selection procedure was performed. In this analysis, the severity of chronic pain  was used as the dependent variable, and the sleep disturbances (PSQI) as well as psychological characteristics  were identified as explanatory variables. First, the forward stepwise selection procedure includes the explanatory variable that could significantly explain the dependent variable . Resting-state fMRI images were collected with an echo planar imaging (EPI) sequence .All MRI images were collected using a 3T Siemens Skyra scanner at the Third Affiliated Hospital of Henan University of Chinese Medicine. Structural MRI data were acquired using a 3D magnetization-prepared rapid gradient-echo (MPRAGE) T1-weighted sequence . The diffusion data for each subject were obtained using a diffusion-weighted, single shot, spin-echo, EPI sequence . The details are described elsewhere [p < 0.05.The structural MRI was analyzed using FreeSurfer  [Randomise function of FSL. Threshold-free cluster enhancement (TFCE) with p < 0.05 as significant was used to obtain cluster-based statistics corrected for multiple comparisons, a method to enhance the cluster-like structures in the voxel-based data [p < 0.05 were thickened for visualization using the TBSS fill script in FSL. The Johns Hopkins University ICBM-DTI-81 white matter labels atlas was used to locate anatomical structures in the MNI152 space.Voxel-wise tract-based spatial statistics of diffusion-weight data was analyzed using TBSS, part of the FMRIB Software Library (FSL) (ki/TBSS) . This meki/TBSS) . Fractioki/TBSS) . We alsosed data , 33. Sighttp://www.fmrib.ox.ac.uk/fsl/). Preprocessing of resting-state fMRI data includes motion correction using MCFLIRT [Resting-state fMRI image processing and data analyses were performed using FMRI Expert Analysis Tool (FEAT), version 5.98, which is part of the Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library . Second is the warp distortion amount for BBR-based function-to-structure realignment as measured by the minimal cost of the head motion as measured by the root mean square of frame-wise displacement. Three participants (two for LDH patients and one for HCs) were excluded because of head movement during the fMRI scan. In addition, four patients were excluded because of illness during scanning.The thalamus was chosen as a seed for the resting-state functional connectivity analyses, and the seed was identified based on the Harvard Oxford subcortical structural atlas (90% threshold), which are population-based probability atlas in MNI-152 standard space . The masZ > 2.3, and a corrected cluster significance threshold of p < 0.05. A two-group unpaired t-test was used for comparing differences in the thalamus-based functional connectivity between LDH patients and HCs. The group-level statistical images were corrected using parametric family-wise error (FWE) method at cluster level, determined by Z > 2.3, and a corrected cluster significance threshold of p < 0.05.Voxel-wise seed-based functional connectivity analysis was completed using standard methods with a general linear model (GLM) framework . NuisancAdditionally, thalamus has complex substructures, and we also performed seed-based functional connectivity analyses for different subregions of thalamus. We adopt the probability atlas of 7 subthalamic regions provided by FMRIB, which were segmented according to their white matter connectivity to cortical regions. Two different subregions of thalamus were selected as seeds for the resting-state functional connectivity analyses, which mainly connect the prefrontal and the somatosensory regions, respectively.http://www.processmarcro.org, version 2.16.3). We tested two models: (1) independent variable was SF-MPQ, BDI was the dependent variable, and functional connectivity of thalamus-DLPFC was the mediator; (2) independent variable was BDI, SF-MPQ was the dependent variable, and functional connectivity of thalamus-DLPFC was the mediator. These analyses determined the indirect effects of thalamus-DLPFC functional connectivity on chronic pain and depression, yielding the 95% confidence intervals (CIs) of the indirect effects. A significant mediation occurs when the 95% confidence intervals did not include zero [The functional connectivity between thalamus and DLPFC was identified to be significantly related to SF-MPQ as well as BDI ratings. Therefore, to further investigate the relationship between chronic pain intensity, depression, and thalamus-DLPFC functional connectivity, a bootstrapped mediation analysis was finally employed. The mediation analyses were performed using the SPSS  version of the PROCESS macro , PPI , VAS , total SF-MPQ scores , and PSQ score  were significantly larger in LDH patients than in HCs ). Furthermore, patients reported higher levels of depression  as well as state and trait anxiety ). In addition, sleep quality  and pain vigilance  were significantly higher in LDH patients than in HCs , whereas not significantly affected by the explanatory variable of SAI , TAI , PSQI , and PVAQ .For LDH patients, multiple linear regression analysis revealed that the dependent variable SF-MPQ was significantly influenced by the explanatory variable of BDI  as well as BDI ratings  in LDH patients.Compared with HCs, FA values in the region of posterior corona radiate (PCR) were significantly smaller in LDH patients . As chroZ > 2.3, p < 0.05 cluster-wise corrected, r = −0.374, p = 0.029 and BDI: r = −0.434, p = 0.010, r = −0.365, p = 0.034), but not with SF-MPQ ratings , whereas functional connectivity between thalamus and insula and between thalamus and ACC was not correlated with SF-MPQ ratings . In addition, the results of the resting-state functional connectivity of subregions for the thalamus are presented in Supplementary Fig. When the thalamus was used as the seed, resting-state functional connectivity demonstrated that thalamus exhibited stronger functional connectivity with the DLPFC, anterior cingulate cortex (ACC), insula, and posterior cingulate cortex (PCC) in LDH patients than in HCs  is poorly addressed. In the present study, we investigated the relationship between brain structural/functional plasticity and the degree of chronic pain as well as pain-related psychological factors in LDH patients, and our findings can be summarized as follows: (1) LDH patients exhibited severe psychophysical disturbs , and depression was found to be an outstanding significant factor to predict chronic pain; (2) we did not observe significant structural plasticity changes for LDH patients, in terms of cortical thickness and subcortical volumes. FA values in LDH patients were identified to be significantly decreased only in the region of posterior corona radiate (PCR) but not correlated with chronic pain or any psychological factors; (3) the main finding of this study is that the functional connectivity between the thalamus and DLPFC was significantly correlated with the subjective ratings of SF-MPQ and BDI in LDH patients, and critically, the thalamus-DLPFC coupling mediated the relationship from chronic pain to depression. Our results suggested that thalamic pathways underlying prefrontal cortex might play a key role in regulation chronic pain and depression of the pathophysiology of LDH and may lead to optimized treatments in clinical practice.In addition to the primary etiological cause, LDH, as a typical chronic low back pain, has profound and prolonged psychophysiological consequences, such as increased depression, as demonstrated by the analysis of the multiple linear regression. Of note, different types of chronic pain conditions have been well described in a large of literature to be comorbid with psychological disorders . Indeed,Structural morphology analyses demonstrated that cortical and subcortical gray matter volumes were comparable between the two groups. In addition, we assessed microstructure properties by using the voxel-wise tract-based spatial statistics method. FA is the most frequently used parameter in DTI studies, and it reflects structural integrity and geometry of axonal fibers . And a dCompared to HCs, LDH patients exhibited a significantly greater resting-state functional connectivity between thalamus with several brain regions, including DLPFC, ACC, insula, and PCC. Thalamus is a main gateway of nociceptive inputs to the cerebral cortex, and deficits of this region may be a reason for generalized sensory abnormalities commonly related to chronic pain . HendersPrevious studies of chronic pain have reported consistent findings with respect to the assocaitions between clinical pain and negative emotional symptoms as well as thalamus-related functional connectivity , 11. CliFirst, the sample size of patients is limited and involves patients with varying severity and duration of disease, which limited the investigation of the detailed role of each mechanism in the development of LDH. Second, only longitudinal studies in larger samples allow us to track the development of the key variables involved over time to shed light on their relationship and develop a causal model between pathopsychophysiological factors and chronic pain severity in LDH. Third, the sample size involving LDH patients is relatively small, which limits our ability to explore in different thalamic nuclei, so that it cannot provide a precise description of the thalamocortical abnormality in LDH patients. Future research using large sample data from ultrahigh-field imaging to dissect the functional neuroanatomy of the thalamus into its components will help determine possible differences in thalamic function related to chronic pain between LDH patients and HCs. Finally, it is not clear whether LDH patients were characterized with possible transmission mechanism from the periphery to the spinal cord, which needs to be elucidated by future work with combined spinal-brain fMRI.Despite the limitations, this study provides further evidence that the modulation of chronic pain on depression was mediated by enhanced functional connectivity between thalamus and DLPFC. Future studies still need large sample sizes or longitudinal studies to replicate and generalize these results across large chronic pain patients. More detailed insights into the structural and functional brain plasticity underlying LDH will shed light on the development of new more targeted treatment options in clinical practice.


Background: Bladder cancer is one of the most common malignancies. Its diagnosis is based on transurethral cystoscopy. Virtual reality (VR) is a three-dimensional world generated through the projection of images, the emission of sounds and other stimuli. VR has been proven to be a very effective “distractor” and, thus, a useful tool in managing pain. The aim of this study was to determine whether the use of VR sets is technically feasible during the cystoscopy and whether the use of VR devices would reduce the degree of ailments associated with the procedure; Methods: The study prospectively included both men and women who qualified for rigid cystoscopy due to both primary and follow-up diagnostics. The study group underwent rigid cystoscopy with the VR set and the control group underwent the procedure without the VR set. Patients enrolled in both groups were subjected to blood pressure, heart rate and saturation measurements before, during and after the procedure. Additionally, the patients were asked to describe the severity of fear, pain sensations and nausea associated with the procedure. Non-verbal pain manifestations were assessed using the adult adjusted Faces, Legs, Activity, Cry and Consolability (FLACC) scale; Results: The study population included 103 patients . Pain intensity differed significantly between the groups, reaching lower values in the VR group. In all analyzed subgroups the use of the VR set was associated with higher levels of nausea. The mean FLACC score reached higher values for patients without the VR set. Blood pressure as well as heart rate increased during the procedure and decreased afterwards. The increase in systolic blood pressure and pulse rate was statistically higher in the control group; Conclusions: This study confirmed that cystoscopy is associated with considerable preprocedural fear and severe pain. Blood pressure and heart rate rise significantly during the cystoscopy. VR sets can lower pain perception during cystoscopy, but they may cause moderate nausea. Bladder cancer (BCa) is one of the most common malignancies. The diagnosis of BCa is mainly based on transurethral cystoscopy (CS) . In the Virtual reality (VR) is defined as a three-dimensional world generated through the projection of images, the emission of sounds and the production of other stimuli. It enables “immersion” in a virtually-created environment . RealistVR sets were originally developed as military training tools and entertainment devices. However, in recent years, VR has been proven to be a very effective “distractor” and thus, a useful tool in managing pain perception.The aim of the study was to determine whether the use of VR sets is technically feasible during the transurethral CS performed under local anaesthesia. In addition, we aimed to prove whether the use of VR devices would reduce the degree of ailments associated with the procedure.The study protocol was approved by the Institutional Bioethics Committee (consent number KB-276/2020 06.05.2020). The study prospectively included both men and women who qualified for rigid cystoscopy due to suspected BCa (primary diagnostics) or due to periodic surveillance after the previous surgical treatment of BCa. Exclusion criteria involved medical contraindications for a VR set , indwelling catheters, CS with intervention, symptomatic urinary tract infection, history of Bacillus Calmette-Guérin (BCG) immunotherapy and inability to cooperate with psychological evaluations. Patients taking medications that could affect their mental states were also disqualified.The randomization was performed according to previously computer-generated schemes. The patients were not informed which group they were assigned to until the start of the procedure. The first group underwent rigid CS with the VR set consisting of goggles and headphones (VR group), and the second group underwent rigid CS without the VR set (control group).The content presented by the VR device was selected after a consultation with ophthalmology, neurology, and otolaryngology specialists, as well as with VR professionals.The procedure details and technical parameters of the device were set and adjusted during the preliminary tests carried out on members of the research team during the simulated procedure, and additionally, during several CS procedures not included in this analysis.Because of the intellectual limitations resulting from age and comorbidity, we chose an image presenting a nature landscape . The image was static to the viewing point and dynamic in terms of the animal activity, plant movement and flowing water. When the subject’s head moved, the image shifted, imitating the sensation of “looking around”. The headphones emitted sounds that imitated the naturally-occurring sounds at the Skogafos waterfall (nature sounds). The intensity of the emitted sound was adjusted so that it was well tolerated by the examined patient, but it also significantly limited the perception of the operating theater noises  and prevented communication with the staff.One urologist (M.Ł.) conducted the vast majority of the procedures and measurements. All CSs were performed in the dorsal lithotomy position, using a lubricating gel containing 2% lidocaine without any systemic sedation or analgesia. Rigid 20 Fr cystourethroscopes were used. Patients had the opportunity to observe the CS on the screen.Patients enrolled in both groups were subjected to detailed clinical observation, including blood pressure (BP), heart rate (HR) and blood oxygen saturation analysis. The measurements were collected in 4–5-min intervals, and the mean values were calculated for the pre-, peri- and postoperative periods. The standard cardiac monitor device was used. Self-perception of fear, pain and nausea were assessed using a numeric rating scale (NRS) ranging from 0  to 10 points . Perception of fear was assessed before the randomization. Pain and nausea perception were assessed a few minutes after the CS completion. The adult-modified Face, Legs, Activity, Cry, Consolability scale (FLACC) was used to assess nonverbal pain manifestations by the assisting nurse, with scores ranging from 0 (no pain) to 10 points (unbearable pain).p < 0.05 was considered statistically significant.Based on the preliminary assessment (data not shown), we calculated that 100 patients were sufficient to achieve desired statistical power. The comparisons were analyzed with the Mann–Whitney and Wilcoxon signed-rank tests. The variations of frequencies were tested using Chi-squared tests. The value of the adjusted The study included 29 females and 74 males (mean age: 66.4 years). The basic characteristics of the patients are presented in In this study, we aimed to assess whether the use of the VR set during rigid CS would reduce the discomfort associated with the procedure. We found that the use of VR was feasible and the VR set was generally well tolerated. Only a few patients reported moderate vertigo or nausea. However, none of the CS procedures were interrupted because of patients’ ailments. The patients did not report any additional problems related to the device that were reasons to stop the procedure.The study confirmed the previous observations that rigid CS is an unpleasant and stressful procedure . The patIn our study, we hypothesized that it would be more suitable to measure fear than anxiety during the short, invasive procedure such as CS. Fear is not widely recognized as a psychopathological symptom. Hence, no previous studies have assessed fear (as an isolated parameter) of CS. However, unlike anxiety, which is considered a diffuse, unfocused, objectless and future-oriented feeling, fear is considered a reaction to a specific, observable danger. Both states, although clearly overlapping, are considerably different. Anxiety is significantly more often associated with muscle tension, vigilance in anticipation of the expected danger, caution (often excessive) and avoidance behaviors. On the other hand, fear is much more often accompanied by a significant intensification of the autonomic stimulation to fight, as well as thoughts of sudden danger  . In our In the available literature, several studies have analyzed the issue of pain during cystoscopy. The described methods of pain alleviation include the use of lidocaine lubrication, high pressure of the irrigation solution and additional maneuvers, such as real-time self-visualization, listening to music, the assisting nurse holding the patient’s hand, watching television and using a stress-ball ,9,10,11.In this study, the pain levels during CS in the control group did not differ from previous findings. The results clearly show that the pain perception in males was significantly higher than in females. Whereas some men described the pain as level 10 (unbearable), some women reported the pain as severe as level 8. This is contrary to the widespread dogma that female CS is painless.The pain level associated with VR CS was significantly lower when compared to the control group. The mean difference reached almost 1 unit. However, this difference was due to differences in the male CS. In females, there was no observable difference in pain sensations between the VR and control group.In addition, patients in the control group showed more pronounced nonverbal pain manifestations as assessed by the FLACC scale. Contrary to the NRS pain measurements, this difference was much more evident in the female population.The influence of pain and fear on homeostasis parameters has been widely proven . TherefoIn this study population, despite the elevated preprocedural homeostasis parameters, significant increases were observed in both BP and HR during cystoscopy. However, the increase was notably less intense in the VR group. These observations were consistent for both genders and might suggest that using VR alleviated some pain or at least efficiently distracted the patients from the negative experience. Shortly after the procedure, the parameters returned to the values recorded before CS in the majority of patients. Again, the change was less severe in patients that received the VR set. Contrary to the fear assessment, the CS result and the number of previous CSs had no influence on the BP and HR (data not shown).Throughout the procedure, the blood oxygen saturation levels were normal in the vast majority of patients. In addition, no significant changes were observed during CS. Although the stress and pain experienced before and during the cystoscopy may have influenced the patients’ breathing patterns, the difference was minor, and the resulting changes did not exceed physiological values.This study faces some limitations. First, it was conducted in one center and in a relatively small population. Second, the VR equipment showed only passive, stationary images without any active tasks . Due to the BCa population characteristics and its limitations, we assumed that active interactions within VR might be too burdensome for the patients. Third, the homeostasis parameters used in the study are not specific to CS. In addition, the FLACC scale was originally developed to analyze the pediatric population. We used an adult-adjusted FLACC scale, as there is no widely used tool to describe nonverbal pain manifestations in adults. Finally, psychometric questionnaires are subjective, and the answers are based on each patient’s comprehension of the questions. Psychometric questionnaires can be influenced by a variety of factors including the disease itself, and are not specific to CS.This study confirmed that CS is unpleasant for patients, especially for men. CS is associated with considerable preprocedural fear, as well as severe pain during the procedure. BP and HR rise significantly during the CS. Moreover, patients presented various nonverbal manifestations of intense pain. Using VR equipment during CS is feasible, but it may cause moderate nausea and vertigo. VR sets can lower pain perception, especially in males.


To compare the ketamine efficacy at a sub-dissociative morphine dose to reduce pain in isolated limb traumatic injuries.A double-blind randomized clinical trial study was carried out on patients referred to emergency departments (EDs) due to isolated limb traumatic injuries. Eligible patients were divided into two groups which one group received 0.1 mg/kg ketamine and the other group received 0.05 mg/kg morphine, intravenously. An observed side effect includes pain scores and vital signs were recorded at baseline of every 5 minutes for 30 minutes.p<0.05); the mean of total pain reduction was greater in the ketamine group during the observation period compared with patients who received morphine (p=0.002).Totally, 73 patients with the mean age of 32.9±10.4 were enrolled of whom 59 (80.8%) individuals were men. The baseline characteristics difference of the two study groups was not statistically significant. The results showed that the change of mean pain score was -6.2 (95% CI: -5.72 to -6.69) points in the group receiving ketamine compared to -5.8 (95%CI: -5.15 to – 6.48) in the group who were administered morphine. At all assessed checkpoints, the pain mean score was lower in the ketamine group than in the morphine group ( The study findings suggest that the sub-dissociative ketamine efficacy in controlling of the acute pain is not lower than morphine sulfate in patients with isolated limb trauma in ED’s. Thus, it can be considered as a safe and effective alternative approach. Pain is a common chief complaint among patients referring to the emergency department (ED). The proper pain control is one of the main tasks of any emergency medicine physician (EMP) -3. To thStudy DesignThis study was a single-center, prospective, randomized, double-blind clinical trial performed in a 1000-bed academic teaching hospital affiliated to Tehran University of Medical Sciences (TUMS) in a one-year period from August 2014 to August 2015. The study was approved by the Tehran University of Medical Sciences Ethics and Review Board (Code: IR.TUMS.REC.1394.1710) and was conducted and reported according to the CONSORT. The investigators adhered fully to the principles of the Helsinki declaration throughout the study. The study details were described to participants’ patients by appropriately qualified staff who were completely independent but had sufficient knowledge of this study. Written informed consent was obtained from each patient and ensuring that the patients understood the information. The study was registered at www.irct.ir (IRCT20150213021063N6).Study PopulationPatient’s convenience sample was enrolled during one-year study period. The study were included patients aged 18 to 55 years who presented to the ED for isolated limb traumatic injury with an acute pain score of 5 or more on a standard 11-point (0-10) numerical rating scale (NRS). The excluded patients were those with altered mental status, unstable vital signs, known underlying hepatic or renal diseases and pregnant patients. Enrollment was carried out at various day’ times and week days including weekends. The sample size was calculated as 35 for each arm of the study by considering α=0.05, β=90%, d=0.2, and variance=2. Sample size was estimated by using the following equation: Randomization, Blinding, and InterventionPatient’s enrollment was performed with the first study investigator by completing data sheets. Medications were prepared and delivered to the nursing personnel by the second study investigator in a blinded fashion. All of the research team, patients and an investigator who prepared drug were participated in this double-blinded study. The enrolled patients were divided into the arms of the study by block randomization and were assigned into ketamine or morphine groups. The first group received 0.1 mg/kg ketamine and the second group was administered 0.05 mg/kg morphine in 10 ml normal saline. The first study investigator were recorded the patient’s baseline vital signs and pain score; vital signs and adverse effects were also recorded every 5 and for 30 minutes after drug administration. Additional painkiller (rescue medicine) was administered at any time upon patient’s request or according to the clinical judgment of the in-charge physician during the study. Outcome MeasurementThe study primary objective was comparing the reductions in patients’ pain based on NRS scores between the two study groups. The secondary goal was to evaluate the need for additional painkiller, side effects, and vital signs changes. Statistical AnalysisAccording to an intention-to-treat principle, all patient’s data was analyzed. A Chi-square test or fisher’s exact test were used to compare rates for categorical measurements and outcome at 30 minutes. ANOVA repeated measure was used to assess differences in pain scores of each group separately over the study period. Furthermore, the independent t-test was performed to evaluate the differences in pain scores between the two groups at different time intervals. All statistical analyses were performed at α<0.05 level and study power was estimated to be 80%. Statistical analyses were conducted by using SPSS version 20 .p=0.712). All the study characteristics of participants’ baseline have shown in p>0.05). p=0.039).Patients’ flow chart has shown in Main Outcomes: Pain Reduction p=0.002) at each measurement time (p=0.066). Additionally, patients with a higher statistically percentage were reached 60% pain reduction in the ketamine group compared with the morphine group (p=0.040) (p=0.430).A downward trend was observed in pain mean score of both study group. The results showed that the change of pain mean score was -6.2 (95% CI: -5.72 to -6.69) points in the group receiving ketamine compared to -5.8 (95% CI: -5.15 to – 6.48) in the group who were administered morphine. As it is depicted, pain mean score was constantly decreased over the study period in both groups. However, the mean score of pain was lower in the ketamine group than in the morphine group, and pain reduction was greater in the ketamine group compared with patients who received morphine (ent time . The patp=0.040) . Only 2 Side Effects I: Vital Signs During Pain Reduction Treatment Changes includes systolic and diastolic blood pressure, heart rate, respiratory rate and arterial oxygen saturation were also monitored and compared between the two groups in the study. There was no statistically significant differences between the two groups .Side Effects II: Complications Due to Pain Reduction Treatment p=0.009). No noticeable adverse effect was reported necessary of the study withdrawal.Due to the pain reduction treatment, complications were another investigated outcome in the current study . The moset al., [et al., [et al., [et al., [et al., [et al., [et al., [et al., [The pain management is a great importance in trauma patients referring to EDs. For a long time, opioids use has been an acceptable option to alleviate pain. The current study compared the morphine and ketamine effects of tranquilizing pain in trauma patients. The results of the study indicated that sub-dissociative ketamine doses is more effective than low morphine doses in pacifying pain. This asset enables pain management with minimum side effects by requiring no medical intervention or intensive care for patients. The current study results were in agreement with the study of Motov et al.,  which shet al., . Majidin[et al.,  also rep[et al.,  who repo[et al.,  was obse[et al.,  who comp[et al.,  and Rich[et al.,  studies.[et al.,  and the In conclusion, the study findings suggest that sub-dissociative ketamine can be consider as a safe and effective approach to control acute pain in trauma patients with isolated limb refer to EDs. It also improves pain relief significantly when compared with intravenous morphine. Notably, ketamine is associated with minor side-effects which are clinically negligible. The ketamine palliative effect has a more rapid onset when compared with morphine.The small sample size is a major limitation of the current study which could affect the findings. The current study was also carried out at a single site which could generate a heterogeneous sample regarding medical emergency conditions and, consequently was reduced the results’ generalizability. Patients were followed for only 30 minutes while this following could provide more and different information for 1 or 2 hours by assessing a long-term pain killers effects. Ethical approval was obtained from the Tehran University of Medical Sciences Ethics and Review Board (No. IR.TUMS.REC.1394.1710).


Despite the control of inflammation, many patients with axial spondyloarthritis (axSpA) still report pain as a significant concern. Our objective was to explore the prognostic value of the painDETECT questionnaire (PDQ) in relation to treatment outcomes in axSpA patients treated in clinical practice. AxSpA patients with high disease activity initiating or switching a biological Disease-Modifying Antirheumatic Drug (bDMARD) were eligible. The PDQ score (range: −1 to 38) was used to distinguish participants with nociceptive pain (NcP) mechanisms from participants with a mixed pain mechanism (MP). The primary outcome was the proportion of individuals achieving a 50% improvement of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 12 weeks; logistic regression analysis models were used to determine the prognostic value of the nociceptive pain phenotype. Changes in continuous outcomes such as the Assessment of SpondyloArthritis International Society (ASAS) core outcome domains were analyzed using analysis of covariance (ANCOVA). Health-related quality of life (HR-QoL) was addressed using the Medical Outcomes Study SF-36. During a period of 22 months, 49 axSpA patients were included. Twenty (41%) had an NcP phenotype according to the PDQ score. BASDAI50 responses were reported by 40% (8/20) and 28% (8/29) NcP and MP groups, respectively. However, a prognostic value was not found in relation to the primary outcome . Across most of the secondary outcomes, axSpA NcP phenotype patients were reported having the most improvements in the HR-QoL measures. These data indicate the influence of personalized management strategies according to patients’ pain phenotypes for stratification of axSpA patients in randomized controlled trials. Axial spondyloarthritis (axSpA) includes both patients who have developed structural damage in the sacroiliac joints , also termed ankylosing spondylitis (AS)) and those without radiographic evidence of structural damage ) . CardinaOur primary objective was to compare the effect of initiating biological Disease-Modifying Antirheumatic Drugs (bDMARDs) on BASDAI50 responses after 12 weeks) in axSpA patients referred with high disease activity who have a nociceptive pain (NcP) profile at baseline, compared with those with a “mixed pain” profile. Our secondary objective was to estimate reported changes in core outcome domains of axSpA from baseline to follow-up according to pain phenotypes. Thirdly, we compared treatment impact on health-related quality of life (HR-QoL) in axSpA patients in terms of how the pain phenotypes differentially affect aspects of physical, mental and social wellbeing. Finally, we explored the association between the Harvey–Bradshaw Index (HBI)  weeks in and outcThe study was registered before patients were enrolled (NCT02948608). As prespecified in the protocol  and elabParticipants were recruited from the Department of Rheumatology, Odense University Hospital, Svendborg/Odense, and the Spine Centre of Southern Denmark, Hospital Lillebaelt, Denmark. We used the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for nr-axSpA (imaging arm)  and the ®, Orion Pharma, Espoo, Finland) (27). If treatment was not tolerated, it was stopped. Second-line therapy (for those switching bDMARD) during the study period was biosimilar Etanercept  administered at a dose of 50 mg subcutaneously every week. As part of clinical practice, patients were allowed to continue their conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) methotrexate and/or sulfasalazine. In accordance with the Danish guidelines for intervention strategy, patients could receive nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticoid injections if needed during the study.Tumor necrosis factor α inhibitors (TNFi) were initiated in accordance with the Danish National Treatment Guidelines developed by the Danish Council for the use of expensive hospital medicines (RADS). First-line TNFI during the study period was a biosimilar Infliximab  and comorbidity obtained by using the Charlson Comorbidity Index (CCI)  was obtaR.A.A. performed a clinical examination. The core domains set recommended by the ASAS/Outcome Measures in Rheumatology (OMERACT) including physical function, pain, spinal mobility, spinal stiffness, patient’s global assessment (PGA), peripheral joints/entheses, acute-phase reactants and fatigue were assessed at each study visit using the instruments explained below. At the follow-up visit, PROMs, a clinical examination and laboratory tests were obtained. Reasons for withdrawal of bDMARD were registered.The painDETECT questionnaire (PDQ) is a self-administered questionnaire that is completed at baseline to determine whether a neuropathic pain component (NeP) is present. The PDQ is composed of questions regarding pain intensity. It consists of three numeric rating scales (NRSs): a pain course pattern, a pain drawing reflecting pain radiation and seven questions addressing somatosensory phenomena . The scoThe Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used for the evaluation of patient disease activity . PhysicaSpinal mobility (SM) was addressed using the Bath Ankylosing Spondylitis Metrology Index. . PeripheTwo questionnaires regarding symptoms of inflammatory bowel disease (IBD) were used at baseline and follow-up: the Harvey–Bradshaw Activity Index (HBI)  and the The eye examination was performed 2–4 weeks after the baseline visit by an ophthalmologist in accordance with normal clinical practice in Denmark. The following symptoms of acute anterior uveitis were registered: pain, redness of the globe, photophobia and reduced visual acuity. Best-corrected visual acuity determined by Snellen, intraocular pressure, slit-lamp examination and dilated fundus examination were performed, and previous signs of anterior uveitis  were recorded. Ocular inflammation (if present) was graded according to the Standardization of Uveitis Nomenclature working group recommendations .Responses to treatment were primarily evaluated according to BASDAI responses. Secondary outcomes include achievement of clinically important improvements (defined as an improvement in the Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) of ≥1.1) and a major improvement (defined as ΔASDAS-CRP ≥ 2.0), as well as a change in core outcome domains.This project followed the EULAR recommendations for patient research partners (PRPs) in scientific research . The stuAs described in the original protocol  and the 2 statistic was used with χ2 approximation, with a two-sided significance level of 0.05 and a total sample size of 54 patients with axSpA, assuming that the proportion of patients with a high PDQ of 50% achieves a statistical power of at least 80% when the proportions having a BASDAI response are 15% and 50% higher versus the other PDQ category. Thus, we aimed to include 60 patients in total (anticipating 30 patients will have a PDQ > 13), corresponding to an approximate power of 84.3% when the proportions with a BASDAI response are 15% and 50%, respectively.For a comparison of two independent binomial proportions (high vs. other PDQ category), Pearson’s χp-values and 95% confidence intervals are two-sided. We did not apply explicit adjustments for multiplicity; instead, the results are interpreted with caution as exploratory findings in the context of multiplicity. The prognostic value of PDQ classification was examined by logistic regression models using STATA version 16 and presented as odds ratios (ORs) with the corresponding 95% confidence interval (CI). According to the SAP, the model was adjusted for age (in years), sex  and axSpA disease classification (r-axSpA or nr-axSpA).The characteristics of the participants were described for each pain profile: Nociceptive Pain (NcP) and “Mixed Pain” (MP) phenotypes defined by PDQ scores <13 and ≥13, respectively. For descriptive statistics, medians and interquartile ranges (IQRs) for continuous data and absolute numbers with corresponding percentages for binary outcomes are presented. For continuous outcomes, changes were adjusted for baseline value and compared using analysis of covariance (ANCOVA). The primary analyses were based on the Intention-to-Treat (ITT) population. In accordance with the ITT principle, all participants who signed the informed consent and with a PDQ evaluation at baseline were included in the analyses regardless of their subsequent adherence to the study protocol. Missing data were handled with a single-imputation (nonresponder) technique. All On an exploratory basis, we determined the association between HBI/SCCAI and outcome measures reflecting disease activity  by using Spearman’s rank correlation coefficients; for consistency in presentation, these were stratified on pain profiles as well.As illustrated in Baseline characteristics are described according to pain profile in Participants with a MP profile presented with worse BASDAI, BASFI, pain, VAS-global, SF-36 PCS, more tender joints and tender points compared at baseline, with those with pure NcP profiles who presented with higher calprotectin in plasma compared with participants with MP. No differences in demographics, medication, comorbidities and prevalence of HLA-B27 were observed. We did not find a statistically significant difference across the two PDQ classification groups in the prevalence of fibromyalgia. Only two patients were found to have signs of previous uveitis at the eye examination (posterior synechiae), and both were HLA-B27 positive. None of the examined showed signs or symptoms of active inflammation.p = 0.035).Changes in core outcome domains from baseline to follow-up did not differ significantly between pain profiles, with the exception of spinal mobility (SM), where the MP profile group reported better SM improvements compared with NcP (−1.3 (−1.6 to −0.9), Mean SF-36 domain scores for the enrolled axSpA patients are illustrated in The baseline HBI scores (ranging from 0 to 16+) were not associated with BASDAI, ASDAS-CRP, CRP or calprotectin for any of the pain profiles . IncreasIn our study, forty-one percent of axSpA patients presented with pure NcP. This was lower than previous studies of pain mechanisms in axSpA ,30. A DaWe anticipated that the response rate to bDMARD therapies would be different according to pain profiles. However, this was surprisingly not confirmed. At baseline, we found statistically significant differences across the two PDQ classification groups in BASDAI, BASFI, VAS-pain, VAS-global, tender joint count (TJC), tender point count (TPC) and SF-36-PCS. These variables have been shown to be associated with (or being a proxy for) widespread pain/NeP/fibromyalgia in axSpA ; therefoThe PDQ did not have a prognostic value in relation to BASDAI50 responses or change in ASDAS-CRP in the regression analyses. However, in light of the small sample size, it does not seem reasonable to reject any prognostic value of the PDQ. A positive PDQ score still attracts the clinician’s attention to the possibility of neuropathic pain component and encourages performing an adequate neurological examination and the consideration of further testing when needed. Although we could not do as such, a proportion of axSpA patients would possibly benefit from the management of non-nociceptive pain with targeted treatment. Further large-scale studies are needed to clarify the prognostic value of PDQ in axSpA patients.Our study confirms that HR-QoL is much reduced in patients with axSpA compared with Danish norms. An interesting observation from our data was that both baseline and follow-up patterns of HR-QoL appear different in each pain profile group, as illustrated by the spydergrams. The patients with a NcP profile reported the greatest improvement in all the domains compared with those with a MP component.The prevalence of sequelae of uveitis in our axSpA population was low. It may be the reflection of increasing awareness of the importance of early diagnosis and subsequent treatment of uveitis among axSpA patients. We did not find any association between baseline questionnaires regarding symptoms of IBD and measures reflecting axSpA disease activity. It was surprising that SCCAI was negatively correlated with fecal calprotectin levels in axSpA patients classified with pure NcP. We found differences between NcP and MP in p-calprotectin. Calprotectin is mainly expressed on leukocytes, in circulating neutrophils and monocytes and in the neutrophils and macrophages of inflamed tissue. In the presence of an ongoing cycle of inflammation, calprotectin levels are increased in plasma and synovial fluid. The level of p-calprotectin differs significantly between the two pain groups, which may reflect the burden of inflammation somehow might be higher in the NcP group.The main strength of this study was the prospective design with a prespecified protocol and statistical analysis plan. Thereby, outcome reporting bias was reduced. Another strength was the use of the ASAS/OMEARCT-endorsed outcome domains. A major concern using cohort study designs is the risk of confounding bias; unlike RCTs, where there is an unbiased distribution of confounding. A limitation of our study was the small study sample size, which restricted the possibility of investigating other potential confounders such as smoking, BMI, bionaive status and educational levels.Even though a mixed pain profile was present in nearly two-thirds of patients with axSpA in this consecutively sampled cohort, associated with worse BASDAI, BASFI, pain, VAS-global, SF-36 PCS levels, and more tender joints at enrolment, it did not have an impact on treatment responses. This could potentially be due to a type-2 error because the signal was there, with potential for personalized medicine, although without statistical power to detect the difference between groups likely because of the sample size. In other words, the PDQ score did not have a prognostic value in relation to achieving BASDAI50 responses or changes in ASDAS-CRP per se. However, further large-scale studies could potentially provide evidence for use of the pain phenotype as a screening model in clinical practice to identify axSpA patients with extra needs.


Chest pain indicating acute coronary syndrome (ACS) accounts for approximately 5-10% of presents in the emergency departments (EDs). Rapid decision making is very important because longer hospital stay is associated with higher financial burden. The aim of this study was to compare current practice with a 2-hour accelerated diagnostic protocol (ADP) to manage chest pain in patients suspected to have ACS.This is a longitudinal follow-up study on 900 patients with negative troponin measured on entrance to the ED and initially low-risk for myocardial infarction according to the emergency department of chest pain assessment score (EDACS) at the Loghman Hakim Hospital, Tehran, Iran in 2018. Patients were divided in two groups (based on odd or even days at admission time) at a ratio of 2:1 (i) current protocol with a second troponin measuring after 6 hours and (ii) ADP with a second troponin measured after 2 hours. Major adverse cardiac events (MACE) associated factors assessed in two groups over 30-days.Totally, the rate of return to EDs with the major adverse cardiac events was 4% (n=24) in the current protocol group and 1% (n=1) in the ADP group within 30 days. The odds ratio for MACE in 30 days in the current protocol was 4.3 times more than ADP group . In multivariable logistic regression analysis, this estimation for the current protocol was 4.10 times more than comparison group .A 2-hour ADP in patients at low-risk for myocardial infarction by EDACS had fewer adverse follow-up events than the current protocol. Acute coronary syndrome (ACS) is a term used to define a range of conditions associated with sudden reduced blood flow to the heart. ACS usually starts suddenly and symptoms include angina, tightness or burning, pain radiating from the chest to the shoulders, dyspnea or unexplained fatigue , 2. ACS Elevations of cTn in blood is used for differential diagnosis of unstable angina from myocardial infarction in people with chest pain or ACS , 6. DiagThe aim of the present study was to compare the use of an ADP with conventional diagnostic assessment in an Iranian emergency department setting. We assessed comparative safety by following low-risk patients with the recurrence of possible major adverse cardiac events for 30 days. This study was a single-center longitudinal following designed with convenience sampling method to compare two follow up pathways which include cardiac Troponin measurement in the current  vs. new  protocol for the diagnostic assessment of patients with positive cardiac chest pain. All patients with chest pain who had a negative troponin  test and normal echocardiography (ECG) result on arrival to the emergency department were eligible. The inclusion criteria were age over 18 years, chest pain, and neck, jaw or arm discomfort with unknown source. Exclusion criteria were ST segment elevation myocardial infarction (STEMI) present on any electrocardiograph (ECG), patients with proven or suspected non-coronary pathology as the cause of chest pain, patients who will require admission regardless of a negative cTn due to other medical conditions or need for other investigations, patient  unable or unwilling to provide informed consent. A total number of 967 patients with chest pain had no ECG change, so normal cTn test was presented in the emergency department of Loghman Hakim Hospital, Tehran, Iran in 2018. They were divided into two groups according to the odd and even days at admission time. Current and accelerated diagnostic (ADP) protocols with approximate ratio (640 patients in current and 327 in new protocol) to follow- up cTn test and ECG changes at two times of 2 and 6 hours after admission. Overall, 67 patients were excluded due to abnormal cTn or ECG changes at the 2 and 6 hours. The remaining patients (600 in current and 300 in new or ADP protocols) were followed up for 30 days recording return visits with symptoms of ACS. All 900 patients were examined by a physician and a clinical history was taken which included recording of risk factors for ACS: hypercholesterolemia, high blood pressure, diabetes, smoking, family history of cardiovascular disease, and history of heart attack. A clinical history was recorded which included the type of pain including whether it radiated to the shoulder and arm, was reproduced on palpation, was reproduced on inspiration, was associated with abnormal sweating (diaphoresis). An Emergency Department Assessment of Chest Pain Score (EDACS) was calculated for each patient . The ADPStatistical analysis. For the report of descriptive results, the mean, standard deviation and number and percentage were used. For data analysis, chi square and Fisher’s Exact also independent t-test and Mann-Whitney U test were used. To predict possible factors, related to the returning of patients within 30 days, multivariable logistic regression analysis was performed . As well as the hazard function curve for comparison of the effect of 2 diagnostic protocol on “return in 30 days” and flow chart of this study indicated. Total analysis executed by SPSS software Version19. There were 967 eligible patients of whom 67 were excluded resulting in 300 (33.3%) patients in the ADP group and 600 (66.7%) in the current protocol group. In this study, 303(50.5%) and 145(48.31%) of patients in current and ADP groups, were males. Chest pain was mostly seen in the 18-45-year group. Past medical history and the clinical manifestation are reported in Within each pathway there was no apparent difference between those with and without a Major Adverse Cardiac Event for any variable with the possible exception of age groups . ResultsIn this longitudinal follow-up study, patients with a new accelerated diagnostic protocol serial troponin measurement on arrival in the ED and 2 hours later discharge earlier with normal ECG and cTn fewer returned to the hospital with cardiac events during 30 days follow-up via phone. This statistical result was interesting to us. There is currently no universally accepted definition for ‘low-risk’ patient for ACS, but there are many options available. Some of these are high-sensitivity troponin assays. Troponin assays are still the most common tests for decision making of patients admitted with acute chest pain. When serial troponin sampling combine with ECG test, the detection sensitivity goes up and false negative decrease. Recently, a new method of patients with acute chest pain follow-up (0 and 2 hours CTn assays) has integrated into clinical practice in the whole of New Zealand (EDACS-ADP or ADAPT-ADP), Queensland, Australia (ADAPT-ADP), and three hospitals in North Carolina, USA (HEART-ADP). Amongst 19,803 patients assessed with EDACS-ADP or ADAPT-ADP and discharged as low-risk, there were no 30-d MACE events where the protocol had been correctly followed . In a stAnother study evaluated advanced and validated EDACS and the 2 hour rapid diagnostic protocol. 1974 and 608 trials approved, EDACS-ADP 42.2%  and 51.3%  classified as low-risk MACE, intraclass correlation coefficient for patients classified as a low risk it was 0.87. As a result, EDACS-ADP identified approximately half of patients admitted to emergency room with chest pain as having low risk of short-term high-sensitivity MACE, a similar improvement similar to that observed previously  regarded as possible low-risk using EDACS, the 2-hour ADP resulted in fewer patients with a follow-up MACE. It is most important that we can be confident, the ADP is at least as safe in patients with angina who did not feel chest pain at time of referral, ECG is usually normal unless there are other cardiovascular problems in the past. During periods of pain, falling or increase in the ST segment may be observed. To diagnose these changes, an ECG test may be requested. If the marked ECG changes are documented , angiography is considered for diagnosis. Even continuous monitoring of blood pressure and pulse can lead to conclusions about angina -12. In tIn patients with ECG changes, the most frequent changes were T invert and T tall changes in the current protocol and 2-hour protocol, respectively. In most patients, pain radiation in the shoulder and arm was seen as the main symptom of the disease. In the case of pain associated with shortness of breath and breathing exacerbation, the majority of patients in both groups were negative and around 78% of the patients did not show abnormal sweating. The most important of limitation in this study was following up via phone. Therefore, recall bias may happen. In conclusion overall, the results of this study showed that the recurrence in patients in a 30-day period was more common in current protocol than a 2-hour ADP protocol. This suggests that it would be safe to adopt the accelerated diagnostic protocol with EDACS in patients presenting with chest pain to Iranian emergency departments. This would reassure many patients much earlier that they are not having a myocardial infarction and would free up physicians and nurses to spend more time treating higher-risk patients.


Postlaparoscopic shoulder pain (PLSP) is a common clinical problem that needs to be addressed by medical professionals who are currently perform laparoscopic surgeries. The purpose of this study was to determine the perioperative clinical factors and demographic characteristics associated with PLSP. A prospective observational study was performed with 442 inpatients undergoing laparoscopic surgery for infertility. The pain visual analogue scale was used as the measuring instrument. To identify the predictors of PLSP, we performed multivariate conditional logistic regression. PLSP was correlated with body mass index . The incidence of shoulder pain and more severe shoulder pain in patients with a lower BMI was significantly higher than it was in patients with a higher BMI, and BMI was significantly negatively correlated with PLSP. Most of the patients (95%) began to experience shoulder pain on the first postoperative day, and it rarely occurred on the day of surgery. Patients with lower BMI presented a higher risk of reporting shoulder pain on the first postoperative day. We should identify high-risk patients in advance and make specific treatment plans according to the characteristics of their symptoms. The main reason is that laparoscopic-assisted surgery has the advantages of decreased postoperative pain8, earlier return of bowel function, lower morbidity and mortality, quicker postoperative recovery and early hospital discharge11.Laparoscopic-assisted surgery has largely replaced traditional open surgeryIn China, an increasing number of patients have chosen laparoscopic-assisted surgery for infertility assessment and treatment for various reasons in recent years. For patients with infertility undergoing laparoscopic-assisted surgery, the procedure aims to diagnose and solve specific causes of infertility. Most patients will be able to undergo pregnancy and childbirth after surgery. Therefore, in addition to the advantages mentioned above, the choice of laparoscopic-assisted surgery is largely due to the small abdominal incision, minimal scarring and the low incidence of abdominal adhesions, which is conducive to the subsequent pregnancy and delivery process.16. The reported incidence of PLSP varies (30%-90%) with different surgical methods and studies. Because there are so many patients undergoing laparoscopic surgery every year, even if we estimate the minimum rate of 30%, the number of patients with this clinical problem is quite alarming17. Similar to other types of laparoscopic surgery, PLSP is a problem that cannot be ignored in infertility patients after laparoscopic-assisted surgery20.Although the abdominal incision is small, unfortunately, many patients complain of postlaparoscopic shoulder pain (PLSP)12. In many cases, the degree of shoulder pain is far greater than that of the incision and internal organs. Most importantly, 72% of patients did not take any opioids to relieve their shoulder pain15. It has also been found that PLSP is less responsive to treatment than incision and visceral pain21. If we do not give effective treatment immediately, continuous pain will not only increase the discomfort of the patients but also may lead to an increase in the incidence of various postoperative complications and delayed rehabilitation, which will significantly increase the cost of care17. Furthermore, continuous pain will strongly reduce the satisfaction of the patients. All of these effects are contrary to the original intentions of performing laparoscopic assisted surgery. Therefore, PLSP is increasingly being recognized as a serious clinical problem.According to previous studies, PLSP can last up to 7 days, and sometimes more than 5 weeks22.The precise mechanism of PLSP has remained unclear until now. At present, most scholars believe that PLSP is associated with referred pain. The central diaphragmatic pleura and the mediastinal pleura are supplied by phrenic innervation (C3-5), while the supraclavicular nerve (C3-4) conducts sensory input from the acromium process. Pain occurs in the neck or scapula when the phrenic nerve is irritated32. Unfortunately, these intervention studies have often found quite varied and sometimes even conflicting results regarding the effectiveness of these interventions, including using drainage34, intraperitoneal instillation of local anesthetics37, pulmonary recruitment manoeuvre40, gasless laparoscopy43, warm and humidified dioxide46, low-pressure pneumoperitoneum47, intraperitoneal normal saline infusion49 and drugs preventatively or therapeutically51. However, few studies have attempted to identify the risk factors for PLSP52. The purpose of this study was to determine the risk factors for PLSP through observation.Many intervention clinical studies aimed at solving PLSP have been conductedThis study was conducted at the Affiliated Yantai Yuhuangding Hospital of Qingdao University from March 2016 to October 2017. It was approved by the clinical trial ethics committee of Yantai Yuhuangding Hospital of Qingdao University (2016–11) and was registered with the Chinese Clinical Trial Registry (ChiCTR-OOC-16008044). This clinical trial is consistent with the ethical principles of the Helsinki declaration. All patients volunteered to participate in the study and signed written informed consent before the trial.A total of 442 hospitalized patients undergoing elective laparoscopic surgery for infertility were included in this study. The exclusion criteria were chronic pain syndromes such as fibromyalgia or neck and shoulder pain, a history of long-term use of daily opioids, allergies to medications used in this study such as fentanyl, propofol, and midazolam, impaired cognitive function or inability to understand the study protocol, communication barriers, unstable cardiovascular disease and hypertension, central nervous system disease, endocrine system diseases, and liver or kidney dysfunction.During the preoperative visit, basic patient information was collected and recorded. The information included the patient's medical history, age, years of education, height, weight, waist circumference and hip circumference. Body mass index (BMI), waist-to-hip ratio, and waist-to-height ratio were calculated.2 pressure in the exhaled air (PetCO2) were recorded before and 15 min after the establishment of artificial pneumoperitoneum. Then, tidal volume and respiratory rate were adjusted according to the airway pressure and PetCO2. Ondansetron (8 mg) was administered intravenously by the anaesthesiologists to minimize postoperative nausea and vomiting when the surgeons began to close the umbilical trocar sites. Neuromuscular relaxation was reversed pharmacologically at the end of surgery with atropine and neostigmine.All patients received similar general anaesthetic and surgical regimens. No premedication was used. Heart rate, arterial blood pressure, and oxygen saturation were monitored in all patients upon arrival at the anaesthesia room. General anaesthesia was induced with midazolam (0.1 mg/kg), fentanyl (4 μg/kg) and propofol (1–2 mg/kg). Cisatracurium infusion (0.15 mg/kg) was used to facilitate tracheal intubation and obtain intraoperative muscle relaxation. Anaesthesia was maintained with oxygen in air (1:2), sevoflurane, propofol and remifentanil. All patients were ventilated with a volume-controlled ventilator . The airway plateau pressure, peak airway pressure and CO2 at 12 mmHg using a standard automated insufflator31. The insufflation gas was not heated or humidified with additional devices46. All operations were conducted by experienced laparoscopic surgeons  using the standard technique with one 10-mm and two 5-mm trocars. CO2 was evacuated at the end of the procedure by manual compression of the abdomen with open trocars21. All patients were kept for observation in the PACU until their condition stabilized before moving them to their designated wards.All patients were placed in the lithotomy and Trendelenburg positions during the operation. Laparoscopy was performed with abdominal insufflation of COThe following prophylactic analgesic standard treatment was used: intravenous propacetamol (1 g) was used approximately 20 min before the end of surgery, and either intravenous pentazocine (30 mg in the PACU) or oral ibuprofen sustained release capsules (300 mg in the ward) were administered on demand.The degree of pain was assessed at 6 h, 12 h, 24 h, 48 h and 72 h postoperatively before the patients left the PACU by a 10-cm visual analogue pain scale (0 = no pain to 10 = unbearable pain). We selected the highest value of shoulder pain score at each time point for statistical analysis. The patients were classified into two groups: the absence of shoulder pain  and shoulder pain (scores higher than zero).32. The formula was as follows:α = 1.96.The sample size was calculated on the basis of the expected incidence of PLSP derived from previous studiesThe estimated sample size for the survey was 368. An additional 20% of patients were recruited to overcome dropouts, refusals and exclusions. The study was completed with 442 patients.The patients were divided into shoulder pain group and absence shoulder pain group. Independent sample t test and Mann Whitney U test were used to compare the differences between the two groups. In order to evaluate the impact of each variable on PLSP, we used univariate binary logistic regression analysis. Then, the influencing factors of PLSP were included in the positive stepwise multiple regression analysis. The patients were divided into four groups according to the Asian BMI standard: group A (BMI < 18.5), group B (18.5 ≤ BMI < 23), group C (23 ≤ BMI < 30) and group D (BMI ≥ 30). The highest VAS score of shoulder pain within 72 h after the operation was compared. Independent-samples t-tests and Pearson’s chi-squared tests were used to compare variables between the groups. P < 0.05 was considered statistically significant. SPSS for Windows  was used for the statistical analyses.Fifty patients were excluded from this study. One case was converted to open surgery because of ovarian cancer detected during the operation, two cases underwent an emergency operation because of intra-abdominal haemorrhage after the laparoscopic operation, and 47 cases were treated by cauterization because of endometriosis found in the diaphragm and upper abdomen during the operation. Finally, 392 patients were included in the statistical analysis.peak1), peak airway pressure 15 min after pneumoperitoneum (P peak2) and the difference between them (P peak2-p peak1), airway plateau pressure before pneumoperitoneum (P platform1), airway plateau pressure 15 min after pneumoperitoneum (P platform 2) and the difference between them (P peak2-P peak1) of patients have influence on PLSP. However, the number of years in school, duration of surgery, duration of pneumoperitoneum, end-tidal carbon dioxide pressure before pneumoperitoneum (PetCO2)1 or 15 min after pneumoperitoneum (PetCO2)2, and the difference between (PetCO2)1 and (PetCO2)2 had no effect on PLSP. Stepwise positive regression analysis showed that BMI was an independent predictor of PLSP (OR = 0.815). The scatter plot of BMI and pain score showed that patients with low BMI were more likely to have shoulder pain after operation, and the degree of shoulder pain was also more severe. (Fig. The basic characteristics of the patients’ shoulder pain are shown in Table re. Fig. . There wum P peak and the re. Fig. .Table 1B53. This study found that BMI was negatively correlated with PLSP. When placing the patient in the Trendelenburg position, we could clearly observe the anatomical structures of the left and right lobes of the liver, the lower margin of the liver, the gallbladder and the diaphragm in thin patients. There is a large space in the upper abdomen. There may be a lot of gas trapped here after the operation. In obese patients, we can only observe the omentum since the rest of the anatomical structure is covered by the omentum, and the upper abdominal space is very small. Gas is unlikely to be retained here after surgery (Fig. 55. The volume of the residual pneumoperitoneum is positively correlated with the intensity of shoulder pain after laparoscopy56. This is one explanation for why PLSP is more common in thin patients.PLSP is generally considered to develop due to diaphragmatic irritation from direct injury or stretching of CO2 gasery Fig. . Previou57. In addition, PLSP is less responsive to analgesics than wound pain21. Proponents of pre-emptive analgesia believe that the most effective pre-emptive analgesia programmes are those that can limit the sensitization of the nervous system throughout the perioperative period59. Because the time characteristics of PLSP are different from abdominal pain58, if we do not consider the time characteristics of PLSP but treat PLSP according to the same plan used for the prevention and treatment of pain of the incision and viscera, the peak plasma concentration may not coincide with the peak PLSP. This may be one of the reasons why traditional interventions cannot effectively alleviate PLSP60.Our study found that PLSP in the vast majority of patients occurred on the first day after surgery. Previous studies have reported that after laparoscopic surgery, visceral pain predominates in the first 24 h but subsides from a peak soon after the operation, whereas shoulder pain, minor on the operative day, worsens and becomes significant on the following day15. For the management of PLSP, we can comply with existing methods but change their timing or duration of administration58. This requires us to identify high-risk patients in advance and develop specific programmes according to the time characteristics of their occurrence. These need further study.Predicting the postoperative pain and/or analgesic needs of individual patients as accurately as possible will help us tailor-made personalized postoperative analgesia methods for each patient, which will certainly reduce the occurrence of severe postoperative pain. Thus, patients undergoing so-called minor surgery should be monitored more closelyThe main limitation of our study is that we did not measure the amount of carbon dioxide left in the abdominal cavity. Therefore, the correlation between the amount of residual carbon dioxide in the abdominal cavity and the severity of pain, as well as its correlation with BMI, is not clear.PLSP was negatively correlated with BMI. The occurrence of PLSP has obvious specific time characteristics. The results of the present study suggest that a series of studies according to the above clinical characteristics are required to explore measures to prevent or minimize shoulder pain resulting from this now well-standardized surgical procedure.


Dear Editor,Neuropathic symptoms secondary to neuromas, following traumatic or iatrogenic causes, can significantly affect the quality of life and socioeconomic integration of patients . Many meThe use of synthetic nerve capping materials to limit pathophysiological axon regeneration have recently been developed to reduce the need for repeat surgeries. It is hypothesized that neural capping allows for epineural recovery within the device but reduces the regeneration of disorganized axons and formation of a bulbous mass that is susceptible to mechanical stimulation and painful adhesion to surrounding scar tissues . A recenp < 0.05). Intraoperatively, the neuromas were excised, and the nerve end placed into the NEUROCAP® and secured with non-resorbable sutures. The nerve and cap were then surrounded with and secured onto the surrounding soft tissues. Postoperatively, the VAS pain score reduced from 73.3 at baseline to 17.3 at 6 weeks follow-up. An international neuropathic pain score system (Douleur Neuropathique 4 or DN4) was reduced from 6.4 to 3.3 and neuroma pain score  reduced from 12.8 to 3.5. All pain scores remained similarly low throughout the 12 months follow-up . Patients with upper-limb peripheral symptomatic end-neuroma were enrolled between February 2016 and March 2017 at three Dutch hospitals. Inclusion and exclusion criteria are listed at ClinicalTrials.gov. A total of 10 patients met the inclusion criteria. Eight patients had an end-neuroma of the superficial radial nerve (SRN) and two of the median nerve. Preoperatively, the locations of the end-neuromas were confirmed by Tinel's test and a decrease in pain after lidocaine block, as demonstrated by a four-fold reduction in the visual analogue scale (VAS) for pain, from 80 to 20 (ollow-up . At 12 mollow-up .Figure Preoperatively, all patients used at least one type of painkillers. On average, the preoperative intensity of each type of neuropathic pain was moderate to severe and for one patient, the worst pain imaginable. After 6 weeks, only three patients required the continued use of painkillers, with the majority reported no pain or only pain of mild intensity. There were no adverse device-related effects, as assessed by an independent Data Safety Monitoring Board. One patient suffered an external trauma within 6 weeks postoperatively, resulting in a seroma, re-operation and removal of the NEUROCAP®. The patient continued follow-up until 3 months and decided to quit the study afterwards. At study exit, the patient had no neuropathic pain and his improved QuickDASH score remained. There were two neuroma recurrences involving the radial sensory nerve, one after an external trauma and the other with an unclear origin; both of which were treated conservatively. Other adverse events that occurred were anticipated and included postoperative pain and numbness of the operated area, inherent to the healing process and did not require intervention.Our results compared favourably with those of


Background: The temporomandibular joint is the one of the most important joints in the human body. It enables numerous orofacial functions such as mastication, swallowing, breathing, speech, emotional communication, and facial expressions. The aim of the study was to evaluate the prevalence of jaw functional limitations and oral behaviors with respect to general health status in patients with temporomandibular joint disorders—myofascial pain with referral.Materials and methods: The study group consisted of 50 individuals  with complete natural dentition. The average age was 23.36 years with ± 0.30 as a standard error. All subjects underwent clinical examination and were diagnosed with myofascial pain with referral according to the Diagnostic Criteria for Temporomandibular Disorders. The survey was conducted in connection with the Jaw Functional Limitation Scale-8 (JFLS-8), Jaw Functional Limitation Scale-20 (JFLS-20), Patient Health Questionnaire-4 (PHQ-4), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-15 (PHQ-15), and Oral Behaviors Checklist (OBC).Results: The most common functional problems in the entire study group were chewing tough food and yawning. In terms of gender, statistically significant differences were noted for chewing tough food and smiling . With respect to Bonferroni correction and Benjamini-Hochberg procedure, the observed differences were not statistically significant. There were no statistically considerable differences in mastication, mandibular mobility, verbal and emotional communication, or global limitations (p > 0.05). Over half (56%) of the respondents had depression of varying severity. Somatic symptoms of different severity were found in 78% of the patients, and 44% of the respondents declared anxiety disorders. The score of the Oral Behavior Checklist (OBC = 27.18) highlighted a high tendency for developing craniomandibular disorders.Conclusion: Patients with myofascial pain with referral, demonstrated a disturbed biopsychosocial profile. The restrictions in yawning and smiling as well as limitations in mastication, mobility, verbal and emotional communication, and global limitations appear to be significant predictors of craniomandibular dysfunction. Depression, stress, and somatic disorders are important factors predisposing patients to the occurrence of myofascial pain with referral. The progression of oral behaviors may indicate the role of somatosensory amplification. Currently, due to the growing number of affected people, temporomandibular disorders are becoming a special disease in the field of dentistry as well as an important public health problem. The prevalence of such conditions is more common among females than males –3. The sTemporomandibular disorders are dysfunctions of multifactorial nature, embedded in the biopsychosocial model –7. The bAccording to the American Academy of Orofacial Pain (AAOP), myofascial disorders of the craniofacial region are characterized by dull, local pain which is aggravated by movements of the mandible , 16–18. The aim of the study was to evaluate the prevalence of jaw functional limitations and oral behaviors with respect to general health status in patients with temporomandibular joint disorders—myofascial pain with referral.Considering that depression and anxiety are important components of biopsychosocial profile predisposing patients to the occurrence of myofascial pain with referral, it was hypothesized that at least one of the following variables—jaw functional limitations, somatization, anxiety and/or oral behavior–has a statistically significant relationship with depressive symptoms. It was also suggested that there will be statistically significant prediction of anxiety by jaw functional limitations, depression, somatization, and oral behavior.The study group consisted of 50 people  with complete natural dentition, who had been referred to the Department of Prosthodontics at the Medical University of Bialystok, Poland. The average age of the subjects was 23.36 years with ± 0.30 as a standard error. All of them underwent a clinical examination according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) (Axes I and II). The patients were diagnosed with myofascial pain with referral (Axis I of DC/TMD) .Craniofacial and/or craniomandibular pain of at least 8 points according to VAS ;Full natural dental arches ;Lack of orthodontic history or retention status over 36 months after the treatment completion.Trauma within the craniofacial and/or craniomandibular area;Surgical treatment within the craniofacial and/or craniomandibular region;Dental therapy supported by an occlusal splint;Prosthetic treatmentPhysioterapeutic rehabilitation within the craniofacial and/or craniomandibular region;Cases with possible health concerns affecting the function of the masticatory muscles;Metabolic diseases;Drugs.The above-mentioned subjects and sample size remain in accordance with the study group described in the previous publication , 22.The following questionnaires associated with jaw functional limitations, oral behaviors, anxiety, depression, and somatization were evaluated:Jaw Functional Limitation Scale-8 (JFLS-8)Jaw Functional Limitation Scale-20 (JFLS-20)Patient Health Questionnaire-4 (PHQ-4)Patient Health Questionnaire-9 (PHQ-9)Generalized Anxiety Disorder-7 (GAD-7)Patient Health Questionnaire-15 (PHQ-15)Oral Behaviors Checklist (OBC) .U-test was used to assess significant differences in the groups divided based on gender. A Pearson's chi-squared test of independence for a 2 × 2 contingency table was applied to compare categorical variables. In the case of small sample size, when the expected number of frequencies was below 5, a one-sided Fisher's exact test was used. All differences with p < 0.05 were considered statistically significant. For the one-sided Fisher's exact test, a post-hoc power analysis was conducted. Statistical power (1-β) was evaluated based on the calculation of the effect size, α and sample size (n). Additionally the sample size required to detect a statistically significant difference between females and males (at the 0.05 level) with a probability of 0.8 (80%) was determined.The Statsoft Statistica 13.3 software , G Power v.3.1.9.4 (Germany) and PQStat 1.8.2.  were used for statistical analyses. The arithmetic mean, median, and measures of differentiation involving standard deviation were calculated. The Mann–Whitney p-value), p = 0.05 was divided by the number of tests . To monitor the false discovery rate the Benjamini–Hochberg procedure was conducted.A multiple-comparison correction was performed. To monitor the family-wise error rate and receive the Bonferroni critical value . No interactions with JFLS-8, JFLS-20, OBC were present in any of these analyses. In the case of GAD-7 no statistically significant relationship with PHQ-15 was noted.The study was conducted upon obtaining the consent of the Bioethics Committee of the Medical University of Bialystok (decision No. R-I-002/322/2016). The research was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association (WMA) as well as the Guidelines for Good Clinical Practice (GCP). Participation in the study was voluntary. All the patients received comprehensive information about the nature, scope of clinical activities and course of the proceedings. Every patient consented in writing to participate in the study. The subjects had the right to withdraw from the experiment at any time without any resulting consequences.p = 0.015451; p = 0.035978, respectively)  . Slightlctively) . With rectively) .p > 0.05; The mean value of the mastication index was 1.93 points in the entire study group (JFLS-20) . In malep > 0.05; Limitations in mastication were found in 17 (34%) participants of the study, including 14 (38%) women and 3 (23%) men . Restricp > 0.05; In relation to PHQ-4, 29 (58%) of the respondents did not declare any health problems . Mild dip > 0.05; More than half (56%) of the respondents had symptoms of depression of varying severity (PHQ-9) . Its milp > 0.05; Low-severity somatic symptoms (PHQ-15) were noted in 21 (42%) subjects . Medium-p > 0.05; Anxiety disorders of varying severity (GAD-7) were declared by 22 (44%) respondents , among wR2 = 0.88422775), and the prediction model was significantly better than the random one , as in the former the average error in evaluating the level of PHQ-9 was SE = 1.5693  = 117.11; p < 0.00; R = 0.94033385] . Semipartial correlations confirmed weak link between GAD-7, PHQ-4 and PHQ-15 with PHQ-9 . The next fourth assumption about homoscedasticity was also met , and the prediction model was significantly better than the random one , as in the former the average error in evaluating the level of GAD-7 was SE = 1.7674  = 121.38; p < 0.00; R = 0.91531073]    and outcome variable (GAD-7) was fulfilled. The multiple regression equation was statistically significant [1531073] . The sec1531073] . The thi.773164) . Semiparctively) . The ploctively) . The nexctively) . The sixctively) . Due to p > 0.05; The Oral Behavior Checklist (OBC) revealed that the most common problem in the entire study group was sleeping in positions causing pressure on the mandible . The aveTemporomandibular disorders are connected with multiple clinical manifestations. They may lead to functional limitations of the masticatory system and/or psychosocial conditions including reduced quality of life . The mosIn the presented study, the main restriction was chewing tough food (JFLS-8) . NormatiInterestingly, the second major restriction in the entire study group was related to yawning . The yawThe lack of possibility of spontaneous yawning might lead to various clinical outcomes. Yawning includes the pandiculation of the masseter, temporal and pterygoid muscles and the prolonged contraction of the submandibular muscles . It is uIn the study on an animal model, Bertolucci suggested that pandiculation and yawning play a significant role in the autoregulation of the locomotor system . It meanBreathing while yawning leads to pressure variations within the ventricular system inside the brain . After eRestrictions of yawning and pandiculation could lead to disturbances in the clearance of somnogenic substances such as prostoglandin (PGD 2), thus intensifying sleepiness . In turnAnother significant problem in the presented study group was difficulty smiling (JFLS-8) . RychlowSmiling is connected with mirroring facial expressions and emotions. The mirror neuron system consists of neurons activated both when people perform certain specific motor actions and when they only recognize similar acts in others . It meanIn relation to JFLS-20, restrictions typical of TMD, i.e., concerning mastication, mandibular motion, emotional and verbal expression, as well as global limitations occurred in about or slightly over 40% of the respondents, respectively , 3. Ohrbr > 0.83) than for JFLS-8 (r > 0.68)  . The aut > 0.68) . Because > 0.68) . Ohrbach > 0.68) . However > 0.68) , althoug > 0.68) .It has been observed that the prevalence of depression in patients with chronic pain amounts to 30–54% , and thap = 0.02)  . Moreove = 0.02) . Xu et a = 0.02) . These r = 0.02) .Somatization, i.e., a tendency to perceive non-specific physical symptoms, corresponds to PHQ-15 , 63, 64.Reiter et al. stressed that depression symptoms are more pronounced in patients with chronic temporomandibular joint pain than in those with its acute phase . FurtherAll of the above-mentioned data indicate that most patients with a disturbed biopsychosocial component of Axis II of DC/TMD require interdisciplinary treatment. It appears advisable to implement cognitive and behavioral methods. Cognitive methods consist of the techniques of distraction, re-evaluation of thoughts, mindfulness, pros and cons, continuity, and daily record of success. Behavioral methods include breath control, relaxation, activity, behavioral changes and experiments, actions aimed at solving problems directly and pharmacology .Other important factors leading to temporomandibular disorders are parafunctions , 69. TheSome authors suggest that oral behaviors remain in a strong relationship with somatosensory amplification that involves hypervigilance of the body. It refers to the selective focus on experienced sensations and increased concentration on oneself , 73. ConThe temporomandibular joint is the one of the most important joints in the human body. It enables numerous orofacial functions such as mastication, swallowing, breathing, speech, emotional communication and facial expressions. Due to multiple potential causes of orofacial dysfunction, it is advisable to involve multidisciplinary treatment in the comprehensive evaluation and therapy of patients with temporomandibular disorders–myofascial pain with referral.Patients with myofascial pain with referral demonstrate a disturbed biopsychosocial profile manifested in a form of disorders of Axis II of DC/TMD. Restrictions in chewing tough food, yawning and smiling seem to be significant predictors of craniomandibular dysfunction. Myofascial pain with referral is connected with limitations in mastication, mobility, verbal and emotional communication as well as global limitations according to JFLS-20. Nearly 40% of patients with myofascial pain with referral suffer from jaw functional restrictions. Depression, stress and somatic disorders analyzed in relation to PHQ-4, PHQ-9, PHQ-15 and GAD-7 are important factors predisposing patients to myofascial pain with referral. The progression of oral behaviors may indicate the role of somatosensory amplification. Patients with myofascial pain with referral and an impaired biopsychosocial profile require multifaceted interdisciplinary treatment.All relevant data is contained within the article.The studies involving human participants were reviewed and approved by the Bioethics Committee of the Medical University of Bialystok, Poland (decision No. R-I-002/322/2016). The patients/participants provided their written informed consent to participate in this study.JK developed and planned the study. JK and KS conducted the research, contributed to sample preparation, and took the lead in writing the manuscript. MG contributed to the interpretation of the results and supervised the project. All authors discussed the results and contributed to the revision of the manuscript, read, and approved the submitted version.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.