Introduction: Mind body techniques such as meditation improve symptoms in children and adults with IBS. Typical courses, however, are lengthy and difficult to administer. We report our experience with a short course of Preksha Dhyana (PD), a child-friendly focused meditation with yoga.Method: Physicians deliver focused meditation while medical assistants taught yoga. Three sessions were administered biweekly with recommendations for daily practice. Pain severity Likert scores were compared with a treatment as usual (TAU) historical control. Anxiety scores were compared from baseline in the PD group.Results: Thirty PD patients aged 9–17  and 52 consecutive TAU group aged 5–17  were reviewed. The biweekly sessions had high (71%) completion rates. Utilization rates of PD were similar to TAU despite added sessions. The PD group had an average time of follow-up of 8.9 ± 9.4 vs. 6.0 ± 3.9 months in the TAU group (p = 0.522). Changes in pain scores from baseline showed improvement in the PD group, 0.67 ± 0.13 vs. TAU 1.39 ± 0.11 (p = 0.0003). In the PD group, anxiety scores improved significantly from baseline . Pain improved in 93% (28/30) and resolved in 47% (14/30).Conclusion: A short course of PD was successfully embedded in a busy pediatric office without additional staffing. The approach proved cost-effective without increasing overall healthcare utilization and showed significant benefits over TAU. Pending RCT confirmation, this offers a cost-effective method to incorporate mind–body techniques into a pediatric office practice. Functional abdominal pain disorders (FAPDs), including functional abdominal pain (FAP), irritable bowel syndrome (IBS), and functional dyspepsia (FD), are complex disorders characterized by chronic abdominal pain without organic or morphologic etiology. Functional bowel disorders are a common cause of illness-related absenteeism and substantially affect the quality of life .Children and adolescents with FAPDs are more likely to miss school, refrain from normative activities, require care, and exhibit psychological difficulties compared with healthy children , 3. It iFAPDs often overlap resulting in low sensitivity for questionnaire and classification . In ROMEasanas (body postures) and pranayama (prescribed breathing patterns). Yoga combined with meditation has the potential to impact a patient's physical and psychological health. Yoga is commonly practiced to reduce stress and pain . Prekshya Dhyana is the practice of meditation and breathing techniques with yoga used to improve one's perception. It has previously been shown to reduce stress, balance the autonomic nervous system, and increase attention possibly through DNA methylation and thus RNA expression . In ourA study conducted by Nyrop et al.  regardinThe use of complementary medicine has been rising due to low cost as well as lack of effectiveness of conventional medicine. Interestingly, other practices that have incorporated alternative medicine found that patients were practicing on their own prior to initiation of clinics and found success among patients and healthcare providers . In prevThis study does have limitations in being retrospective and lacking standardized questionnaires for anxiety and pain. However, the intent of the study was to see if our short intervention was cost-effective compared to those treated as usual in a busy clinical practice. Routine questionnaires for stress, anxiety, and depression were not part of the standard of care and so were not justified in this setting. Long-term use of techniques taught was not systematically followed as intended as many reported resolution of symptoms at the end of the intervention and did not need to return for follow-up. A follow-up telephone survey was not part of the IRB approved study but would have been helpful. Dietary counseling was provided to all patients with functional abdominal pain disorder, regardless of group, based on principles of following recommended dietary allowances. To what extent this was followed or played in symptom improvement between groups was not specifically evaluated. Medication use was slightly higher in the PD group, but not significantly so. This does support the use of the mind–body approach as complementary to TAU. However, we cannot exclude medication resulting in the improvement of pain and anxiety as opposed to PD.A prospective randomized study with age and gender matched of patients that are enrolled in IMC compared to TAU would provide more accurate information with regards to utility. In addition, the use of a validated questionnaire for diagnosis along with follow-up of clinical metrics such as pain and anxiety would give more complete comparison between groups, while careful logging of adherence to the recommendations would be important to measure.True cost was not obtained as it is difficult to estimate for patients, though overall visit numbers suggest that this was not increased in those participating in integrative medicine clinic.Despite the limitations, we were able to demonstrate a positive impact of the program and how a simple structure can be incorporated into a busy private practice.Preksha Dhyana into a busy private clinic as complementary care for patients that met the criteria for the spectrum of FAPD including IBS, with significant improvements shown in the patient's pain and anxiety. While further, more controlled studies are necessary to confirm the effects of a short course of meditation and yoga, this study provides a promising and feasible direction for future practice.We showed utility and feasibility in incorporating The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Orlando Health-Arnold Palmer Medical Center Institutional Review Board. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.DM devised the project, the main conceptual ideas, and proof outline. VM and AM wrote the manuscript in consultation with SP, NM, and DM. VM, AM, SP, LI, SR, BA, and DM worked on data entry. VM and DM performed calculations. All authors contributed to the article 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.


Background and Objectives: Chronic post-thoracotomy pain syndrome (PTPS) is a very common and uncomfortable complication, occurring frequently after thoracic operations, leading to the necessity of further medication and hospitalizations. One important risk factor in developing chronic pain is the chest closure technique, which can lead to chronic intercostal nerve damage. This study proposes an alternative nerve-sparring closure technique to standard peri-costal sutures, aimed toward minimizing the risk of chronic pain in selected patients. Materials and Methods: We performed a prospective randomized study on 311 patients operated for various thoracic pathology over a period of 12 months, evaluating incision types, chest closure technique, and number of drains with drainage duration. The patients were divided into three groups: peri-costal (PC), proposed extra-costal (EC), and simple (SC) suture, respectively. Pain was measured on day 1, 2, 5, 7, and at 6 months post-operatively using the Visual Analogic Scale. Results: No significant differences in pain level were recorded in the first two post-operative days between the PC and EC groups. However, a significant decrease in pain level was observed on day 5 and at 6 months post-operatively, with a mean level of 3.5 ± 1.8, 1.2 ± 1 for the EC group compared to a mean value of 5.3 ± 1.6, 3.2 ± 1.5, respectively. No significant differences were observed regarding other evaluated variables. Conclusions: The lower recorded pain scores in patients with extra-costal chest closure are a strong argument to use this technique. Its ease of use is similar to the classic peri-costal closure, and the time needed to perform it is not significantly increased. The association of this technique with less invasive procedures and short drainage duration limits chronic post-operative pain. This procedure may represent an option for decreasing healthcare costs associated with the management of PTPS. A surgeon has to deal over the course of his career not only with the specific pathology of his patients, but also with the management of pain. Thoracic incisions are known to be amongst the most painful surgical approaches, generating acute post-operative pain, but also chronic pain, with frequencies varying between 40% and 60% ,2,3. ThiThe most widespread thoracotomy closure technique is the placement of one or two peri-costal stitches, because it is a fast and easy technique . In mostThis paper describes an alternative thoracotomy closure technique intended to minimize chronic post-operative pain by minimizing pressure on the intercostal nerve, suited to close the chest in selected cases.For the purpose of this study, we included all patients that underwent a thoracic surgery procedure that required a thoracotomy, mini-thoracotomy, or video-assisted thoracic surgery (VATS) approach, admitted to our ward over a 12-month period. Patients who presented pre-operative pain at the procedure site, previous use of analgetic treatment up to one month pre-operatively, ipsilateral previous thoracotomy, ipsilateral shoulder pain, past history of rib fractures at thoracotomy site, psychiatric illness, or refusal to participate in the study were excluded from our study. All patients underwent various surgical procedures using the following approaches: axillar or posterolateral thoracotomy, axillar mini-thoracotomy, or VATS procedures. Major surgical procedures were performed through an open approach, whereas the VATS approach was indicated for diagnostic procedures, such as pleural lung or mediastinal biopsies and small wedge resections. In all cases the latissimus dorsi muscle was transected, with muscle sparring of the anterior serratus muscle. The intercostal muscles were carefully divided using the electrocautery just at 4 mm from the superior margin of the inferior rib, carefully, not to damage the intercostal vasculo-nervous bundle. Rib spreaders were used for patients with mini-thoracotomy or open thoracotomy, with gradual retraction to spear the rib. After completion of the procedure, one or two soft 24F chest tubes were placed, depending on estimated post-operative air leaks. The anesthesia procedure comprised of general anesthesia with selective oro-tracheal intubation. No local anesthesia was used. The post-operative pain for the patients included in this study was assessed and treated exclusively by the anesthesiology team. Pain was measured using VAS scale  recordedNo peri-operative epidural analgesia was used for any patients. The post-operative pain medication was standardized to all patients. Post-operative pain treatment consisted of 100 mg i.v. Ketoprofenum administered at 8 h, along with 10 mg/mL i.v. Acetaminophen if the patients had good liver function in the first 5 post-operative days. If the liver function was abnormal, due to associated pathology, Nefopamum 20 mg/mL was administered slowly i.v. three times/day, and if the recorded pain scores remained high the dose of nefopanum was increased up to a maximum value of 120 mg/day.We divided the patients into three groups: PC—peri-costal chest closure; EC—extra-costal chest closure; and SC—simple closure. Randomization was performed for patients undergoing open procedures with regard to type of closure (PC vs. EC), patients surgically treated through VATS approach underwent simple closure, being considered as the control group and, therefore, no randomization was performed in this group. Half the patients were operated on in 2019, then the study was interrupted because of the outbreak of SARS-CoV2 pandemic and was resumed in April 2020 when the special protocols and in-hospital circuits were established, and a normal surgical activity was resumed. The PC group comprised of patients who had their chest closed in a standard fashion by using sutures passed around the ribs, in a peri-costal way —left: twThe EC group of patients received chest closure through a novel stitching procedure using extra-costal sutures, a procedure that was introduced in our clinic to obtain less pressure on the intercostal space. The suturing technique comprises of the following steps: one peri-costal suture is passed through the middle of the incision and is used to approximate the ribs. This stitch is removed after placement of the extra-costal sutures, as shown in the figure below —right.We placed the extra-costal stitches from the back to the front of the incision with 1–1.5 cm spacing between stitches A,B, one The third group, SC (n = 90), benefitted by simple muscular sutures due to small incisions. All these patients underwent VATS procedures; thus, no rib retractor was used.The institutional review board of our university approved this study (No. 3880/4 February 2019), all patients were informed regarding the purpose of the study and written consent was obtained prior to surgery; refusal to participate lead to exclusion from our study. All 3 groups were blinded to what chest closure technique was used. A minimum of 80 patients/group was targeted to ensure significant differences between recorded pain and to prevent losing track of the patients in the follow-up period.p value of <0.05 was considered statistically significant.Statistical analysis was performed using SPSS software for Windows version 21 . Descriptive analysis of continuous data was presented as mean and standard deviation. Pearson’s chi square test, one- and two-way ANOVA tests were used for the assessment of correlation between evaluated groups. A A total of 311 patients were enrolled in this trial and divided into three groups depending on suture closing technique PC (n = 113), EC (n = 108), and SC (n = 90). Demographic data are summarized in There were no significant differences between the patients in group PC and EC, in terms of gender distribution, type of surgical procedure, or length of surgery. Only two deaths were recorded in the immediate post-operative period, both in the PC group, being unrelated to the chest closure type. No post-operative wound infection, bleeding or thoracic herniation was recorded for the study group.p < 0.001). On the 5th post-operative day, mean pain level for the PC group maintained at 5.3 ± 1.7, whereas for patients in the EC group mean value of VAS decreased to 3.5 ± 1.8. Lower values were recorded for both groups on the 7th post-operative day, however with a higher mean value in the PC group (4 ± 1.6) compared to that of EC patients (2.5 ± 1.7). In the SC group, considered as a control group, surgical approach was most commonly performed through VATS, these patients having significantly smaller incisions (max. 3 cm) compared to the other study groups, and thus recording significantly lower pain scores at all time points (p < 0.001). Regarding post-operative pain management, aside from standard pain medication, opioid treatment was reserved to patients (n = 45) with VAS scores higher than 8, until the recorded pain value went below 6. If the use of opioids did not have the estimated effect in pain relief, we applied local anesthesia to the thoracotomized intercostal space, and also to both spaces above and below the thoracotomy (n = 3).Post-operative pain level was assessed at day 1, 2, 5, 7, and at 6 months, respectively . No statp < 0.001). Patients with persistent high scores (>7 on VAS) at 6 months after surgery were evaluated through imaging studies to evaluate potential causes for the pain. Patients in the PC group presented on computed tomography scans with narrowing of the intercostal spaces and bony bridges, as shown in Pain levels at 6 months following surgery recorded significantly higher values in PC patients (3.2 ± 1.5) than those recorded in the EC group  and lengths, usage of rib retractors. It is known that rib fractures are associated with higher pain scores on the long term ,16. ThatHowever, not only the approach and procedure type planning are important, the chest closure has a key role in pain prevention . If the Our extra-costal closure is very easy to execute, requiring only a few minutes, and no further dissection being necessary, since the sutures are passed only in and out through the intercostal muscles, at distance from the intercostal nerves. Uniform placement of these stitches ensures an even distribution of pressure on the thoracotomized space and prevents lung herniation, making it possible to be used for even long thoracotomies, while the removal of the approximation wire relaxes it, keeping low pressure on the nerve. In our cohort we had no lung herniation. One downside of our closure is that careful division of the intercostals associated with soft material protection in the event rib spreader usage, in order to preserve intercostal muscle mass, are the key to ensure the technique’s success and efficiency in terms of pain. Any damage to the intercostal muscles could lead to impossibility of applying the extra-costal closure.We showed that extra-costal suture, if performed properly, minimizes pain scores at 6 months post-op., with a mean of 1.8 points versus the standard peri-costal technique.The patients in the SC group generated lower pain scores because the incisions used were smaller (max. 3 cm) and no rib retractors were placed. Additionally, for these patients the chest drain was placed in the same intercostal space used for the surgical procedure, thus eliminating compression of different nerves. Pain at 6 months, although of lower intensity was still present even is this group.Because pain is, by nature, subjective, and each individual has his own perception of pain intensity, it is a very difficult symptom to quantify. For this reason our study has been performed in only one department, using the same surgical teams, but, far more importantly, the same anesthesiology team, who managed all the patients in the first post-operative days. The surgical techniques used were standardized, with extra focus on the chest closure technique. Pain medication was uniform in all patients, to create similar post-operative conditions. The group selection was well matched and all the patients were blinded to the chest closure technique used.In spite of all this, we identified some very important limitations in our trial. One limitation is that in our attempt to make the pain objective we used pain scales, which provide subjective data recorded from the patients. We observed that many patients had difficulties in providing an exact number corresponding to pain from the pain scale and many patients with lower scores asked for pain medication, while others with higher scores were reluctant to use painkillers. Additionally, due to the fact that in our country the health system is under-financed, correlated with high cost of the endo-staplers and endoscopic consumables, the VATS techniques are very limited to diagnostic procedures, such as pleural biopsy, mediastinal lymph node biopsy, and the procedures with curative purpose were limited to wedge resections for benign disease—tuberculomas, emphysematous disease. Thus, including more ample surgical procedures in the VATS group was not possible and may determine to a certain degree bias in recorded pain values.Another possible limitation is the fact that the study had a gap caused by the SARS-CoV2 pandemic, which could have had an impact on pain data recorded from our patients, who might have reported lower pain scores to avoid direct prolonged contact with the personnel and to minimize in-hospital stay for fear of the virus.As we have shown, extra-costal suture of the chest is a reliable technique compared to the classic closure type. Although it is not appliable in all cases. The patients that are candidates for this technique must be selected carefully, and the surgery and post-operative plan must be established very clearly, in a personalized fashion.Our study shows that extra-costal closure has good results in terms of chronic pain, but the cohort had strict inclusion criteria. The day-to-day hospital activity brings in front of the thoracic surgeon many people, fundamentally different as individuals, exceeding the inclusion criteria of this study. Some patients have a history of anxiety, which has been proven to be associated with higher recorded pain scale values, so they would benefit well from this less painful closure type. Additionally, the patients’ anatomy is particular for each case, some of the patients have thick intercostal muscles, but many patients have debilitating diseases that lead to poor nutrition and therefore poor muscle quality. The extra-costal suture is a muscular suture as described in this paper, so poor muscle quality has a very high risk of developing intercostal muscle rupture and consequent lung herniation, although in our cohorts we recorded none such event. If rib fractures occur at thoracotomy after applying the retractor the recorded pain values are higher, because the pain is bone related rather than produced by nerve compression due to peri-costal sutures, so these patients do not benefit by the advantages provided by the extra-costal suture.So, the choice of the extra-costal closure must be tailored to each individual patient, taking into account educational and psychological factors, patient anatomy, surgery related incidents  that could make the surgeon change the surgical strategy “on-the-go”.In conclusion, the extra-costal chest closure is a cheap, easy and fast, safe and effective in reducing the apparition of chronic PTPS. This technique was initially designed for patients with small thoracotomies, but we have proven that it is safe to use even for longer incisions, if the patients anatomy allows it . The procedure’s success is proved by our study’s results and the multiple advantages with virtually no long-term complications, along with the possibility to apply it even in the case of long thoracotomies fully justifies its use. The choice of using this technique over the classic closure should be made for each patient in a personalized fashion, if there are no rib fractures when performing the thoracotomy.


ObjectivesEpiduroscopy is a minimally invasive procedure that is used in pain therapy to treat lumbar and root pain that is resistant to medical and infiltrative therapies. The indications for periduroscopy are partly shared with those of spinal cord stimulation (SCS): failed back surgery syndrome (FBSS) and stenosis of the vertebral canal in particular. The costs and risks of periduroscopy are considerably lower than those of SCS. The purpose of this study is to evaluate the clinical and economic advantages of integrating periduroscopy as a step prior to SCS for patients with severe lumbar or radicular pain that is unresponsive to pharmacological and infiltrative treatments.Materials and MethodsPatients were enrolled if they had FBSS and spinal stenosis with indications for SCS and accepted periduroscopy treatment before the possible SCS trial. Patients were followed up for 24 months with evaluations of clinical data on the day after the procedure and at one and 24 months. The pain trend, satisfaction with the periduroscopy procedure, and the incidence of SCS implants in the study period were analyzed.ResultsA total of 106 patients were enrolled. Immediately after the procedure and in the first month, the reduction of pain and the level of patient satisfaction were high, but they were drastically reduced at 24 months with a progressive reappearance of symptoms that substantially overlapped with the pre-surgery levels. At 24 months, 48% of the patients underwent a neurostimulation trial, and a significant percentage of them were able to avoid the implantation of an SCS.ConclusionsPeriduroscopy appears to be rational as a step prior to SCS in terms of the improvement of pain symptoms in the short term, the definitive results in a significant percentage of patients, and the significant economic savings for the health system. The story of epiduroscopy is one of intuition . It is tThe first endoscopic study of the spinal canal was made using arthroscopic equipment and vertebral columns removed from a cadaver, dating back to Burman  in the eEpiduroscopy is a minimally invasive technique that is useful for assessing the epidural space through a flexible instrument connected to an optical fiber. In addition to simple clinical evaluation, epiduroscopy allows for treatments such as the targeted delivery of drugs, debridement of adhesions, and reduction of inflammatory factors with copious lavage -7. Even Spinal cord stimulation (SCS) was first described and applied by Shealy  in the lSCS may evoke the release of serotonin and norepinephrine into the dorsal horn from descending fibers originating in the supraspinal pain-modulatory structures . Other cThe most common complication in SCS is hardware problems, which include electrode migrations and lead fracture . The mosAccording to the "Pain in Europe" study , up to 1The aim of this study is to determine whether epiduroscopy is capable of playing a significant role in the treatment regimen of severe lumbar pain that does not respond to standard medical therapies.This study was approved by the responsible ethics committee, and informed consent was acquired from all patients. We enrolled 106 patients with failed back surgery syndrome (FBSS) and stenosis of the canal. Patients were enrolled with the following inclusion criteria:- Age 18-85 years- Patients with FBSS and spinal stenosis- Able to sign an informed consent formThe following exclusion criteria were applied:- Patients with clinically unstable disease - Patients who have been diagnosed with severe neuropsychiatric disease and have received pharmacological treatment under constant medical supervision for which there is a contraindication for invasive treatments- History of vertebral fractures- Tumors or infections affecting the spine- Visual impairment - Chronic primary or secondary headache- Pregnancy- Coagulopathies (INR > 1. 5)Analgesic visit and follow-upThe patients underwent an antalgic visit before admission with an evaluation of the blood count, coagulation, ECG, and anesthesiological examination. Pain characteristics were assessed before the periduroscopic procedure, immediately after the procedure, at one month, and at 24 months using a questionnaire, in which the Numeric Rating Scale (NRS) and Global Perceived Effect (GPE) indices were analyzed. The NRS value was calculated by asking the patients about their minimum, average, and maximum intensity of pain during the day on a numerical scale of one to 10. The GPE value was calculated by asking patients to rate their pain relief compared to baseline as > 50%, between 30 and 50%, and < 30%. The costs incurred by the National Health Service (NHS) for the periduroscopic adhesiolysis procedure (LOA) and SCS were analyzed (costs in 2016-2018).PeriduroscopyAll the procedures were performed by a single operator who had experience with more than 80 procedures. The procedures were performed with the Resascope System , which is composed of a 10F adjustable epidural video-guided catheter with an external diameter of 3.3 mm, a length of 30 cm, and two channels. One channel is for saline infusion for washing the epidural space, thus improving visibility, and the other one is for the collection of the fluid. Three entry channels are used for the insertion of flexible fiber optics and other tools and have an internal diameter of 1.25 mm.DemographicsWe recruited 106 patients (41 men and 65 women) who underwent periduroscopic adhesiolysis and were diagnosed with FBSS (92 pcs) or canal stenosis (14 pcs). The median age was 57 years (range 30-80 years).Adverse events, screening failure, and dropoutDuring the procedure, three adverse events that led to stopping the procedure were recorded: retinal hemorrhage, significant peridural bleeding, and hemodynamic instability. During the first month, three patients were excluded from the study due to no longer fulfilling the inclusion and exclusion criteria. It was not possible to administer the questionnaire to six patients after the procedure, to 11 patients at the follow-up at one month, and to 25 patients at the follow-up at 24 months. Thus, there were 58 patients in the study at 24 months  of the 58 patients analyzed at 24 months benefited from the SCS implant. The data seem to suggest that the periduroscopic adhesiolysis procedure tends to be an effective intermediate treatment to distinguish cases of pain mixed with a more significant inflammatory component, where epiduroscopy would be more effective, as well as cases of mixed pain with a more significant neuropathic component, where SCS is the only effective therapeutic option.The cost per patient of the two procedures is significantly higher for SCS  than epiduroscopy  due to the high cost of the internal pulse generator (IPG) and device with the same length of hospitalization. Considering the 24-month follow-up with 58 patients, a therapeutic procedure that provides epiduroscopy plus the SCS implanted  would be more economical than a procedure that provides for the preventive implantation of SCS for all patients without epiduroscopy attempt before , with a total saving of € 305.106 .The critical number of dropouts poses limitations to our study at 24 months and caused a substantial dispersion of data. We cannot say whether the dropout patients sought new surgical interventions or other medical therapy. As the primary center for the region, we can most likely affirm that those patients did not move to other pain centers for SCS implantation, but we cannot be completely sure. Further studies are needed to identify predictive factors that can predict which of the two methods will be more effective and to evaluate what other treatments will be effective after 24 months in patients who do not undergo spinal cord stimulation and have a lower NRS and GPE at baseline.The use of periduroscopic adhesiolysis as an intermediate procedure before SCS and can be included in the treatment regimen of severe lumbar pain that is refractory to pharmacological treatments and to reduce the use of SCS implants to save resources for the NHS. The analgesic relief of the periduroscopic procedure tends to lose efficacy after 24 months, but an increase in SCS implants does not accompany this trend. Further studies are needed to determine predictive factors that are capable of predicting the best treatment for the clinical needs of individual patients.


Pain assessment in brain-injured patients in the intensive care unit (ICU) is challenging and existing scales may not be representative of behavioral reactions expressed by this specific group. This study aimed to validate the French-Canadian and English revised versions of the Critical-Care Pain Observation Tool (CPOT-Neuro) for brain-injured ICU patients.n = 226), and a second data set (n = 87) was obtained when a change in the level of consciousness (LOC) was observed after study enrollment. Three LOC groups were included: (a) unconscious ; (b) altered LOC (GCS 9–12); and (c) conscious (GCS 13–15).A prospective cohort study was conducted in three Canadian and one American sites. Patients with a traumatic or a non-traumatic brain injury were assessed with the CPOT-Neuro by trained raters  before, during, and after nociceptive procedures  and non-nociceptive procedures . Patients who were conscious and delirium-free were asked to provide their self-report of pain intensity (0–10). A first data set was completed for all participants (p < 0.001). CPOT-Neuro scores were not different across LOC groups. Moderate correlations between CPOT-Neuro and self-reported pain intensity scores were found at rest and during nociceptive procedures . CPOT-Neuro cut-off scores ≥ 2 and ≥ 3 were found to adequately classify mild to severe self-reported pain ≥ 1 and moderate to severe self-reported pain ≥ 5, respectively. Interrater reliability of raters’ CPOT-Neuro scores was supported with intraclass correlation coefficients > 0.69.Higher CPOT-Neuro scores were found during nociceptive procedures compared to rest and non-nociceptive procedures in both data sets (The CPOT-Neuro was found to be valid in this multi-site sample of brain-injured ICU patients at various LOC. Implementation studies are necessary to evaluate the tool’s performance in clinical practice.The online version contains supplementary material available at 10.1186/s13054-021-03561-1. Validation of behavioral pain scales in critically ill brain-injured patients in the intensive care unit (ICU) was identified as an area in need of future research in the 2013 clinical practice guidelines of the Society of Critical-Care Medicine , and the ability of CPOT-Neuro to detect self-reported pain in brain-injured ICU patients ;Ability of CPOT-Neuro scores to discriminate between non-nociceptive and nociceptive procedures, and when feasible, before and after opioid administration ;Agreement of CPOT-Neuro scores between trained research staff and ICU nurses (interrater reliability)The purpose of this study was to validate the use of the French-Canadian and English revised versions of the CPOT for brain-injured ICU patients: the CPOT-Neuro. Specific objectives were to examine the:A prospective cohort with repeated-measures design was used for this multicenter validation study. This design allowed the testing of the reliability and the validity of the French-Canadian and English versions of the CPOT-Neuro with the collection of data across several procedures and time points.This study was conducted in four neurotraumatology ICU settings across Canada  and the USA . One of these settings was a French-speaking one , one was bilingual , and two were English-speaking settings . These ICU facilities had similar capacity (22–30 beds) admitting 1000–1500 patients annually. Individualized prescriptions were used for pain management in all sites.We sought a heterogeneous population of brain-injured ICU patients as we aimed to validate the CPOT-Neuro to be generalizable for a diverse brain-injured population, rather than specific to patients with a single diagnosis. Accordingly, patients meeting the following inclusion criteria were eligible: (1) 18 years and older; (2) admitted for brain injury to the ICU for less than 4 weeks ; and (3) had a score ≥ 4 on the Glasgow Coma Scale (GCS: ). To redData collection was performed before and during non-nociceptive  and nociceptive  or using signs , and to rate their pain intensity using the 0–10 Faces Pain Thermometer (FPT) visual format . The patThe CPOT-Neuro is an adaptation of the original CPOT. The original tool  includesIn the adaptation process, each item and score of the original CPOT were reviewed in accordance with observational data of pain-related behaviors in brain-injured ICU patients , 18, 30.Modifications were made to all items of the tool. Scores of 0 remained unchanged for facial expression, body movements, muscle tension, compliance with the ventilator, and vocalization. For the facial expression item, the score of 1 was modified to only include brow lowering. Brow lowering was identified as a frequent reaction to a painful procedure in brain-injured ICU patients no matter their LOC , 18, andThe CPOT-Neuro was initially adapted in French-Canadian from the original CPOT French-Canadian version  and thenThe raters included 11 research staff and 36 ICU nurses. Research staff included 2 nursing researchers, 2 clinical research coordinators, 6 nursing research trainees, and one medical student. ICU nurses were mainly female (89%), held a college (33%) or a university degree (66%), and had an experience in the ICU ranging from 2 to 34 years (median = 8.00 [IQR = 5.25–16.75]). In one Canadian ICU, only research staff completed CPOT-Neuro assessments. In other ICUs, both research staff and ICU nurses completed CPOT-Neuro assessments.The raters were trained by the PI who is also the author of the CPOT/CPOT-Neuro (CG) employing a standardized training session based on the one used for the original CPOT . The traScreening of delirium) were asked the question “Do you have pain?”, and answer “yes or no” verbally or with other signs . Then, they were asked to rate their pain level with the 0–10 Faces Pain Thermometer (FPT) visual format. The FPT has been developed and tested in critically ill adults by the PI [r = 0.80–0.86 with a descriptive rating scale: [At each time point after the completion of the CPOT-Neuro, conscious patients who were able to self-report their pain and not delirious  and clinical data from the patient’s medical chart such as diagnosis, severity of illness (APACHE II score: ), neuroaPrior to data collection, delirium was screened in all conscious patients who were able to communicate verbally or use signs . Delirium can compromise the reliability of self-reports . TrainedThe sample size for this study was calculated based on the requirements for the evaluation of criterion validation using the reference standard measure of pain (patient self-reporting), and to include brain-injured ICU patients at various LOC which is representative of this population. Using MedCalc and G*Power for sample size estimation, a minimal sample size of 52 conscious patients able to self-report their pain was needed to obtain a moderate correlation of 0.50 as found in previous CPOT validation studies , 43, 44 p > 0.05 at all assessment time points, and skewness and kurtosis indices >  ± 2 [U tests were performed to compare CPOT-Neuro scores across analgesia/sedation regimen, medical diagnosis, and sedation level groups. Criterion validation was estimated using the Spearman’s rho correlation coefficient between the patients’ self-report of pain intensity and CPOT-Neuro scores. The Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the ability of the CPOT-Neuro to classify patients who self-reported the presence versus absence of pain and different pain intensity levels , and to determine the best cut-off score at these pain intensity levels. Discriminative validation of CPOT-Neuro scores across time points and procedures was examined using the Wilcoxon Signed Ranks test. Finally, interrater reliability between the research staff and ICU nurses was examined using the Intraclass Correlation Coefficient (ICC) (two-way mixed model). Missing data were not replaced. Data analyses were performed by a PhD-prepared health professional who was not involved in data collection.SPSS software (version 24.0) was used for data analysis. Descriptive statistics were calculated for socio-demographic and clinical data. Nonparametric tests were used given that variables were not normally distributed as supported by Kolmogorov–Smirnov and Shapiro–Wilk tests with s >  ± 2  for mostA total of 226 patients participated and had a first data set collected. Of these, 87 had a second data set collected when they experienced a change in their LOC during their ICU stay  and medical diagnosis . Similar results were obtained for the second data set, where 54% and 44% of patients did not receive analgesia/sedation, 37% and 40% received continuous analgesia and/or sedation, and only 9% and 15% had a bolus of analgesia within one hour before turning and other procedures, respectively. In addition, total CPOT-Neuro scores during turning and other nociceptive procedures were not different across analgesia/sedation regimen  and medical diagnosis .Regarding analgesia and sedation for the first data set, more than half of patients did not receive analgesia/sedation before the nociceptive procedures , some received continuous analgesia and/or sedation , and only 5% and 4% of patients had a bolus of analgesia/sedation within one hour before turning and other procedures, respectively. Total CPOT-Neuro scores during turning and other nociceptive procedures were not significantly different across analgesia/sedation regimen  when patients were at rest, post-administration of an opioid, and during non-nociceptive procedures such as NIBP and soft touch Table . At thesFrom those who were conscious, 52% could communicate but 19% of them screened positive for delirium and could not provide a reliable self-report of pain. CPOT-Neuro scores were compared with the pain intensity (Table p < 0.001) and other nociceptive procedures . At rest, CPOT-Neuro scores correlated significantly with self-reported pain intensity before turning  and before other nociceptive procedures .The CPOT-Neuro scores correlated moderately with self-reported pain intensity during turning  for the presence versus absence of pain (yes/no) during turning (n = 77). Sensitivity was 77% and specificity was 69% corresponding to a CPOT-Neuro cut-off score ≥ 2. The same cut-off score was obtained for the presence of pain during other nociceptive procedures (n = 30) with an AUC of 0.84 , and both sensitivity and specificity were 83%.The ROC curve analysis indicated an Area Under the Curve (AUC) of 0.76 , NIBP  and soft touch . After opioid administration, total CPOT-Neuro scores were significantly lower compared to before administration . Total scores were similar during turning and other nociceptive procedures . Total CPOT-Neuro scores were not significantly different across LOC, with medians of 3 in all 3 groups during turning and other nociceptive procedures . Similarly, total CPOT-Neuro scores were not statistically different across sedation levels. Medians were 3 during turning and other nociceptive procedures for most groups except for a median of 2 in the awake group during turning .For the first data set, total CPOT-Neuro scores were significantly higher during turning compared to rest . Again, total CPOT-Neuro scores were not different across LOC, with medians of 3 for all 3 groups during turning (n = 81) , and medians of 2.5 and 3 during other nociceptive procedures (n = 27)   in the altered LOC (n = 10) and conscious group (n = 17), respectively. In addition, total CPOT-Neuro scores during turning were not statistically different across sedation levels, with medians of 2 in the awake group (n = 18), 3 in the sedated group (n = 50), and 4 in the agitated group (n = 13) . Similar results were found during other nociceptive procedures, with medians of 2 in the sedated group (n = 15), 3 in the awake group (n = 6), and 3.5 in the agitated group (n = 6) .For the second data set, similar results were found, except for opioid administration, which could be assessed for only 11 patients . An ICC = 0.70  was found during other nociceptive procedures.The interrater reliability of CPOT-Neuro scores between the research staff and ICU nurses was highest during turning with an ICC = 0.76 : 0.68–0.82; This is the first validation study of the French-Canadian and English versions of the CPOT-Neuro. The findings supported the validity and the interrater reliability of the tool. This validation was conducted among a heterogeneous sample of brain-injured ICU patients with various LOC and RASS scores ranging from − 4 to + 3. More than half of our study sample were conscious patients and 44% presented an altered LOC or unconsciousness.Moderate positive correlations  were fouThe CPOT-Neuro could adequately classify patients who reported the presence of pain and various levels of pain intensity during nociceptive procedures. Overall, the performance of the CPOT-Neuro was better than reported for the original version of the CPOT in a previous study with brain-injured ICU patients (AUC = 0.72) . The CPOn = 15). The modifications made in the development process of the CPOT-Neuro allowed a better representation of behavioral reactions exhibited by brain-injured ICU patients [The CPOT-Neuro was able to discriminate between nociceptive and non-nociceptive procedures as well as prior to and post-administration of an opioid dose which is clinically relevant. Indeed, we expect from a pain tool to discriminate between painful and non-painful conditions and to detect decreases in pain scores following opioid administration. Regarding the CPOT-Neuro items, it is worth mentioning that the frequency of a score of 2 for facial expression was higher in the CPOT-Neuro (36–49%) compared to original version of the CPOT (12–22%) during nociceptive procedures , 11. Chopatients .The CPOT-Neuro scores were similar across LOC groups and sedation levels during nociceptive procedures. This is a strength of this revised tool compared to the use of the original version of the CPOT in brain-injured ICU patients. Indeed, previous studies reported low CPOT scores (< 2) during nociceptive procedures in unconscious or deeply sedated brain-injured ICU patients , 20, 26 Interrater reliability results were acceptable and met standards for reliability coefficients . ICC wasIn this study, we collected both CPOT-Neuro and self-reported pain scores for research purposes. The patient’s self-report of pain remains the reference standard measure of pain in those able to communicate in a reliable manner, and should be obtained whenever possible in clinical practice , 54. TheSeveral limitations must be addressed. Although we aimed for a heterogeneous sample of brain-injured ICU patients, those unconscious or agitated were less represented (< 20%) and further validation in these groups is required. It was not possible to blind raters to procedures leading to possible bias when scoring with the CPOT-Neuro during nociceptive procedures. However, the evaluation of interrater reliability allowed us to minimize this bias, and the data analyst was not involved in data collection. It was challenging to collect pain self-reports as more than half of conscious and awake patients had delirium or possible cognitive deficits related to their brain injury. Delirium can affect the capacity of an individual to communicate in a reliable manner, and self-reports of delirious patients were weakly (< 0.25) and non-significantly correlated to behavioral pain scores (with CPOT and BPS) in a previous study . TherefoThe French-Canadian and English versions of the CPOT-Neuro were found to be valid and reliable in this multi-site sample of brain-injured ICU patients at various LOC and levels of sedation. Indeed, the performance of the CPOT-Neuro appeared superior to the CPOT based on previous validation studies in brain-injured ICU patients. The feasibility of its use for validation purposes was described in a separate paper , but impAdditional file 1. Supplemental Material: French-Canadian and English versions of the CPOT-Neuro and Directives of Use


Background: Bertolotti syndrome is the association of lumbosacral transitional vertebrae and low back pain or sciatica. Lumbosacral transitional vertebrae are vertebrae with large transverse processes that (1) articulate or fuse with the sacrum or ilium and (2) have a caudal disc space. Bertolotti syndrome is relatively common, with an incidence of 4.6% to 7% in patients with low back pain. The exact etiology of Bertolotti syndrome remains uncertain, although several hypotheses have been proposed.Case Report: A 17-year-old male presented with a long history of low back pain refractory to conservative treatment including medications, activity modification, and physical therapy. Unilateral Bertolotti syndrome was suspected. The diagnosis was confirmed with bupivacaine injection at the transitional articulation. The patient was treated with surgical resection of his enlarged left-sided L5 transverse process, resulting in complete resolution of pain.Conclusion: Lumbosacral transitional vertebrae are relatively common, so Bertolotti syndrome should be on the list of differential diagnoses for low back pain. LSTV are relatively common, with an incidence of 4% to 30%.3 A transitional articulation with corresponding low back pain or sciatica has been termed Bertolotti syndrome. The incidence of Bertolotti syndrome in patients with low back pain is between 4.6% and 7%.4Mario Bertolotti first described the association of lumbosacral transitional vertebrae (LSTV) and low back pain in 1917.4 If left untreated, Bertolotti syndrome may adversely affect activities of daily living and recreational activities. Treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), physical therapy, injections, radiofrequency ablation, and surgery.Bertolotti syndrome can be challenging to diagnose given the numerous causes of low back pain. Adding to the difficulty of diagnosis, the exact etiology of how Bertolotti syndrome causes pain remains debated. Bertolotti syndrome can present at any age but typically presents in relatively younger patients.We present the case of a patient with Bertolotti syndrome and outline the successful surgical management of the condition.A 17-year-old male presented to the orthopedic clinic with a 2-year history of left-sided low back pain that he rated as 8 of 10 on the visual analog scale. Pain was most notable with twisting motions, such as hitting a baseball. The patient was initially seen by his pediatrician who referred him to an outside nonoperative orthopedic specialist 2 years prior to our presentation. Workup included radiographs and magnetic resonance imaging (MRI). Transitional anatomy was not mentioned at that time, and MRI was unremarkable. The patient was diagnosed with muscular strain as the etiology of his back pain. Conservative measures included a course of physical therapy, NSAIDs, muscle relaxers, and oral pain medications. Each of these treatments helped, but pain remained significant with activities. Activity modification was the most effective treatment, and the patient did not participate in sports. The patient subsequently moved and was seen by a new pediatrician. The new pediatrician referred the patient to our orthopedic clinic for treatment.On physical examination, the patient had a normal gait. The spine had normal range of motion and no global imbalance. Strength, sensation, and deep tendon reflexes were normal and symmetric to bilateral lower extremities. Pain was re-created with simultaneous lumbar extension and left lateral flexion. Plain film radiographs revealed an L5 vertebra with prominent transverse processes bilaterally, with the left transverse process articulating with the sacrum . MRI wit5 with the unilateral left transverse process articulating with the sacrum. Surgical treatments, including lumbar fusion vs transitional articulation resection, were discussed, and the patient elected resection.A diagnostic left transitional articulation injection of 10 mL of 0.5% bupivacaine under fluoroscopy provided complete pain relief for 8 hours. The diagnosis of Bertolotti syndrome secondary to transitional articulation was confirmed by the complete resolution of symptoms after the diagnostic bupivacaine injection. The Bertolotti syndrome was classified as type IIA under the Castellvi classification,Using a combination of rongeurs, a high-speed drill, and osteotomes, the left transitional articulation was resected under fluoroscopy. Approximately 7 mm of hypertrophic left transverse process was resected , which w6 Other authors believe that the transitional articulation between the transitional vertebra and the sacrum may limit motion and change the dynamics of the intervertebral discs adjacent to the transitional vertebra. Elster discovered that disc bulges were 9 times higher at the level immediately above the transitional vertebra.3 Aihara et al postulated that less degenerative changes occur below transitional vertebrae because the anomalous articulations restrict the motion between L5 and S1.7 Other authors do not believe that LSTV and back pain are associated.9 The controversy about etiology and even the existence of Bertolotti syndrome contributes to the difficulty in diagnosis.The exact etiology of Bertolotti syndrome remains debated. Some believe that the pain stems from degenerative and biomechanical changes at the transitional articulation.5 Type I defects have a large transverse process >19 mm. Type II defects have a diarthrodial joint between the transverse process and sacrum and/or ilium. Type III defects have bony union between the transverse process and sacrum and/or ilium. Type IV defects have a unilateral type II defect and contralateral type III defect. Types I, II, and III can be subdivided into subset A with a unilateral defect and subset B with bilateral defects. In a study of 841 patients with LSTV, Nardo et al found that types I (41.7%) and II (41.4%) were most common, and types III (11.5%) and IV (5.2%) were less common.10 Our patient had a type IIA transitional vertebra with a left-sided unilateral transverse process with articulation with the sacrum.Castellvi et al categorized transitional vertebrae based on the type of connection each vertebra had to the sacrum or ilium .5 Type I6 This broad differential diagnosis likely contributes to delayed or missed diagnoses. Delayed diagnoses likely adversely affect patients’ quality of life through pain and activity restrictions, as was the case for our patient. Workup typically starts with radiographs that demonstrate transitional anatomy. MRI may outline degenerative disc changes or disc herniations that may be more common in patients with Bertolotti syndrome than in patients without transitional anatomy.6 Computed tomography may identify stenosis and osteophytes.6 Anesthetics or steroids can be injected at the transitional articulation to both diagnose and treat the pain. Injections can help diagnosis by confirming transitional articulation as the site of pain, although no study has confirmed the prognostic value of injections.6 Because transitional articulation injections are relatively low-risk procedures, the authors’ opinion is that diagnostic injections should be strongly considered prior to surgical treatment. One factor that sparks consideration for Bertolotti syndrome is younger age. Quinlan et al found that patients with Bertolotti syndrome were typically younger  compared with patients with single-level disc degeneration  and multilevel disc degeneration  based on MRI findings.4Diagnosis of Bertolotti syndrome may be difficult. Differential diagnosis for back pain is broad and includes myofascial pain, sacroiliac pain, fracture (including spondylolysis), spondylolisthesis, scoliosis, disc degeneration/herniation, infection, and malignancy.6 Treatment options in the literature include conservative therapy, local injection, radiofrequency ablation, and surgery. Conservative therapy, including physical therapy and NSAIDs, is recommended initially.6 Injection can subsequently be used for diagnostic and therapeutic purposes. Almeida et al used radiofrequency ablation before surgical resection in 5 patients and found that 3 patients had only partial pain control.6 Two patients had significant improvement after radiofrequency ablation and were completely asymptomatic after surgical resection.6The optimal treatment for Bertolotti syndrome is still under investigation and remains debated.9 Postoperatively, 10 patients had improved low back pain, and 7 of the 10 had no back pain. The study findings suggest operative treatment for select patients with Bertolotti syndrome: (1) transitional articulation resection for patients with refractory chronic pain truly associated with the transitional joint and no disc degeneration and (2) posterolateral fusion for patients with degeneration in the disc below the transitional vertebra. Three of the 8 patients who underwent posterolateral fusion required repeat operations , and 3 of the 8 patients who underwent transitional articulation resection required repeat operations .9Surgical intervention, which can include resection of the transitional articulation or posterolateral fusion, may be considered after failure of conservative management. Santavirta et al studied 16 surgically treated patients; half received transitional articulation resection and half received posterolateral fusion.Because our patient failed nonoperative treatment, responded to a transitional articulation injection, and had no substantial disc degeneration noted on MRI, the senior author of this paper felt that transitional articulation resection was the best surgical treatment for the patient. Complications associated with surgical treatment include the risks of any spine surgery , continued pain, and reoperation.Bertolotti syndrome is the association of low back pain or sciatica and a lumbosacral transitional vertebra that articulates with the sacrum or ilium. The pain is postulated to be secondary to degenerative or biomechanical changes. Treatment for Bertolotti syndrome remains controversial. Surgical options include transitional articulation resection and/or posterolateral fusion, and optimal surgical treatment requires attention to each patient's unique pathologic anatomy. LSTV are a relatively common finding; therefore, Bertolotti syndrome should be on the list of differential diagnoses for low back pain.


Predicting acute postoperative pain based on presurgery physiological measures could provide valuable insights into individualized, effective analgesic strategies, thus helping improve the analgesic efficacy. Considering the strong correlation between pain perception and neural oscillations, we hypothesize that acute postoperative pain could be predicted by neural oscillations measured shortly before the surgery. Here, we explored the relationship between neural oscillations 2 hours before the thoracoscopic surgery and the subjective intensity of acute postoperative pain. The spectral power density of resting-state beta and gamma band oscillations at the frontocentral region was significantly different between patients with different levels of acute postoperative pain . A positive correlation was also observed between the spectral power density of resting-state beta and gamma band oscillations and subjective reports of postoperative pain. Then, we predicted the level of acute postoperative pain based on features of neural oscillations using machine learning techniques, which achieved a prediction accuracy of 92.54% and a correlation coefficient between the real pain intensities and the predicted pain intensities of 0.84. Altogether, the prediction of acute postoperative pain based on neural oscillations measured before the surgery is feasible and could meet the clinical needs in the future for better control of postoperative pain and other unwanted negative effects. The study was registered on the Clinical Trial Registry ( More than 230 million major surgeries are performed annually around the world . Even wiPain is a sensory and emotional experience with a high level of variability across different individuals . ImportaConsidering the strong correlation between pain perception and neural oscillations, we hypothesize that acute postoperative pain could be predicted by neural oscillations measured shortly before the surgery. In practice, this research aim could be achieved based on the combination of neuroimaging techniques to record neural oscillations and machine learning techniques , 20 to pHere, neural oscillations were measured using the EEG technique shortly before the surgery, for which the technique is clinically feasible in most situations as EEG can be used directly at the patients' bedside. The relationship between neural oscillations before the surgery and the subjective intensity of acute postoperative pain was quantified using spectral analysis and partial correlation analysis. Afterward, machine learning techniques were applied to predict the intensity of postoperative pain based on EEG recordings shortly before the surgery. Ideally, surgery patients with a high risk of postoperative pain could be identified before the surgery, which could provide a vital measure to optimize the analgesic strategy for better control of the postoperative pain and other negative outcomes.https://register.clinicaltrials.gov/) with the registration number NCT03761576.The clinical study was conducted at the Department of Anesthesiology of the Peking University People's Hospital, Beijing, China. The Medical Ethics Committee of the Peking University People's Hospital approved the study protocol. A written informed consent was obtained from all participants. The study was registered on the Clinical Trial Registry  age between 35 and 65 years, (2) education levels beyond secondary school, (3) American Society of Anesthesiologist (ASA) grade I-II, (4) preferred to use postoperative patient-controlled analgesia (PCA), and (5) signed informed consent. Exclusion criteria were (1) neurological diseases, (2) psychiatric diseases or psychiatric family history, (3) traumatic brain injury or postcraniotomy, (4) chronic pain suffers or preoperative opioid users, and (5) thoracotomy needed or planned to return to Intensive Care Unit after surgery. The detailed demographic information is summarized in st, 2nd, and 3rd days after the surgery was collected from all patients. Specifically, the highest postoperative pain over the past 24 hours was assessed on an 11-point numerical rating scale (NRS)  at 10-14 o'clock on the 1st and 2nd days after the surgery. On the 3rd day after the surgery, the highest postoperative pain over the past 24 hours was assessed using the same NRS, but after the chest analgesic tube was removed. Please note that the highest postoperative pain over the past 24 hours was obtained by the evaluation of pain at rest and pain due to movements, e.g., coughing and breathing. As recommended by Zalon in 2014 [rd day after the surgery were considered with moderate/high pain, while patients with NRS scores of 3 or lower than 3 were considered without low pain. All patients were examined by the same investigator, and all patients were reminded that they could withdraw from the experiment at any time for any reason, but none did so.As showed in  in 2014 , cliniciμg/kg). Then, rocuronium (0.6-1 mg/kg) was intubated with a double-lumen endotracheal tube, for which the position was confirmed by fiberoptic bronchoscopy. Anesthesia was maintained with 1% sevoflurane, propofol (0.1-0.3 μg/kg/min), and remifentanil (0.1–0.3 μg/kg/min) during the surgery. More sufentanil and rocuronium were supplied when needed, and the total amount of sufentanil should be no more than 0.6 μg/kg. Flurbiprofen axetil (100 mg) was started to be administrated 30 min before the end of the surgery. Along with the infusion of flurbiprofen axetil (8 mg/h), the patient-controlled analgesia (PCA) with oxycodone  was used for all patients as soon as they were able to operate the system.Please note that after EEG data collection, patients first received local anesthesia  and then received general anesthesia according to the local clinical standards to ensure the safety of the surgery. Patients received thoracic paravertebral block at T4 and T7 on the affected side with an infusion of 0.4% bupivacaine (20 ml) before general anesthesia. The induction of anesthesia was achieved using midazolam (0.02-0.04 mg/kg), propofol (1-2 mg/kg), and sufentanil . The NuAmps amplifier (Model 7181) was set with a sampling rate of 1000 Hz and with a signal bandpass filter from 0.01 to 100 Hz. The ground electrode was positioned 10 mm anterior to Fz, and the right mastoid electrode (M2) was used as the online reference. During EEG data collection , all subjects were instructed to keep awake, relaxed, and eyes closed, since the test-retest reliability of resting-state EEG data was higher in the eyes closed condition than in the eyes open condition [Patients lay in a bed with a semirecumbent position in a silent, temperature-controlled room. The EEG cap was mounted on their head with conducting gel inserted for each electrode, and all electrode impedances were kept lower than 10 kondition .p = 0.19). Moreover, epochs contaminated by gross artifacts  were automatically rejected. The proportion of epochs rejected was not significantly different between the low-pain and moderate/high-pain groups .EEG data were preprocessed using EEGLAB . Continut-test was performed for each frequency  and each electrode, and the significant level  was corrected using a false discovery rate (FDR) procedure [p value smaller than the defined threshold (pfdr < 0.05) for more than 5 Hz were considered as significant. Partial correlation analysis was also performed between EEG power at different frequency bands and acute postoperative pain  to assess their relationship while controlling for the effect of age and removing the possible outliers. Please note that the outliers were identified using the threshold of three standard deviations of EEG power, i.e., the data was identified as an outlier if its value was three standard deviations away from the mean [For each patient, the preprocessed EEG data were transformed to the frequency domain using Welch's method  , yieldinrocedure . Additiothe mean .N subjects) into N − 1 training subjects and 1 test subject, and the same procedure was repeatedly performed N times to ensure that every subject was used as the test subject once. The classification accuracy and correlation coefficient (R) between the real pain intensities and the predicted pain intensities were used to evaluate the prediction performance of LDA and MLR, respectively.We performed the linear discriminant analysis (LDA) , a typicTo assess the contribution of EEG feature at each electrode and each frequency on the prediction performance, the LDA and MLR were firstly performed for each electrode in the spatial domain and each frequency in the frequency domain. For both classification and regression, all EEG features were tested once, and the maximal values of prediction accuracy for classification and correlation coefficient for regression at the electrode level and the frequency level were, respectively, used to evaluate the contribution of these features in the machine learning model.To achieve better prediction performance, EEG features at all electrodes and all frequencies  were used in the multivariate machine learning model. In the present study, there were 160 features for each electrode (from 0.5 Hz to 80 Hz with a resolution of 0.5 Hz) and 30 electrodes. In total, the feature dimension was 4800 (160 frequency bins × 30 electrodes), and the sample size was 67 (67 patients). This is a typical small sample size pattern recognition problem with a high feature dimension. In this case, the curse of feature dimensionality is the main problem for both classification and regression. To address this issue, feature selection is required before performing prediction. In addition, feature selection is an effective strategy for dimension reduction to prevent overfitting. Here, we firstly shrunk the features in the frequency domain to the range of 20-70 Hz, since there was no significant difference between the two groups for all channels outside the frequency range . Secondly, Sequential Floating Forward Selection (SFFS) method was used as a wrapper approach for additional feature selection . As a het-test . Group differences in HADS scores , doses of oxycodone, and postoperative pain  were evaluated using independent-sample t-tests. All statistical analyses were carried out in SPSS 25.0 , and the statistical significance level was set at 0.05.Demographic information of patients in the moderate/high-pain group and the low-pain group was compared using chi-square tests  and an independent-sample rd day after the surgery, and 2 patients with postoperative infection . Moreover, data from 7 patients were excluded from the following analysis due to the poor quality of EEG data. As a result, 67 patients were eligible for inclusion. According to the postoperative pain on the 3rd day after the surgery, the eligible patients were assigned to the two groups: moderate/high-pain group (n = 33) and low-pain group (n = 34). As demonstrated in nd day after the surgery) were significantly higher for patients in the moderate/high-pain group than those in the low-pain group .We screened 84 patients undergoing thoracoscopic surgery for eligibility. As summarized in pfdr < 0.05). When taken separately, beta (14-30 Hz) and gamma (31-50 Hz) band powers in the moderate/high-pain group were both significantly higher than those in the low-pain group . To test the robustness of results, we also performed partial correlation analysis between EEG power at beta and gamma frequency bands and acute postoperative pain  while controlling for the effect of age and removing the possible outliers which lay three standard deviations away from the mean. Both beta band power  and gamma band power  were significantly correlated with acute postoperative pain . These results suggested that the combination of EEG features at the spatial and frequency domains would provide complementary information to achieve better prediction performance than any single EEG feature.To achieve better prediction performance, EEG features at all electrodes and all frequencies  were used in the multivariate machine learning model. The SFFS algorithm was stopped with 50 extracted features for both classification and regression. For classification, LDA with 50 features provided a prediction accuracy of 92.54% in the LOOCV test, i.e., 5 out of 67 patients have been misclassified. For regression, the MLR with 50 features also showed good prediction performance , i.e., trd day after the surgery. EEG data collected 2 hours before the surgery showed that patients in the moderate/high-pain group had significantly higher spectral power density of resting-state beta and gamma band oscillations at the frontocentral region than patients in the low-pain group  according to the subjective reports of pain intensity on the 3in group . In addiin group . Importard day after the surgery), for which the incidence of postoperative pain was similarly high in previous studies [nd day after the surgery between the moderate/high-pain group and the low-pain group. The inadequate management of postoperative pain calls for more effective analgesic strategies. Successful prediction of acute postoperative pain using physiological measures before the surgery would offer valuable information on who needs to be treated preemptively, thus paving the way for more effective and individualized analgesia.With the improved understanding of pain analgesic mechanisms, more and more analgesia techniques have been developed to manage postoperative pain –38. Alth studies –42. PleaIn the present study, the analysis of resting-state EEG data collected 2 hours before the surgery showed that the spectral power density of beta and gamma band oscillations at the frontocentral region was able to distinguish patients with different levels of acute postoperative pain. Additionally, the spectral power density of resting-state beta and gamma band oscillations was positively correlated with the subjective report of postoperative pain.A series of neural oscillations plays an important role in encoding pain perception for both healthy and disease conditions , 43–45. Gamma band oscillations, which are believed to play a crucial role in cortical integration and perception , 49, 51,Also, our results showed that pain-related beta and gamma band oscillations were mostly recorded from the frontocentral region. This is reminiscent of previous studies on acute and chronic pain , 12, 16.The relationship between neural oscillations and acute postoperative pain provided a solid basis for the prediction of postoperative pain with physiological measures before the surgery. The use of machine learning techniques  achieved a prediction accuracy of 92.54% and a correlation coefficient of 0.84 based on resting-state EEG activities that were recorded 2 hours before the surgery. Ideally, the combination of resting-state EEG recording technique and machine learning algorithms would yield diagnostic biomarkers of acute postoperative pain. This diagnostic biomarker would be important for the development of effective analgesic strategies in the perioperative period, which would be helpful in controlling postoperative pain in surgery patients , 22, 53.Several additional limitations in the present study should be noted. First, the current clinical experimental design would possibly be confounded by some unwanted factors. Although a standardized operative procedure was adopted for all patients, there were some variations during the surgery , which might also affect the acute postoperative pain. Second, the sample size of the present study is limited, and the age, the educational level, and the type of surgery varied a lot among subjects. In addition, more patients scheduled for other types of surgery should be considered in future studies to verify the identified EEG-based biomarker of postoperative pain. Third, this study did not testify the specificity of EEG oscillations to acute pain. Some studies suggest that gamma oscillations selectively encode phasic and tonic thermal pain , 16, butIn conclusion, we provided solid evidence for the close relationship between the spectral power density of resting-state beta and gamma band oscillations at the frontocentral region and subjective reports of postoperative pain. Moreover, we predicted the level of acute postoperative pain based on features of neural oscillations using machine learning techniques, which achieved a prediction accuracy of 92.54% and a correlation coefficient between the real pain intensities and the predicted pain intensities of 0.84. Therefore, the prediction of acute postoperative pain based on neural oscillations measured before the surgery is feasible and could hopefully meet the clinical needs in the future, thus helping optimize the analgesic strategy for better control of postoperative pain and other unwanted negative effects.


This study aimed to investigate the influential factors of postoperative pain trajectories and morphine consumption after hepatic cancer surgery with a particular interest in multimodal analgesia.Patients receiving hepatic cancer surgery at a tertiary medical center were enrolled between 2011 and 2016. Postoperative pain scores and potentially influential factors like patient characteristics and the analgesic used were collected. Latent curve analysis was conducted to investigate predictors of postoperative pain trajectories and a linear regression model was used to explore factors associated with postoperative morphine consumption.P < 0.001) but reduced morphine demand was noted in the elderly (P < 0.001) and standing acetaminophen users (P = 0.003). Longer anesthesia time was associated with higher baseline pain levels (P < 0.001). In contrast, male gender (P < 0.001) and standing non-steroidal anti-inflammatory drugs (NSAIDs) use (P = 0.012) were associated with faster pain resolution over time.450 patients were collected, the daily pain scores during the first postoperative week ranged from 2.0 to 3.0 on average. Male and higher body weight were associated with more morphine consumption (both Multimodal analgesia with standing acetaminophen and NSAIDs had benefits of opioid-sparing and faster pain resolution, respectively, to patients receiving hepatic cancer surgery. Hepatocellular carcinoma (HCC), the most frequent primary liver cancer, often derives from chronic liver disease . AlthougMultimodal analgesia is the concept of combining different analgesic modalities that work through different mechanisms of action to achieve better pain relief while reducing opioid consumption as well as drug-related adverse effects –8. SinceIn order to investigate the influential factors of postoperative pain trajectories in patients with hepatic cancer surgery, we conducted this retrospective study and employed latent curve analysis to explore factors associated with the variations in postoperative pain trajectories over time. We hypothesized that the use of multimodal analgesics, along with other patient characteristics and surgical features, would modify the postoperative pain trajectories over time and reduce opioid consumption. Furthermore, the final predictive models which best accounted for the changes in postoperative pain trajectories over time, opioid consumption, and length of hospital stay after hepatic cancer surgery would also be determined after the model selection processes.After the approval of the Institutional Review Board of Taipei Veterans General Hospital, (IRB-TPEVGH No. 2019-07-004BC), we conducted this retrospective study in our hospital and the inclusion criteria were patients undergoing curative surgery for stage I-III hepatocellular carcinoma with postoperative intravenous patient-controlled analgesia (IVPCA) between March 2011 and December 2016. The exclusion criteria were repeat surgery, liver transplantation for HCC, or distant metastasis diagnosed at the time of surgery. All data were extracted from our electronic medical record system by an anesthesiologist not involved in statistical analysis. Data quality was verified through random sampling by the authors.via an infusion pump  to deliver morphine with a bolus dose of 0.8–1.2 mg and a lockout interval of 6 min and typically continued for about 3 days after surgery. Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) might also be used for postoperative pain relief during the course of IVPCA or after the end of the IVPCA course on the 4th postoperative day.In brief, liver cancer surgery was performed under general anesthesia with inhalation agents and neuromuscular blocking. Intravenous fentanyl 2–4 ug/kg was also given at the induction of general anesthesia and no other analgesics were used intra-operatively. IVPCA was administered after surgery The primary endpoint was postoperative pain scores evaluated using a self-report numerical rating scale (NRS) from 0 to 10, with 10 being the maximum imaginable pain and 0 indicating no pain at all, by nurses in charge at least one time per day after surgery. In this study, the mean daily NRS pain scores during the first postoperative week were collected and employed in the subsequent analyses. The secondary endpoints were morphine consumption during the first three postoperative days and length of hospital stay (LOS) after surgery. Other collected variables included comorbidities, severity of liver cirrhosis, serum aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Besides, surgical features such as blood loss (log-transformed), perioperative transfusion , uses of laparoscopic or robot-assisted techniques, and anesthesia time (log-transformed) were gathered as well.Patient attributes and pain scores are presented as mean with SD or count with percentage as appropriate. Right-skewed continuous variables like surgical blood loss and anesthesia time were log-transformed. Latent curve analysis with two parameters, intercept and slope, for baseline and decreasing trend of postoperative pain trajectories, respectively, was performed to evaluate how analgesic modalities and patient characteristics affected the variations in pain scores over time. A backward model selection strategy was used to identify explanatory variables of the intercept and slope parameters and determine the final multiple predictors model. The details of statistical technique on latent curve analysis refer to the previous literature . The rooA total of 450 patients undergoing liver cancer surgery were included in the analysis and their characteristics are presented in The results of the univariate analysis using the single predictor latent curve model are presented in With respect to the explanatory model of morphine consumption during the first three postoperative days, four predictors were identified after the model selection in In the present study, latent curve analysis was applied to model the longitudinal data of postoperative pain scores in patients receiving hepatic cancer surgery with IVPCA, and the potentially influential factors of postoperative pain trajectory were also investigated. We demonstrated that acetaminophen reduced morphine consumption during the postoperative period, whereas NSAIDs hasten pain resolution over time. When investigating the efficacy between different types of non-opioid analgesics, most studies took 24-h total morphine consumption as the primary outcome –17. UponContemporary pain management is committed to finding the best combination regimens of non-opioid analgesics as opioid-sparing strategies, yet no well-established “gold standards” for specific procedures exist currently . Prior mOur study demonstrated that older patients tended to consume less morphine but aging neither affected baseline pain level nor hasten pain resolution. Prior reports showed that older age had lower pain sensitivity and better pain resolution from analgesics compared with their younger counterparts –26, compSome studies have addressed the relationship between body weight and postoperative pain intensity, as well as analgesic consumption, and the conclusions were conflicting . Our stuSeveral predictors of LOS after hepatic cancer surgery were identified in the current study. Among them, laparoscopic or robotic surgery showed the strongest tendency (18%) to decrease LOS after hepatic cancer surgery. The result was supported by other studies, including large-scale meta-analyses , 30. On There were some limitations to the present study. First, this was an observational study and it was not possible to assess the effects of unobserved variables like preoperative pain scores, chronic analgesic medications, psychologic distress, and so on. Uncollected factors like physician preference might also be associated with the use of standing NSAIDs or acetaminophen and should be considered in future studies. Second, the study was conducted at a single medical center and the generalizability of our findings awaits further investigations. Third, the evaluation of adverse events related to multimodal analgesias, such as nausea, vomiting, sedation, gastrointestinal bleeding, and pruritus , 36 was In conclusion, standing acetaminophen and NSAIDs had benefits of opioid-sparing and faster pain resolution, respectively, to patients receiving hepatic cancer surgery with IVPCA. However, their uses were not associated with LOS after hepatic cancer surgery. Latent curve analysis provided valuable information about the variations in postoperative pain trajectories over time and their influential factors. Future studies should further explore the relationships between more explanatory variables and dynamic changes in postoperative pain trajectories over time and elucidate their underlying mechanisms.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Institutional Review Board of Taipei Veterans General Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.C-YY contributed to data acquisition and manuscript drafting. W-KC contributed to data validation and draft preparation. H-LW contributed to study coordination and data acquisition. G-YC helped review and revise the manuscript. Y-HT contributed to data acquisition. K-YC contributed to conceptualization, statistical analysis, and manuscript revision. All authors have read and agreed to the published version of the manuscript.This research was funded by Taipei Veterans General Hospital (V109C-063), Anesthesiology Research and Development Foundation, Taipei, Taiwan (ARDF10902), Yen Tjing Ling Medical Foundation, Taipei, Taiwan (CI-109-29), and Ministry of Science and Technology, Taipei, Taiwan, R.O.C. (MOST109-2511-H-075-003-MY2).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. 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Although TRPA1 could be a target for pain treatment in CRPS patients, we also discuss the paradoxical situation in this review. Nociceptor activation decreases the risk of bone destruction via CGRP secretion from free nerve endings. Thus, TRPA1 inhibition could cause severe bone atrophy. However, the suitable therapeutic strategy is controversial because the pathologic mechanisms of bone atrophy in CRPS are unclear. Therefore, we propose focusing on the remission of abnormal bone turnover observed in CRPS using a recently developed concept: senso-immunology.Complex regional pain syndrome (CRPS) is a chronic pain syndrome that occurs in tissue injuries as the result of surgery, trauma, or ischemia. The clinical features of this severely painful condition include redness and swelling of the affected skin. Intriguingly, it was recently suggested that transient receptor potential ankyrin 1 (TRPA1) is involved in chronic post-ischemia pain, a CRPS model. TRPA1 is a non-selective cation channel expressed in calcitonin gene-related peptide (CGRP)-positive primary nociceptors that becomes highly activated in ischemic conditions, leading to the generation of pain. In this review, we summarize the history of TRPA1 and its involvement in pain sensation, inflammation, and CRPS. Furthermore, bone atrophy is also thought to be a characteristic clinical sign of CRPS. The altered bone microstructure of CRPS patients is thought to be caused by aggravated bone resorption  Complex regional pain syndrome (CRPS) is a chronic pain disease triggered by an inciting injury, such as fracture or surgery, affecting nearly 26 people per million worldwide . CRPS geThe first case report of a patient suspected to have CRPS occurred in the 16th century when Ambroise Pare noted that King Charles IX of France was suffering from severe arm pain after bloodletting . In 1864Various epidemiologic studies of CRPS have been conducted. The first report was by Sandroni et al. in 2003 , and altCRPS can be triggered by fractures of the upper limbs, especially in the forearm . When CRCRPS patients present with various symptoms, including severe pain in the affected limb, sensory disturbance, autonomic dysfunction, motor malfunction, skin atrophy with a hot or cold temperature, and localized bone atrophy. The characteristic symptom in the early stage of the disease is an intense burning or throbbing pain in the affected limb  that is CRPS symptoms are exacerbated by movement, contact, environmental temperature changes, and psychological stress and sometimes become intense at night , 12. MotAlthough the precise mechanism of CRPS development remains unelucidated, the most widely accepted etiology is a combination of various factors, such as tissue inflammation, the neuroimmunologic response, sensitization of the nociceptive nervous system, and autonomic dysfunction, which are triggered by the inciting trauma. It has also been suggested that genetic tendencies and psychological state influence CRPS development.An immune response is considered the basis for CRPS development Table 1.Interaction between nociceptive neurons and the sympathetic nervous system in CRPS patients has been suggested because pain is intensified following sympathetic nerve stimulation . This inThe continual firing of peripheral nociceptive neurons enhances the efficiency of the synaptic transmission of nociceptive stimuli in the dorsal horn of the spinal cord . NeuropeThe association of specific genotypes with CRPS has been explored, and one case-control study reported that human leukocyte antigen subtype DQ1 was highly expressed in patients with CRPS type 1 . FurtherIt is believed that disruption of the psychological stress response triggers the CRPS development. Patients who already have post-traumatic stress disorder are more likely to develop CRPS . Severe There is no “gold standard” test to diagnose CRPS, and clinical diagnosis is made by identifying signs of the disease from the patient’s medical history and performing a physical examination. The first diagnostic criteria were presented in 1994 by the International Association for the Study of Pain . HoweverVarious examination techniques are used to assist in CRPS diagnosis. Thermography is commonly used, and changes in skin temperature are one of the CRPS severity score criteria . A diffeThe current therapeutic strategy for CRPS is a combination of physiotherapy, occupational therapy, psychotherapy, neuropathic pain medication, anti-inflammatory agents, and interventional treatment , 44, 45.CRPS treatment guidelines recommend a multifaceted approach that includes physical therapy, occupational therapy, and psychotherapy . Due to Graded motor imagery proceeds in three stages. In the first stage, the patient recognizes the left and right limbs by looking at pictures. In the second stage, the patient imagines the movement of the limb position shown in the pictures. In the third stage, the patient observes the limb position and movement of the healthy limb reflected in a mirror to give the illusion of moving the affected limb . A gradeCRPS pain induces catastrophic thinking, and patients avoid using the affected limb. Therefore, treatments that assist in coping with pain through psychotherapy, such as relaxation training, thermal biofeedback, and graded exposure therapy, are also effective . PhysicaNeuropathic pain medication is used to improve the neurologic symptoms of CRPS . GabapenAlthough local inflammation or neuroinflammation is associated with CRPS onset and chronicity in the early stage of CRPS, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to reduce CRPS symptoms is ineffective . NSAIDs A sympathetic nerve block is commonly used to treat patients with CRPS. A lumbar sympathetic nerve block is performed in patients with CRPS in the lower limbs, and a stellate ganglion block is performed in patients with CRPS in the upper limbs. However, the conclusion of a Cochrane review of the effectiveness of a sympathetic block for CRPS was controversial because it was determined neither effective nor ineffective due to the overall low level of evidence . FurtherSCS is an interventional technique that electrically stimulates the dorsal horn of the spinal cord . An elecDRG stimulation is a relatively new technology that followed SCS. It electrically stimulates the DRG, which is an aggregate of afferent nerve cell bodies. A series of cases suggested the efficacy of DRG stimulation in CRPS patients . The ACCTRPA1 is a non-selective cation channel that belongs to the TRP superfamily , 68 and 2O2) and nitric oxide (NO) into the tissue. These endogenous substances are generated during ischemia, and the released H2O2 activates TRPA1  dimers but not by the dephosphorylation of tyrosine residues in KCC2 monomers , 95. In via dopamine receptor D1, but not D2, in bone marrow-derived macrophages (via prokineticin receptor 2 (PROKR2)-positive DRG neurons and dorsal motor nuclei of the vagus (DMV) pathway in the electroacupuncture . BOT is frequently used to treat arthritis, especially knee osteoarthritis , a Kampo formula consisting of six crude extracts (rthritis . We prevrthritis . Furtherrthritis . Becausec effect  and an ac effect . Additioc effect , 136, isc effect , liquiric effect , 139, glc effect , 141, anc effect . The ideSinomenium acutum, has recently been reported to prevent calvarial osteolysis by decreasing the number of mature osteoclasts (Magnoflorine, an alkaloid derived from plants such as eoclasts . Calvarieoclasts . RANK lieoclasts . Magnofleoclasts . Meanwhieoclasts . Furthereoclasts . AlthougThe development of the disease concept of CRPS and its biomedical study were initiated by anesthesiologists in the late 20th century . HoweverEven with the accumulation of clinical research over the decades, the etiology and pathogenesis of CRPS, as well as appropriate treatment strategies, are still being explored. A severe injury, such as a fracture in an extremity, causes prolonged and exacerbated inflammation and localized abnormal bone metabolism due to the immune response triggered by the neuropeptides released from nociceptive neurons around the tissue. Thus, we suggest using the term senso-immunology to describe the immunologic interaction between nociceptive neurons and damaged tissues or bones. This review suggests that regional bone metabolic abnormalities may play an essential role in CRPS development, particularly in CRPS type 1. It would be desirable to treat patients with CRPS by suppressing excessive inflammation around the damaged tissue and improving bone metabolism, with particular emphasis on suppressing osteoclast differentiation. Although bisphosphonates have been shown to be an effective treatment for CRPS in recent years, we believe that a variety of treatment options should be offered, taking into consideration the adverse events. We propose that Oriental herbal medicines may also be effective because many medicinal plants regulate bone metabolism and possess anti-inflammatory properties, and Kampo formulae, which are the ideal combinations of these plants, might be an effective treatment for CRPS. Because there are few clinical and basic research reports on Kampo formulae, further research and accumulation of clinical evidence are necessary.TO, YT, KM, and MK performed the literature search, designed the figures and tables, and wrote the manuscript of the review. MS performed the literature search, wrote, and supervised, the review. All authors approved the submitted version of the article.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.