Introduction. Psychosocial and somatosensory factors are involved in the pathophysiology of chronic migraine (CM) and chronic temporomandibular disorders (TMD). Objective. To compare and assess the relationship between pain catastrophizing and kinesiophobia in patients with CM or chronic TMD. Method. Cross-sectional study of 20 women with CM, 19 with chronic TMD, and 20 healthy volunteers. Pain catastrophizing and kinesiophobia were assessed. The level of education, pain intensity, and magnitude of temporal summation of stimuli in the masseter (STM) and tibialis (STT) muscles were also evaluated. Results. There were significant differences between the CM and chronic TMD groups, compared with the group of asymptomatic subjects, for all variables (p < .05) except kinesiophobia when comparing patients with CM and healthy women. Moderate correlations between kinesiophobia and catastrophizing  were obtained, and the strongest association was between kinesiophobia and magnification . The strongest associations among physical variables were found between the STM on both sides  and between the left and right STT . Conclusion. No differences were observed in pain catastrophizing and kinesiophobia between women with CM and with chronic TMD. Women with CM or chronic TMD showed higher levels of pain catastrophizing than asymptomatic subjects. Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or is described in terms of such damage . AccordiHeadaches and orofacial pain are a problem that affects a significant percentage of the population , 2. PrimOrofacial pain is defined as that which includes various manifestations in the face or oral cavity and includes numerous conditions, such as temporomandibular disorders (TMDs) . The preNumerous studies have confirmed the important role of psychological and societal variables in CM and chronic TMD , 19, as The scientific evidence has shown that a percentage of these patients are susceptible to developing a central sensitization process –27, whicA number of authors have used the magnitude of the temporal summation of stimuli as an indicator of a possible impairment in the processing of pain related to the presence of central sensitization in a number of diseases , as is tIn terms of the relationship between educational level and health status, a low educational level has been associated with greater pain catastrophizing and depressive symptoms when faced with pain .Thus, our study's primary hypothesis was that patients with a diagnosis of CM or chronic TMD would show no differences in the previously recorded variables regarding pathophysiology.The primary objective of the study was to compare and assess the relationship between pain catastrophizing and a fear of movement in patients with CM or with chronic TMD. The secondary objective was to assess the association between the somatosensory and psychological variables in these patients.A cross-sectional study was conducted at La Paz University Hospital (HULP), with the approval of its ethics committee (PI-1241). Data were collected between October 2013 and April 2014. We followed the international recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology checklist  for streThe participants were recruited simultaneously through the Departments of Neurology or Maxillofacial Surgery of HULP and the Spanish Association of Patients with Headaches, who were diagnosed with CM by a neurologist. The study also included asymptomatic participants with sociodemographic characteristics similar to those of the patients with CM or with chronic TMD. The former acted as controls and were occasionally companions of the HULP patients.Each patient of legal age was placed into one of the following groups according to their diagnosis: (a) diagnosis of CM (according to the ICHD-3rd ed.) or (b) diagnosis of muscle, joint, and/or combined chronic TMD according to the RDC/TMD classification.The following exclusion criteria were considered for the patients: concomitance with systemic rheumatic disease  or CNS disease; nonchronic headache (according to ICHD-3rd ed.) in the CM group; a combined diagnosis of CM and TMD of any type; recent trauma or recent surgery in the head, face, neck, or chest; and pregnancy. All the exclusion criteria were checked using the medical history and physician judgment.To assess the fear of movement and pain-related fear, we used the Spanish-validated version of the Tampa Scale for Kinesiophobia, which has good psychometric properties . The levThe only qualitative variable included was education level, which was divided into primary (1), secondary (2), and university (3) studies.To prevent selection bias, we established a number of previously defined inclusion and exclusion criteria to decrease the differences within the study population. To prevent classification bias, the patients had to have a previous diagnosis from a medical specialist. Another bias of considerable importance could have been the consumption of medication. To avoid this bias, the scheduled patients were reminded not to consume any type of analgesic (except for those patients with preventive medication) in the 24 hours before the visit.Finally, to address information bias, all the participants were provided with structured information on the study.The sample size was calculated with the G.Power 3.1 program (University of Düsseldorf). According to our pilot study, we determined that a total of 50 participants divided into 3 groups were needed to obtain a minimum correlation of 0.4 (moderate) among the variables, accepting an alpha error of 0.05 and a statistical power of 90%.We used SPSS version 2.0 for the data analysis and the Kolmogorov-Smirnov test for the normality tests. We employed the analysis of variance or the Kruskal-Wallis test to compare the means according to their distribution and Spearman's test to assess the correlation coefficient among the various variables for clinical sample. The results are presented with a 95% confidence interval (CI) for all the variables. The correlation coefficient was interpreted according to the values proposed by Cohen .A total of 59 female patients were recruited, with an average age of 44.88 ± 12.24 years (mean ± SD) with a weight of 64.93 ± 11.05 kg and a height of 1.64 ± 0.06 m .p > .05). All the values are shown in According to the diagnoses, 20 patients had CM, 19 patients had TMD, and 20 were asymptomatic. One-way ANOVA showed no statistically significant differences in age, weight, and height between the groups (p > .05).Regarding education level, 8.5% had primary-, 39% had secondary-, and 52.5% had university-level education. No statistically significant differences were found between the groups , its subscale rumination , and hopelessness . No statistically significant differences were found in magnification (p = .151) and kinesiophobia (p = .053)  .p = .002), including rumination , magnification , hopelessness , and kinesiophobia   .No statistically significant differences were observed between the CM and TMD groups in pain catastrophizing and kinesiophobia.χ2 = 41.67; p = .000) and in magnitude of the temporal summation in the trigeminal area    or the temporal summation in the trigeminal area  and extratrigeminal area .The pain intensity, the magnitude of the temporal summation, and the educational level did not have normally distributed data. Statistically significant differences were observed in the Kruskal-Wallis test between both the CM and TMD groups with the asymptomatic group in pain intensity (p = .02)  and in t = .005) . No statρ = 0.46; p = .001) for all the clinical samples. Chronicity had a moderate and positive correlation with catastrophizing  and kinesiophobia . Pain catastrophizing showed a moderate and positive correlation with pain intensity .A Spearman correlation coefficient showed moderate and positive correlation between pain catastrophizing and kinesiophobia . A very strong and positive correlation was found between both sides of the masseter in the temporal summation in the trigeminal area  and between both sides of the tibialis anterior in the temporal summation in the extratrigeminal area   .ρ = 0.74; p = .00).Finally, a strong positive correlation between chronicity and pain intensity was observed . A moderate and negative correlation was found between chronicity and hopelessness .In the CM group, a moderate and positive correlation was observed between the magnification of pain and kinesiophobia . Moreover, the correlation analysis revealed the presence of covariance between the levels of the 2 variables and the pain chronicity and intensity, such that the greater the catastrophism and/or kinesiophobia, the greater the pain chronicity and intensity. Previous studies have shown a positive moderate correlation between the level of pain catastrophizing and the pain intensity or severity in patients with different types of chronic pain , 21, 41.Differences in the level of kinesiophobia were only observed between the TMD group and the asymptomatic participants. This difference could be because the TMD diagnosis also included joint pain; therefore, a possible mechanical disorder could cause fear of movement. This situation does not occur in CH.Finally, chronicity is associated with pain catastrophizing and kinesiophobia. Previously, other authors have noted that both pain catastrophizing and kinesiophobia can be predictors of chronic pain, especially when pain-related disability is present .In this study, significant differences were observed when comparing the asymptomatic group with the CM and TMD groups. We observed no differences, however, between the latter 2 groups. As with our study, a previous study on patients with CM and episodic migraines showed significant differences compared with allodynia perceived in the various study groups .The theory that associates chronic pain with supraspinal involvement is supported by a number of research studies of patients with chronic pain that found differences compared with the asymptomatic group using temporal summation tests, such as the pinprick stimuli test. A number of authors have observed generalized hyperalgesia in these patients beyond the area where the painful symptoms initially started, which could lead us to consider a central sensitization model . AnotherIn contrast, Raphael  found noAlthough pain intensity showed differences between clinical groups (CM and chronic TMD) compared with asymptomatic participants, no differences were observed between the asymptomatic participants and the patients with CM or with chronic TMD. Some studies have already observed comorbidity between these two disorders . TherefoNo significant differences in terms of educational level among the groups were found in our study. In contrast, several previous studies conducted with patients with headaches showed a relationship between pain intensity and educational level. Chu et al. (2013) conducted a study on 1507 patients diagnosed with tension type headache (TTH) and migraine and showed that a university education was related to a lower prevalence of primary headaches in women . The difTwo more research studies supporting the previous study revealed the negative correlation between educational level and the risk of developing migraines in women. The differences compared with our study could correspond to the fact that Le et al. had a sample composed of Danish men and women diagnosed with episodic migraine. In contrast, 100% of the sample from the study by Winter et al. were women diagnosed with different types of head pain, including headache , 54.This study provides important information on the psychological factors of women with CM or with chronic TMD. These women showed higher levels of pain catastrophizing than asymptomatic subjects, which partially supports the applicability of the fear-avoidance model to these populations.Chronicity has proven to be a factor associated with the presence of catastrophism and kinesiophobia; therefore, the prompt treatment of patients with pain might be useful to prevent the appearance of these two conditions. Developing strategies that combine psychological approaches to cognition or behavior and trying to modulate the pain perceived by patients with CM and chronic TMD are of great importance. Moreover, it is essential to consider the coping strategies for chronic craniofacial pain and their relationship with educational level. Drossman et al., in a study on patients with gastrointestinal disorders, showed a negative correlation between educational level and pain catastrophizing in terms of coping strategies . Both thThis study has several limitations. One of the significant limitations of cross-sectional studies is the inability to establish causal relationships. The usefulness of this type of study, however, lies in creating new working hypotheses. Another limitation of our study is the possibility of potential sources of risk, such as the consumption of medication, despite the measures employed to avoid them. Regarding medication, medication overuse headache (MOH) has a high degree of comorbidity with CM. The psychological and physical aspects of these patients can differ from those of patients without MOH; thus the presence of this condition could have altered the results. The fact that data was lost in some of the questionnaires completed by the patients is also worth noting. The fact that the sample comes from a specific area (north of Madrid) could cause the results to vary when compared with other geographic areas. More than half of the sample had a higher than average education level. The relationship that this educational level could have with pain perception and on constructs such as fear of movement or pain catastrophizing has already been studied. A small part of the sample comes from an association of patients, which could involve especially motivated patients and those predisposed to collaboration. The data could not be extrapolated to men because this sample was composed exclusively of women. Thus, another limitation could be considered in regard to the patients' menstrual cycle phase. The authors believed that the groups were balanced in regard to fertility phase because there were no differences between the ages of the groups evaluated. However, the phase of the menstrual cycle in which they were at the time was not measured. Having been evaluated randomly, authors believe that the range of hormonal phases would be similar between groups, but this situation cannot be assured. Finally, another limitation is not having evaluated other psychosocial factors such as depression and anxiety, as well as their potential interactions, given that previous studies have observed an association with CM and TMD , 56.In conclusion, no differences were observed in pain catastrophizing and kinesiophobia between women with CM and with chronic TMD. Women with CM or chronic TMD showed higher levels of pain catastrophizing than asymptomatic subjects. Only patients with chronic TMD had higher kinesiophobia than asymptomatic subjects.


Soft tissue injuries commonly present to the emergency department (ED), often with acute pain. They cause significant suffering and morbidity if not adequately treated. Paracetamol and ibuprofen are commonly used analgesics, but it remains unknown if either one or the combination of both is superior for pain control.To investigate the analgesic effect of paracetamol, ibuprofen and the combination of both in the treatment of soft tissue injury in an ED, and the side effect profile of these drugs.Double-blind, double dummy, placebo-controlled randomised controlled trial. 782 adult patients presenting with soft tissue injury without obvious fractures attending the ED of a university hospital in the New Territories of Hong Kong were recruited. Patients were randomised using a random number table into three parallel arms of paracetamol only, ibuprofen only and a combination of paracetamol and ibuprofen in a 1:1:1 ratio. The primary outcome measure was pain score at rest and on activity in the first 2 hours and first 3 days. Data was analysed on an intention to treat basis.There was no statistically significant difference in pain score in the initial two hours between the three groups, and no clinically significant difference in pain score in the first three days.There was no difference in analgesic effects or side effects observed using oral paracetamol, ibuprofen or a combination of both in patients with mild to moderate pain after soft tissue injuries attending the ED.NCT00528658).The study is registered with ClinicalTrials.gov (no.  Soft tissue injuries comprises of various types of injuries including contusions, sprains, crush injuries, cuts and lacerations. They can occur in different body regions including the limbs, neck and back, or the trunk. Specific guidelines and recommendations are available for the treatment for low back pain –3, ankleNSAIDs are cyclo-oxygenase inhibitors which have anti-inflammatory, analgesic and anti-pyretic effects and inhibit platelet aggregation . Non-steIbuprofen is a NSAID that has a low incidence of serious side effects and is thought to be the safest NSAID available –13. It iAlthough paracetamol is a safe and cheap analgesic, its analgesic effect is thought by many physicians to be inferior to that of the NSAIDs , 15. A CAlthough there have been prospective studies comparing different oral NSAIDs in the treatment of post-operative pain –19, therThis was a double-blind, double dummy, three-arm parallel, placebo controlled trial comparing oral paracetamol, ibuprofen and a combination of both, with an allocation ratio of 1:1:1. Ethical approval was obtained from the local institutional research ethics committee, the Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee (reference no.: CRE-2004.266-T). The study was registered with ClinicalTrials.gov (no. NCT00528658). The study was planned in 2004 and 2005 and conducted between 2006 and 2009. However, competing work demands and priorities have led to long delays in the preparation of this manuscript which the principal investigator deeply regrets. We present it for publication now to complete the study and make our results publicly available.This single centre study was conducted in the ED of a university teaching hospital serving the New Territories East region of Hong Kong. At the time of the study, the ED in Prince of Wales Hospital received over 170,000 new patients per annum and served a population of approximately 1,500,000.All patients ≥18 years presenting to the ED with an isolated soft tissue injury without any suspicion of a clinically significant fracture between the hours of 9am to 5pm, Monday to Friday, were considered for the study.Patients were excluded if they have contraindications to the use of paracetamol or ibuprofen including a history of indigestion, gastro-duodenal ulceration, bleeding disorders, recent anticoagulation, pregnancy, adverse reaction to paracetamol or NSAIDs/ibuprofen, cardiac failure, hepatic or kidney problems, rectal bleeding or chronic NSAID consumption, asthma, chronic obstructive airways disease, or chronic pain syndromes. Patients were also excluded if they had had analgesia in the four hours prior to recruitment, if they appeared to have other injuries or if they had a physical, visual or cognitive impairment that might make the use of the visual analogue scale unreliable.Patients were randomly allocated to one of three treatment groups using a random number table , 21. ThePatients received either one true analgesic—paracetamol 1000 mg and placebo mimicking ibuprofen, or ibuprofen 400 mg and placebo mimicking paracetamol; or, two true analgesics—paracetamol 1000 mg and ibuprofen 400 mg. Paracetamol is given every 6 hours, and ibuprofen every 8 hours. The research nurse, the physician and the patient were blinded to the treatment allocations with the use of double placebo.Informed, written consent was obtained from each patient. Patients were given the study drugs and observed for a minimum of two hours in the ED. During this time patients were asked to record the level of pain using a visual analogue pain score (VAPS)  and initThe primary outcome of the study was the pain score at rest and pain score on activity in the first 2 hours and first 3 days following administration of oral paracetamol, oral ibuprofen or the combination of both. Previous research has also shown that ‘no worse than mild pain’ (30/100mm on a 100mm VAS), is an important outcome and cut-off for demonstrating an adequate response in analgesic trials , and theData was collected by a research nurse who was also responsible for ED staff information, motivation and feedback talks, for entry of data into a database, following up on the patients in the subsequent two days. Notes were made of re-attendance, protocol deviations, prescriptions of additional analgesia or other medication, and time to full recovery.2 test or Mann-Whitney U test [Data was analysed on an intention to treat basis and all statistical analyses involved two-tailed tests. Baseline characteristics of the three treatments was analysed using the χy U test , 21. They U test , 25 and In a previously published trial with two NSAIDs and paracetamol, adverse drug effects were seen in 1.4% in the least affected group and 4.4% in the worst affected group . Using aA total of 1332 patients who attended the ED with soft tissue injuries were screened, and 549 patients did not meet the inclusion and exclusion criteria. 783 were randomized into the three groups: 261 patients were randomised to paracetamol and placebo, 258 were allocated to receive ibuprofen and placebo and 263 were randomised to receive both. One patient in the paracetamol group was later excluded due to human error. 83.9% of patients completed follow up after 3 days, and 40.2% of patients completed follow up at 28 days. The CONSORT flow diagram is shown in Baseline characteristics of the 782 participants are shown in The mean age (SD) was 39 years (14.0), and 64.5% were male. Median time between injury and arrival at hospital was 1 day or less. The most common causes of injury included sprains (43–46%) or contusions (33–34%); 26–29% had a cut and less than 10% had a crush injury. The most common injury site was hands and fingers (21–27%), followed by the back (15–18%) and the ankle (16–17%). At rest, the mean (SD) pain scores at baseline for paracetamol, ibuprofen and combined treatment groups were 30.5 (20.6) mm, 30.9 (21.7) mm and 32.9 (21.0) mm respectively, and with activity were 63.1 (18.3) mm, 61.7 (18.4) mm and 60.5 (18.9) mm.Before intervention, the percentage of those with VAS 30/100mm or above (moderate to severe pain) were similar for all three groups at rest (42.1–42.8%) and on activity (93.4–94.6%).The reduction in mean pain score (95% CI) at rest in the initial two hours was 12mm (10–14 mm) in the paracetamol group, 12mm (10–15 mm)in the ibuprofen group, and 13mm (11–15 mm) in the combined group.The reduction in mean pain score (95% CI) on activity was 17mm (15–19 mm) for paracetamol, 17mm (14–20 mm) for ibuprofen, and 15mm (12–17 mm) for the combined group. Changes in VAS for pain for the first two hours is shown in All three treatment regimens were considered clinically effective in reducing pain at two hours. There were no significant differences in mean pain scores between the three intervention groups at rest  or on activity .In patients with initial moderate to severe pain, the proportion of patients with adequate response (VAS <30mm) at 2 hours was not different for the three groups at rest  or on activity .The reduction in mean pain score (95% CI) at rest at 3 days was 18mm (15–21 mm) in the paracetamol group, 19mm (16–22 mm) in the ibuprofen group, and 20mm (17–23 mm) in the combined group.The reduction in mean pain score (95% CI) on activity was 31mm (28–34 mm) for paracetamol, 30mm (26–34 mm) for ibuprofen, and 32mm (29–36 mm) for combined group. Change in VAS for pain for the first three days is shown in Reduction in pain at rest and on activity for the three treatment groups were all clinically significant. Again the reductions were similar between the three intervention groups and were not statistically significant at rest  or on activity . The primary outcomes are summarised in In patients with initial moderate to severe pain, the proportion of patients with adequate response (VAS <30mm) at 3 days was not different for the three groups at rest  or on activity . The results were shown in There was no serious adverse events which required admission, and no episodes of gastrointestinal haemorrhage, shortness of breath or chest pain were reported for all three arms. Minor adverse events were infrequent, with sleepiness the most frequently reported adverse event at the ED phase, and sleepiness, GI discomfort and dizziness at day 28. For each category of adverse events, there were no significant differences between the three treatment groups in the proportion of patients. The difference in the proportion of patients with more than one adverse event was also not significant . Overall satisfaction level with the analgesic drug provided and with the clinical ED management was recorded on day 28. The overall satisfaction level was from 7–7.5/10. Again no significant difference was found between the three treatment groups with analgesic drug satisfaction  and satisfaction with overall ED clinical management . In this randomised controlled trial, there was no demonstrable difference in analgesic efficacy or side effects observed between paracetamol, ibuprofen or a combination of both in the ED treatment of soft tissue injuries. Although inflammation has been postulated to be the main reason for pain following soft tissue injury, this study has demonstrated that paracetamol is as effective as ibuprofen, a non-steroidal anti-inflammatory drug.Others have recently reported the lack of efficacy of paracetamol as a single agent for the relief of low back pain . While lIn a previous meta-analysis, ibuprofen was shown to be consistently superior to paracetamol in a range of conditions . This waApart from the finding that paracetamol was as effective as ibuprofen, what was perhaps equally surprising was the lack of additional analgesic value with the combination of NSAID and paracetamol. Many authorities, including the WHO, have suggested the use of combination analgesia for some time now . In a reAnother surprise was the lack of serious adverse events noted in the study. There were no admissions with gastrointestinal bleeding, for example, which we had been specifically looking to identify given the propensity for Hong Kong Chinese to develop NSAID induced gastroduodenal ulceration and erosions . Our stuAs the population is aging all around the world and particularly in Hong Kong, we expect to see more and more elderly patients with co-morbidities attending the ED with soft tissue injuries. Although ibuprofen has a relatively safe side effect profile according to previous studies and our current findings, there will be increasing numbers of patients who have contraindications to the use of NSAIDs and the continuation of analgesic medication after discharge maybe a problem. The findings of this trial should reassure ED clinicians and others dealing with soft tissue injuries that providing an adequate dose of oral paracetamol is as effective as ibuprofen and the combination of both.The strengths of the study lie in its randomised, controlled and double-blind design that enabled the analgesic efficacy and safety of paracetamol, ibuprofen and their combination to be explored in the ED management of soft tissue injury. The strength of the study lies in its pragmatic design and included a range of soft tissue injuries and body regions including ankle sprains and simple lower back pain. The trial was properly designed with an adequate sample size, and answers an important clinical question.There are several limitations to the study. Firstly the baseline VAS at rest or on activity was not severe, as reflected by the percentage of those with ‘no worse than mild pain’ at baseline, and therefore the results may not apply to those with more severe injuries with higher baseline VAS scores. Secondly, only a modest dose of ibuprofen (1.2 gram daily) was used in this study, and therefore the potential analgesic effect of ibuprofen may be under-estimated. We acknowledge that the use of the acid base rather than the fast acting formulae of ibuprofen, and food intake with ibuprofen might have limited the analgesic effect. However this may also account for the lack of observed major adverse effects that has been described in the literature. It should be noted though that the typical dose of ibuprofen prescribed in Hong Kong is only 200mg three times daily, which is half the dose used in this study. The efficacy of such a small dose must be called into question given the results observed here.The potential effect of ibuprofen might be further under-estimated as participants were asked to document their pain scores one hour after taking their analgesia four times daily while ibuprofen was administered eight hourly (three times daily).This trial has found that there is no difference in analgesic efficacy between oral paracetamol, oral ibuprofen and the combination of both paracetamol and ibuprofen for patients with mild to moderate pain after soft tissue injuries. Further studies including cost effectiveness data and the effects of gastroprotective agents in this setting may be of value in determining the overall place of ibuprofen and paracetamol in the management of soft tissue injury.S1 FileCONSORT Checklist.(DOC)Click here for additional data file.S2 FileTrial research protocol.(DOC)Click here for additional data file.


In such cases, management of neuropathy may be delayed and CIPN symptoms may become severe. In this pilot study, we attempted an objective evaluation of CIPN using a quantitative pain measurement system  ÷ lowest perceptible current value × 100. We compared the pain degrees by Pain Vision® during CIPN development with the value obtained before chemotherapy initiation.The subjects were patients with gynecologic cancer who underwent chemotherapy using taxane and platinum drugs. The grade of the peripheral sensory nerve disorder was based on the Common Terminology Criteria for Adverse Events (CTC-AE) ver. 4.0 and was evaluated before the initiation of therapy and up to six chemotherapy cycles. A symptom scale assessed by the patients using a peripheral neuropathy questionnaire (PNQ) was also evaluated. Simultaneously during these evaluations, graded electric current was applied from the probe to a fingertip and measured both the lowest perceptible current and lowest current perceived as pain by Pain Vision® at grade 1 and 2 CIPN development according to the evaluation (CTC-AE) was significantly decreased compared to that before chemotherapy initiation . Changes in the pain degree by Pain Vision® were also found during scale B and C, D CIPN development in the patient evaluation (PNQ) . In the 13 patients in whom CIPN did not occur, no significant decrease in the pain degree by Pain Vision® was detected (p = 0.764). There was no discontinuation of the measurements because of adverse events such as discomfort from the electric current.Forty-one patients were enrolled. In the evaluation by a medical professional, 28 (64.3%) patients developed CIPN during 2.5 ± 1.1 chemotherapy cycles (mean ± standard deviation). The pain degree by Pain Vision® was associated with the onset of CIPN symptoms. Particularly, detection of CIPN by Pain Vision® was possible, though most of the CIPN that occurred was low grade or mild symptom. Pain Vision® might become a noninvasive and convenient objective CIPN detection tool to supplement subjective CIPN evaluation.The decrease in the pain degree measured by Pain VisionThe study approval number in the institution; H25–140. Registered December 17, 2013. Chemotherapy-induced peripheral neuropathy (CIPN) is a refractory side effect developed in a dose-cumulative manner when a taxane, platinum-based anticancer drug, or vinca alkaloid is used. The symptoms of CIPN develop as the glove-and-stocking type of hypesthesia, hyperesthesia, or dysesthesia of the peripheral hands and feet . The regAn antidepressant . The objectivity of a CIPN evaluation performed by a medical professional might be poor in cases where the patient has mild symptomatic expression. In fact, the underestimation of symptoms was pointed out in a comparison of evaluations by medical professionals and patients , 11. The®  is a device for quantitative analyses of perception and painful sensations .Tab.Tabver. ® was performed by affixing a probe  to a fingertip , and multiple comparison by Fisher’s least significant difference (Fisher’s LSD) test was performed before chemotherapy initiation as control. Changes in the pain degree by Pain Vision® in patients in whom CIPN did not occur was also examined by one-way ANOVA, and then differences in the pain degree by Pain Vision® between chemotherapy initiation and after each cycle were tested using multiple comparison tests (Dunnett test). Both tests were judged as significant at a 5% level for hazard ratios. The statistics software used was Excel statistics 2012 .Changes in the pain degree by Pain VisionThis study conducted with the permission of the Iwate Medical University School of Medicine Ethical Review Board (H25–140).n = 29) and those with diabetes (n = 6), rheumatoid arthritis (n = 2), lymphedema (n = 1), and those who did not agree to participate (n = 3) were excluded from the study. The CIPN evaluations of the 57 patients who agreed to participate in the study were performed continuously. The analysis was performed on 41 patients after excluding 10 patients who discontinued treatment because of disease progression and 6 patients lost to follow-up because of a hospital transfer. The patients’ backgrounds for these analyses were presented in Table A CONSORT diagram for this study was shown in Fig. ® at symptom development (grades 1 and 2) significantly decreased compared with that before chemotherapy initiation (p = 0.024 by ANOVA and grade 1 [n = 60 (27 patients)]: 126.0 ± 114.5 vs. 69.8 ± 46.8, p = 0.001; grade 2 [n = 8 (3 patients)]: 126.0 ± 114.5 vs. 32.8 ± 32.6, p = 0.004). However, the significant difference of the pain degree between grade 1 and 2 was not observed   significantly decreased compared with that before chemotherapy initiation ]: 115.9 ± 112.4 vs. 70.6 ± 56.5, p = 0.005; scales C, D [n = 17 (8 patients)]: 115.9 ± 112.4 vs. 46.3 ± 42.9, p = 0.004). However, the significant difference of the pain degree between scale B and C, D was not observed  , 136.6 ± 167.4 (13 patient), 78.1 ± 113.0 (12 patient), 115.0 ± 127.8 (12 patient), 289.0 ± 521.8 (12 patient), and 407.6 ± 793.3 (8 patient), respectively. No significant decrease in the pain degree by Pain Vision® was detected as compared with cycle 1(before the chemotherapy initiation) (p = 0.325 by ANOVA).CIPN occurred in 28 68.3%) patients from 2.5 ± 1.1 (mean ± standard deviation) chemotherapy cycles in the evaluation by a medical professional (CTC-AE). In these patients, severe CIPN  did not occur. During the 68 cycles in which CIPN was detected in these 28 patients in the evaluation by a medical professional (CTC-AE). Grade 1 and 2 of CIPN finally occurred in 60 cycles (27 patients) and 8 cycles (3 patients), respectively. Among 3 patients who develop grade 2, 1 patient was grade 2 since onset of symptom. Others 2 patients developed grade 2 after they experienced grade 1. The pain degree by Pain Vision% patient® did not cause discomfort from the electric current flowing to the fingertip, and there was no discontinuation of the measurement by patient request.The measurement by PainVision® were rarely affected by psychogenic factors [®. They considered that an evaluation by Pain Vision® was able to remove the influence of a placebo effect [® was effective for an objective evaluation of neuropathic pain. However, an investigation of CIPN has not been previously reported. To our knowledge, this study was the first pilot study to investigate the potential of Pain Vision® for the objective evaluation of CIPN.It was reported that evaluations by Pain Vision factors . Fujii eo effect . Pain Vi® was associated with the onset of CIPN symptoms. Though most of the CIPN that occurred featured comparatively mild symptoms , a significant decrease in the pain degree was detected by Pain Vision®. In this study using Pain Vision®, we determined the lowest perceptible current and the current at which pain was perceived, and calculated the pain degree. Correction by the lowest perceptible current reduces the variation in the measurement result caused by measurement conditions such as the positions of the electrode and subcutaneous nerves and individual differences in how patients feel pain [® at CIPN development was caused by an increase in the lowest perceptible current from hypesthesia, a decrease in the current perceived to cause pain from a decrease in the pain threshold, or both of these changes. It was thought that this neuropathic etiology was primarily due to PTX. PTX causes CIPN according to its cumulative dose. In patients with metastatic breast cancer, the mean cumulative PTX dose at which CIPN develops at grade 2 or greater was reported as 715 mg/m2 [2 or more, CIPN induced by PTX seemed certain to occur. Moreover, the percentages of CIPN of all grades in a previous report were 15.4% and 46.9% in a comparison of pegylated liposomal doxorubicin + CBDCA and PTX + CBDCA therapy for the first occurrence of ovarian cancer, respectively [® stimulates Aβ fibers responsible for sensing touch and pressure efficiently and quantifies their sensitivity. Therefore, it was thought that Pain Vision® sensed dysesthesia caused by PTX as a decrease in the pain degree as well.In the present results, the decrease in the pain degree measured by Pain Visioneel pain . It seem15 mg/m2 . Becauseectively . From thectively . It is t® could be replicated with other anticancer drugs  besides PTX. Secondly, 10 patients in whom CIPN did not occur and five patients who had CIPN in this study were using a drug that may relieve peripheral neuropathy . The use of these drugs might influence the perception of current in the Pain Vision® evaluation and CIPN symptoms. An investigation is required in the future regarding the change in the pain degree by Pain Vision® before and after the use of drugs providing CIPN relief and when symptoms were relieved by these drugs. Furthermore, an investigation is required regarding the magnitude of the change in the pain degree by Pain Vision® at which we should suspect CIPN development and whether there is a cutoff value for the change in the pain degree by Pain Vision®. The decrease in the pain degree appeared to correlate with the progression of symptoms. However, some patients had no correlation between threshold level by pain vision® and medical interview (CTCAE and PNQ). While medical professional evaluation (CTC-AE) showed CIPN in 68 cases (28 patients), the pain degree did not decrease in 21 cases (13 patients). Similar observation was present in 23 cases (11 patients) in patient evaluation (PNQ). Psychogenic effect was considered as the explanation. For example, even if CIPN does not occur physiologically, patients might notice a symptom. A sense of fear for the electric current or habituation might also affect a reaction time to push the switch. As other reasons, dry condition of the finger, adhesiveness of the electrode to a finger-tip might affect the threshold. There were also no significant differences in the pain degree between patients with CTC-AE grade 1 and grade 2. Similarly, even PNQ scale was similar. Therefore, it was believed that there were only 3 and 8 patients with CTC-AE grade 2 and PNQ scale, respectively. Future studies with larger sample size are warranted.The limitations of this study and details that we should consider in future were as follows. Primarily, it should be considered whether the detection of CIPN by Pain Vision® might become a noninvasive, simple, and easy-to-perform objective evaluation procedure to supplement existing CIPN evaluations was suggested by the present results.The possibility that Pain Vision


Ketamine has been well studied for its efficacy as an analgesic agent. However, intranasal (IN) administration of ketamine has only recently been studied in the emergency setting. The objective of this study was to elucidate the efficacy and adverse effects of a sub-dissociative dose of IN Ketamine compared to IV and IM morphine.A single-center, randomized, prospective, parallel clinical trial of efficacy and safety of IN ketamine compared to IV and IM morphine for analgesia in the emergency department (ED). A convenience sample of 90 patients aged 18–70 experiencing moderate-severe acute traumatic pain  were randomized to receive either 1.0 mg/kg IN ketamine, 0.1 mg/kg IV MO or 0.15 mg/kg IM MO. Pain relief and adverse effects were recorded for 1 h post-administration. The primary outcome was efficacy of IN ketamine compared to IV and IM MO, measured by “time-to-onset” (defined as a ≥15 mm pain decrease on VAS), as well as time to and degree of maximal pain reduction.The 3 study groups showed a highly significant, similar maximal pain reduction of 56 ± 26 mm for IN Ketamine, and 59 ± 22 and 48 ± 30 for IV MO and IM MO, respectively. IN Ketamine provided clinically-comparable results to those of IV MO with regards to time to onset  as well as in time to maximal pain reduction (40.4 ± 16.3) versus (33.4 ± 18), respectively.IN ketamine shows efficacy and safety comparable to IV and IM MO. Given the benefits of this mode of analgesia in emergencies, it should be further studied for potential clinical applications.NCT02817477Retrospectively registered on 27 June 2016. ClinicalTrials.gov ID: The online version of this article (doi:10.1186/s12873-016-0107-0) contains supplementary material, which is available to authorized users. Opiates are the current mainstay of severe pain relief in the pre-hospital setting as well as the Emergency Department (ED). Despite their efficacy, opiates such as morphine are inconvenient, as they necessitate either an intravenous (IV) catheter to be placed or an intramuscular (IM) injection to be administered. Intranasal (IN) administration of opiates is gaining momentum –3 but isKetamine, an NMDA-antagonist has been widely studied for its efficacy in analgesia and anesthesia. However, administration of ketamine via the IN route, especially in adults, has only recently been studied and requires further elucidation in the acute setting , 6. ReceThis was a single-center, randomized, prospective, open label, parallel clinical trial of efficacy and safety of IN ketamine compared to IV and IM morphine for analgesia in acute traumatic pain in the ED. A convenience sample of 90 patients aged 18–70 years experiencing moderate to severe orthopedic pain ) were randomized to receive either IN ketamine, IV morphine or IM morphine. Pain was measured on a 100 mm VAS prior to administration of analgesia and at 5 min intervals for 1 h following administration. Adverse effects were recorded. Patients were enrolled during times when a trained medical student researcher (see below) was available for data collection, on a single random day each week, during either the morning or evening shifts. These sampling times were varied to avoid any selection bias. The study took place between September 2012 and April 2014.The study took place at a large, university-affiliated, Trauma Level I urban hospital serving a population of over 360,000 residents and over one million daily commuters. The ED serves over 140,000 adults annually. Institutional Review Board approval was received. Trained medical students collected the data, and were supported by the ED physicians, nursing staff, and orthopedic surgeons. Opiate delivery and informed consent procedures were performed and collected by licensed medical staff; IN ketamine administration and data collection was completed by the student research technicians. Research assistants performing the actual study procedure were last-year medical students who had undergone a 1 h tutorial by one of the principal investigators, involving the study aims and methodology, relevant drug pharmacology, potential side effects and complications, problem-solving and drug delivery optimization, research assistant - research subject interaction etc. During the first 3–5 procedures each research assistant was closely supervised by an experienced researcher, until deemed sufficiently proficient for independent work.Patients aged 18–70 years, with mild to moderate blunt trauma  causing moderate to severe pain (≥80 mm score on a 100 mm VAS) were eligible for participation in the study. Additional inclusion criteria were: a Glasgow Coma Score (GCS) of 15, body weight of 50–110 kg, systolic blood pressure of 90–160 mmHg, heart rate <100 bpm. Patients were also required to have an American Society of Anesthesiologists (ASA) score of 1 or 2, deny head injury, and deny regular use of opiates. Exclusion criteria included any analgesia received within the prior 3 h, allergic sensitivity to morphine or ketamine, a large meal ingested within the previous hour, pregnancy, deviated nasal septum or trauma to the nose, and a history of a psychiatric condition. Despite evidence that ketamine does not exacerbate intracranial hemorrhage in patients with head trauma [Ketamine Hydrochloride for Injection 50 mg/mL  was used in the study. The atomization device used to dispense the medication was the Intranasal Mucosal Atomization Device .All potentially eligible patients were approached upon arrival to the ED and asked for their level of pain. Patients meeting the eligibility criteria were offered participation in the study by a physician unaffiliated with the research. Once written informed consent was obtained, patients were randomized to IN ketamine, IM morphine or IV morphine, in a 1:1:1 ratio, using a randomization scheme that utilized the last digit of their Government-issued Personal Identification Numbers. Vital signs including blood pressure, heart rate, respiratory rate, and oxygen saturation were obtained, and an initial VAS reading was obtained immediately prior to administration of analgesia. Patients were then given either 1 mg/kg IN ketamine, 0.15 mg/kg IM morphine, or 0.1 mg/kg slow IV bolus of morphine. Patient weight was rounded to the nearest five kilograms, and the dose was calculated accordingly.IN administration involved visually assuring that the nares were patent, followed by the administration of ketamine spray in 0.1–0.2 mL aliquots into each nare from a 1cc syringe at intervals of 10–30 s. Patients were instructed to report post-nasal drip of ketamine which resulted in increased intervals and augmentation of the angle and distance of the atomization device from the nare. IV morphine was administered in a slow bolus over 30–60 s. IM morphine was administered via a gluteal muscle injection by a registered ED nurse.Vital signs and VAS measurements were obtained at 5 min intervals for 60 min. For VAS pain-assessments, patients were approached and asked to mark their pain level on subsequent 100 mm lines representing pain from 0 to 100 %. This was self-reported pain and was not dependent on the researcher. Adverse effects were recorded at the end of 1 h using the ‘Opiate Related Symptom Distress Scale’  and inclThe primary outcome was effectiveness of IN ketamine in decreasing pain intensity, compared to IV and IM morphine. This was measured by the time to achievement of a clinically meaningful pain reduction (defined as 15 mm pain reduction on the VAS), degree and time to maximal pain reduction. A value of 13 mm VAS score reduction was previously shown to be clinically-significant , and ourSample size was determined based on calculations performed for previous studies examining analgesics in an ED setting , 14. RanDescriptive statistics are given as median, mean and standard deviation for continuous variables and frequency distribution for categorical variables. A comparison of treatment group means was performed using a one-way Analysis of variance (ANOVA). The multiple comparisons adjustment method of “Hochberg’s GT2” was employed for pair-wise comparisons between the groups. Dichotomous side-effects were compared using the Chi Square test or Fisher Exact test. When results of the overall test were significant, the False Discovery Rate method for adjustment of significance level was employed for pair-wise comparisons between the groups. An ANOVA with repeated measures was performed to assess the time trend and difference between the groups with respect to pain over time measurement. Statistical analysis was performed by SAS for Windows version 9.2.As a convenience sample, all patients entering the orthopedic trauma bay in the ED were approached when student researchers were available. Data was collected between September 2012 and April 2014. Of those approached, 90 patients were randomized to receive IN ketamine, IV Morphine or IM morphine. Five patients were lost to follow-up in the IN ketamine group due to ED interventions such as casting or imaging, which precluded the intensive assessment required for the study. The reason for the disproportionate IN ketamine subject loss was the more rapid administration after randomization and consent. Four patients in the IN ketamine and two patients in the IM morphine group were excluded due to improper dosing. Two patients of the IV Morphine group did not receive the allocated intervention due to improper dosing, and one patient in the IN ketamine group changed their minds before the intervention. One patient in the IM MO group was excluded due to disclosure of chronic opiate use after intervention  and 51 of the recruited patients were men (68.0 %). Table 8–68 and The average delivered dose of each drug was equal to the planned dose, i.e. 1.0 mg/kg for IN ketamine, 0.10 mg/kg for IV MO, and 0.15 mg/kg for IM MO.p = 0.611). TTO was significantly different (p = 0.000) between groups (Table p = 0.30) and 26.0 min (95 % CI 20.3–31.7 min) for IM morphine (p = 0.003).Analgesic efficacy was measured via three parameters: time to onset was the primary efficacy outcome, maximal pain reduction, and the time to maximal pain reduction. Time to onset (TTO) was measured as the period of time until the patient reached a 15 mm VAS score reduction. In all patients, the average TTO was 16.7 min (95 % CI 13.7–19.7 min). Five patients overall (6.8 %) were non-responsive to treatment, meaning that they never achieved the 15 mm VAS pain reduction: 11 % of the IM morphine group, 4 % of the IN ketamine patients and 4 % of the IV morphine patients (ps Table . Averagep = 0.3). Time to maximal pain reduction was also not significantly different for IN ketamine versus either of the morphine groups: 40.4 min for IN ketamine (95 % CI 33.9–46.9 min), 33.4 min for IV morphine (95 % CI 26.2–40.6 min), and 46.7 min for IM morphine (95 % CI 41.1–52.3 min) (p = 0.019 between IM morphine and IV morphine only).Maximal pain reduction was not significantly different among the three groups, with a 56 mm, 59 mm, and 48 mm pain reduction for the IN ketamine, IV morphine, and IM morphine groups, respectively .At the end of the 1-h period of observation, patients were asked to state their satisfaction with the administered medication on a 100 mm VAS. IM morphine and IV morphine had similar results with a mean satisfaction score of 73.9 mm (95 % CI 62.9–84.9 mm), and 70.2 mm (95 % CI 55.2–85.2 mm), respectively and 58.7 mm (95 % CI 45.3–72.1 mm) for IN ketamine  resulted in anosmia in a woman suffering from breakthrough oncological pain . In our We believe this study is easily generalizable to any ED, and indeed any pre-hospital or military situation. Since the pharmacokinetics of ketamine are well studied and understood, we have simply studied the safety and efficacy of the IN administration of ketamine in the acute care population. Generalizability of our data may be limited by our inclusion of only moderate-severe pain patients (80–100 mm VAS). In fact, many ED patients were excluded simply because they did not self-report pain of that intensity. Perhaps expanding to all pain levels above 60 mm VAS would be more applicable to clinical practice. Generalizability could also be increased by expanding the types of injuries studied. This study examined orthopedic limb and spine injuries; perhaps the addition of blunt chest injury and rib fractures could increase clinical utility.Limitations of this study were mostly technical and relevant to the IN drug delivery. Atomization of IN ketamine was sometimes difficult to control using the syringe system we chose. The amount atomized with every push of the syringe was somewhat variable, leading sometimes to runoff into the pharynx. Studies of IN delivery show that volumes greater than 300 μl per nostril may be difficult to absorb through the nasal mucosa, leading to reduced drug absorption . FurtherIN ketamine showed efficacy and safety comparable to the current standard-of-care for acute traumatic pain in the ED, IM and IV morphine. IN ketamine provided rapid pain relief without causing hemodynamic instability or respiratory side-effects, was easy to administer and may thus be an important option for ED settings, pre-hospital trauma management, as well as in battlefield and disaster medicine. Further studies are needed in order to define optimal concentrations and doses of IN ketamine, as well as improved delivery devices able to deliver a controlled quantity of ketamine to the patient.


Critically ill patients admitted to intensive care unit (ICU) may suffer from different painful stimuli, but the assessment of pain is difficult because most of them are almost sedated and unable to self-report. Thus, it is important to optimize evaluation of pain in these patients. The main aim of this study was to compare two commonly used scales for pain evaluation: Critical Care Pain Observation Tool (CPOT) and Behavioral Pain Scale (BPS), in both conscious and unconscious patients. Secondary aims were (1) to identifying the most relevant parameters to determine pain scales changes during nursing procedures, (2) to compare both pain scales with visual analog scale (VAS), and (3) to identify the best combination of scales for evaluation of pain in patients unable to communicate.In this observational study, 101 patients were evaluated for a total of 303 consecutive observations during 3 days after ICU admission. Measurements with both scales were obtained 1 min before, during, and 20 min after nursing procedures in both conscious (n.41) and unconscious (n.60) patients; furthermore, VAS was recorded when possible in conscious patients only. We calculated criterion and discriminant validity to both scales . The accuracy of individual scales was evaluated. The sensitivity and the specificity of CPOT and BPS scores were assessed. Kappa coefficients with the quadratic weight were used to reflect agreement between the two scales, and we calculated the effect size to identify the strength of a phenomenon.p < 0.0001). BPS was found to be more specific (91.7 %) than CPOT (70.8 %), but less sensitive . COPT and BPS scores were significantly correlated with VAS (p < 0.0001). The combination of BPS and CPOT resulted in better sensitivity 80.4 %. Facial expression was the main parameter to determine pain scales changes effect size = 1.4.CPOT and BPS showed a good criterion and discriminant validity (In critically ill mechanically ventilated patients, both CPOT and BPS can be used for assessment of pain intensity with different sensitivity and specificity. The combination of both BPS and CPOT might result in improved accuracy to detect pain compared to scales alone.NCT01669486 Pain management in critically ill patients is a complex process, but relevant to the clinical management. Pain is highly underestimated although it seems to be the patients’ worst memory in intensive care unit (ICU) , 2 even The aims of the present study were the following: (1) to compare CPOT and BPS separately, in conscious and unconscious critically ill mechanically ventilated patients; (2) to identify the most relevant parameters to determine pain scales changes during nursing procedures; (3) to compare both pain scales with VAS; and (4) to identify the best combination of scales for evaluation of pain in patients unable to communicate.This was a prospective, mono-centric study registered at ClinicalTrials.gov (ID NCT01669486). The study was conducted in the ICU at “Ospedale di Circolo Fondazione Macchi Varese”. The study was revising by the local Ethical Committee (protocol n.0003412), and informed consent was obtained from the relatives or patients according to local regulations.The staff is made up of 12 doctors and 28 nurses for 12 beds in a general intensive care unit. The patients-nurse ratio is 2:1 by day and 3:1 by night. The medical staff is also completed by five physicians in training. The most active phase of nursing care was made every morning and every afternoon. The nurses performed maneuvres for taking care of hygiene, therapy administration, and continuous monitoring of vital parameters. They are graduated in nursing after 3 years at university school and 2 years of master in intensive care. The medical staff is provided by physician graduated in medicine and surgery and specialized in anesthesia and intensive care after 5 years in training. The medical staff during the study was responsible for the assessment of pain through the acquisition of the behavioral scale scores. Assessments have been carried out by medical staff trained to identify the presence of pain with two scales. These observations were not blinded. In the morning, nurses provide patients’ passive turning, cleaning, and repositioning; they perform airway suctioning, medications, and catheter management. In the afternoon, nurses provide only patient cleaning and repositioning. To get standardized measurements before, during, and after the maximum level of pain stimuli, we analyzed the behavioral scale scores during the nursing care performed in the morning .The patients were evaluated with the Glasgow Coma Scale (GCS) and Sedation Agitation Scale (SAS). The conscious patients were identified with a GCS >10 and SAS = 4 (avoiding too agitated and too sedated patients to determine VAS).Pain evaluation was performed in conscious and unconscious patients before, during, and 20 min after nursing care , 18. Incx/Y graphic . In this case, the true positive corresponds to 100 % and the false positive correspond to 0 %. The AUC measures the ability of the scales to discriminate between patients who did or did not feel pain. The accuracy of individual scales was evaluated using calculation of sensitivity multiplied by the prevalence of positive to the sum of the observations  added to the specificity multiplied by the prevalence of negatives . Kappa coefficients with the quadratic weight were used to reflect agreement between the two scales [The statistical calculations were performed with in MedCalc for Windows, version 12.1.4.0. First, we calculate the sample size. The sample size calculation determined the number of the patients to enroll, and it was calculated a “priori” and based on 0.05 type I error and 0.20 type II error with a difference expected of 10 % order of magnitude in the area under the curve (AUC) area. We evaluated the validity to both scales, as criterion validity and discriminant validity. Discriminant validity refers to the ability of an instrument to measure the presence or the absence of the variable. In this study, the discriminant was correlated with the mean scores of both scales before and during the nursing care, 20 min after and during the procedure, and before and 20 min after the procedure, in conscious and unconscious patients. This correlation was calculated with Wilcoxon coefficient, which is a non-parametric test to determinate whether two samples come from the same statistical population, in the presence of ordinal values and continuous distribution. Box plot is a way to describe groups of numerical data through their quartiles. Criterion validity refers to the ability of an instrument to accurately measure the phenomenon of interest, in this case, the measurement of pain. It was evaluated by correlating the observed CPOT and BPS scores to the “gold standard” of pain measurement, i.e., VAS, when possible in conscious patients, and using the Spearman rank correlation coefficient (rs). Additionally, the sensitivity and the specificity of CPOT and BPS scores with ROC curve were assessed, only in conscious patients. The best discriminating between real and false positive is obtained by a curve passing in the upper left corner of at o scales . The effo scales .P value <0.05.The level of significance accepted was a In the study period Fig. , 253 patThe medical patients were affected to respiratory failure, from pulmonary edema and pneumonia. The surgical ones instead included patients undergoing abdominal, vascular, and thoracic surgery and multiple trauma. In addition to usual devices like central lines, arterial line, gastric tube, tracheal tube, and urinary catheter, these patients presented additionally surgical incisions, drainages, and open abdomen treatment.Z = −12.3, p < 0.0001; conscious Z = −6.93, p < 0.0001; unconscious Z = −10.68, p < 0.0001) and during and after nursing care . We observed similar results with CPOT .We calculated discriminant validity for BPS and CPOT in overall, conscious and unconscious patients. BPS showed a statistically significant difference during nursing care .p < 0.0001 CPOT rs = 0.48; p < 0.0001).The criterion validity of BPS and CPOT scale showed a strong correlation with VAS, including all measurements  CPOT and BPS separately increased during nursing care in both unconscious and conscious patients and were significantly correlated; (2) facial expression showed greater changes for pain assessment; (3) in conscious patients, during nursing care, BPS showed higher specificity, and lower sensitivity compared to CPOT; and (4) the combination of both BPS and CPOT resulted in improved accuracy to detect pain compared to individual pain scales. Thus, against our expectations, our data suggest that CPOT was actually equivalent to BPS in sensitivity and accuracy for pain evaluation because none scale have better sensitivity and specificity to each other .Our data suggest that using both BPS and CPOT during nursing care or other painful intervention might improve the evaluation of pain. To our knowledge, this is the first study suggesting that the combination of BPS and CPOT may be considered as a valuable tool for pain assessment in mechanically ventilated critically ill patients , 23, 24.In the present study, we evaluated patients requiring mechanical ventilation and admitted to a general ICU. Thus, our results may be more easily applicable to a mixed population of critically ill patients. Few previous studies simultaneously recorded BPS and CPOT as well as VAS , 25, 26.Our results are in line with those reported in previous studies showing that both BPS and CPOT increase during nursing care and return back to baseline in a short period of time . The diaThus, we hypothesized that of both BPS and CPOT, scales might result in improved accuracy to detect pain compared to each scale alone. The accuracy was evaluated by summing the scores of both scales for each individual observation. We found that during nursing care, the combination of BPS and CPOT resulted in better sensitivity. On the other hand, its specificity was higher than CPOT but lower than BPS. However, it was not possible to assess the best type of combination between the two scales, due to the higher prevalence of true positive cases and the limited sample size. In our study we did not find patients with delirium, and this may have been due to the optimization of the level of sedation.Our study has limitations to be addressed. First, we evaluated only nursing care and no other possible painful maneuvers like suctioning. Second, the pain scales used are subjective to the operator and not objective. However, only one trained assessor evaluated pain for each patient. Third, we did not found any case of delirium in our analyzed patients, and this may be due to the level of sedative drugs applied, and/or to the feasibility of the CAM-ICU application in our population of critically ills patients.Fourth, a relatively small group of patients was analyzed. Further studies are required to confirm our results in a larger population of patients.Both CPOT and BPS scales are applicable to detect pain in conscious and unconscious critically ill mechanically ventilated patients, but with different sensitivity and specificity. The association of both scales might improve the efficiency for pain assessment. The level of consciousness does not affect the perception of pain during nursing care.


Cardiovascular complications, stroke or transient ischemic attacks, multiple FD-related complications and pain were also associated with decreased utilities. Overall, no change in utility was seen in patients on ERT over a mean follow-up of 6.1 years. FD leads to a decreased QoL compared to the general population. Disease complications and pain both negatively influence QoL. Adequate assessment and treatment of pain as well as improved strategies to prevent disease complications are needed to improve QoL in the FD population.Quality of life (QoL) is decreased in patients with Fabry disease (FD). To improve QoL, it is important to understand the influence of FD related characteristics, symptoms, and complications. In this retrospective cohort study we explored the effect of pain (measured by the Brief Pain Inventory), phenotype, treatment, and FD-related complications on QoL. QoL data of Fabry patients as assessed by the EuroQol five dimension questionnaire (EQ-5D) from two international centers of excellence were collected. The aim of this study was to evaluate the effect of sex, phenotype, age, different states of disease severity, pain, and ERT on EQ-5D utilities. For 286 adult FD patients  2240 EQ-5Ds were available. QoL is decreased in men as well as women with FD, especially in older men with a classical phenotype. At age 50, utility was lower in men with classical FD compared to those with non-classical disease  contains supplementary material, which is available to authorized users. Fabry disease  is a rare X-linked lysosomal storage disorder with a heterogeneous disease course. The disease is caused by a deficiency of the enzyme α-galactosidase A (enzyme commission no. 3.2.1.22) due to mutations in the GLA-gene. This results in accumulation of globotriaosylceramide (Gb3) and related sphingolipids in cells throughout the body and may cause clinical complications, especially in kidney, heart, and brain. Despite the X-linked inheritance pattern, women are affected as well, and may develop similar symptoms and complications as men , The Netherlands; and Royal Free London NHS Foundation Trust (RFH), United Kingdom) were merged into one database. This cohort represents part of a larger study  with a definite FD diagnosis according to previously developed criteria  to assess the presence and severity of pain and its influence on daily life. All BPI scores closest to the utility with a maximum window of ±3 months were used. The BPI assesses pain at its worst, average pain, and pain interference with life. The interference score measures the influence of pain on general activity, walking, work, mood, enjoyment of life, relations and sleep. It is the mean of at least four of these items. Worst pain, average pain, and the interference score are graded from 0 (pain is absent) to 10 (worst possible pain)   using the CKD-EPI formula  CKD Work Group R (version 3.1.5) and SPSS for Windows, version 22.0  were used. First, utilities per sex and phenotype were calculated, followed by a second order polynomial regression mixed effect model with a random intercept and slope to evaluate the effect of age on utilities, stratified for sex and phenotype. To evaluate the relation between BPI score and utility, the polynomial mixed effect model was extended by including BPI scores as covariate.P-values <0.05 were considered statistically significant.Second, the effect of ERT on utilities was investigated with a linear mixed model including time on ERT and age at ERT initiation as time-dependent covariates and a mixed model of the difference between the utility at baseline and follow up measurements. Since QoL is known to fluctuate over time, patients were only included in this analysis if they completed an EQ-5D within 3 months before the start of ERT. Finally, utilities per disease state for the combined cohort of men and women with classical and non-classical disease were modeled. To account for the fact that one patient may have filled in more than one EQ-5D per disease state, a linear mixed effect model with the disease state as covariate and a random intercept was used to evaluate the utility per disease state. Patient numbers were too small to include sex and phenotype. In order to analyze the effect of eGFR, LVM, and WML on QoL within the “organ involvement” disease state, univariate, and multivariate analyses were performed within this group. Data are presented as mean ± standard deviation (SD) or median and range dependent on the distribution of data. Where appropriate, 95% confidence intervals (95% CI) are given. The merged database contained data on 439 patients from the AMC and the RFH, of whom 27 patients did not fulfill the criteria for a definite diagnosis, 12 had insufficient baseline data for assessment of disease severity and no follow-up data, and 114 patients did not complete one or more EQ-5D measurements. Two-hundred-eighty-six FD patients (117 patients from the AMC and 169 patients from the RFH) with a mean age: 42.5 ± 12.5 years completed 2240 EQ-5Ds. Each patient completed on average 7.8 ± 4.5 EQ-5Ds during a mean follow-up period of 5.4 ± 3.2 years. Classically affected patients completed more EQ-5Ds compared to non-classically affected patients. Table The health profile of the first completed EQ-5D Table  shows thp = 0.037) compared to a man with non-classical FD of the same age. At age 60 this mean difference has increased to 0.21 points . This illustrates the progressive worsening of utilities in men with classical FD with increasing age. In women and men with non-classical FD the decline in utilities with age was less strong . Similarly, an increase in BPI worst pain score  or BPI interference score  resulted in lower utilities. A sensitivity analysis without the pain/discomfort domain in the calculation of the utilities did not change the results.In total 1559 BPIs of 276 patients were matched to an EQ-5D. Of the patients that completed BPIs 45.3% were men, 61.2% had the classical phenotype, and the mean age was 44.8 ± 14.9 years. Utilities decreased with higher BPI scores: with every one point higher BPI average pain score, the utility decreased on average by 0.045 points . Furthermore, there was no relation between change in utility, time on ERT  and age at ERT initiation . In a subgroup analysis, we found that utilities increased after initiation of ERT in the 13 men with classical FD . This was primarily attributable to three patients with a very low utility before the start of ERT due to extreme pain/discomfort which improved substantially after the start of treatment. One of them started taking carbamazepine for his neuropathic pain during the same period, leading to a substantial decrease in neuropathic pain in the months thereafter. Without these three patients no change in utility was observed . Additional subgroup analyses revealed that no annualized change in utility was observed in women with classical or non-classical disease, while in men with non-classical FD a 0.027 point decline per year on ERT  was found.For the evaluation of the effect of ERT on utilities, 61 patients were analyzed who completed at least one EQ-5D before the initiation of ERT. The mean age of patients at ERT initiation was 44.2 ± 15.5 years, and the mean follow-up time after initiation of ERT was 6.1 ± 2.5 years. The median utility score before ERT was 0.796 (−0.166–1.000). Utility remained unchanged after start of treatment  who showed divergent utility scores. The lowest utility was found in the ‘multiple complications’ disease state . The ‘neuropathic pain’ disease state also showed a trend toward lower utility compared to the ‘no organ involvement’ disease state (p = 0.053).Table This study shows that QoL in patients with FD is related to phenotype, age, pain, and disease severity. Obviously, these features are related to each other; classically affected patients of older age will have more severe disease with a higher chance of developing FD-related complications and thus a decreased QoL. Additional analyses to study the independent effects of these features on QoL were not feasible due to limited patient numbers and the expectation of high multicollinearity.The mean utility of FD patients in the present study ranged from 0.75 in men with classical FD to 0.81 in men with non-classical disease, and QoL decreased with advancing age. Comparison of the health profile of these patients to the health profile of the general population in the UK and the Netherlands supports a higher prevalence of impaired QoL in FD ESM 2(PDF 99 kb)ESM 3(PDF 154 kb)


To determine the effects of intra-operative Korean traditional music on pain experienced by Korean patients undergoing sequential bilateral cataract surgery.This was a two-sequence, two-period, and two-treatment crossover study. Fifty-two patients with cataracts were divided into two groups by block randomization, and bilateral cataract surgery was performed. In group 1, patients listened to Korean traditional music (KTM) during their first but not second cataract surgery. This sequence was reversed for patients in group 2. After each surgery, patients scored their pain intensity (PI) using a visual analog scale (VAS) ranging from 0 to 10, where 0 was ‘no pain’ and 10 was ‘unbearable pain.’p = 0.013). However, there were no statistically significant differences in blood pressure or pulse rates.There was a statistically significant reduction in the mean VAS score with KTM (3.1 ± 2.0) compared to that without KTM (4.1 ± 2.2; KTM had a significant effect on reducing pain experienced by patients during cataract surgery. This may be useful in the context of other surgical procedures to reduce pain in Korean patients. Loss of vision is one of the most feared disabilities , and catProgressive improvements in cataract surgical techniques have resulted in a decline in intra-operative discomfort, allowing the stepwise change from general anesthesia to regional anesthesia (a block) to simple topical anesthesia. Although there are differing views regarding the use of anesthesia, surgeons have increasingly favored topical anesthesia as the default method for phacoemulsification , 6, 7.Interestingly, music accompanied by verbal assurance as adjuvant treatment can be used in elderly patients, who are vulnerable to the side effects of sedatives . Many stStudies on the effects of music in patients undergoing ophthalmic surgery have also shown varied outcomes. For example, Bellan et al.  reportedTherefore, in this study, we examined the effects of KTM, playing throughout the entire procedure, on patient pain scores and blood pressure measurements during surgical procedures in delayed bilateral sequential cataract recipients.n is the sample size; z, the value for the selected alpha level, for example 1.96 for (0.05), that is at 95%. Confidence level; 1−β, the statistical power; and dE, the effective size. It was decided to include 30 patients per group to provide for possible dropouts.Sample size for this study was estimated with a 95% confidence interval, statistical power 80%, and effective size of 0.6, and the required sample size was 22 subjects using the following formula.This was a randomized, two-sequence, two-period, and two-treatment crossover design , 18 wherA total of 52 Korean patients with cataracts were randomly divided into two sequence groups; twenty-three patients in one group received the cataract surgery sequentially with and without KTM (in that order) and 29 patients in other group received the cataract surgery in the reverse sequence. The washout period between the first and second surgery was set at around 10 days according to the patients’ recovery conditions.Eligibility criteria were as follows: willing to listen to music during surgery; and the absence of other ocular diseases, hearing disorders, or communication disorders.gayageum,’ ‘haegeum’ , and an electronic keyboard. The song was chosen by a music expert and was played repeatedly during the procedure. The song had a simple melody without lyrics and with a limited dynamic range. It was played through earphones with an MP3 player during operation for patients in the KTM group. The patients were able to adjust the volume, and there was no interference with communication with the surgeon.The ages and cultural backgrounds of the patients were taken into account for selection of the particular song; the song was recorded with ‘The primary endpoint was pain score, rated directly by the patients after surgery using the visual analog scale (VAS), in which a score of 0 indicated no pain, and a score of 10 indicated unbearable pain. As reference endpoints, systolic and diastolic blood pressures and pulse rates were assessed intra-operatively and postoperatively with the patients in the supine position .For the surgical procedure, a continuous curvilinear capsulorhexis approximately 5.5 mm in diameter was made using forceps. Cataracts were removed by phacoemulsification through a 3.0-mm temporal corneal incision for the foldable intraocular lens. All intraocular lenses were implanted in the capsular bag. Postoperative topical therapy consisted of fluoroquinolone and steroid eye drops for 1 month.All data were analyzed using SAS for Windows (version 8.0.0). The significance level was 5%.A total of 52 patients with bilateral cataracts were recruited to participate in the study. Patients ranged in age, with 13.5% of patients in their 50s, 26.9% of patients in their 60s, 50.0% of patients in their 70s, and 9.6% of patients in their 80s (Table p = 0.013). Analysis of variance was used to determine whether there was a carryover effect in the crossover; this result failed to reach statistical significance , giving our analysis a patient-centered approach. Other studies have shown relationships between music and pain and/or anxiety; however, this study was designed to evaluate the effects of KTM on pain utilizing a crossover design. This study showed that KTM had a statistically significant effect on reducing pain during cataract surgery regardless of the sequence and that KTM was more effective for patients with high blood pressure. This finding may be translatable to other surgeries performed on Korean patients under local anesthesia; however, further studies are required.


Objectives: The 0–10 Numeric Rating Scale (NRS) is often used in pain management. The aims of our study were to determine the cut-off points for mild, moderate, and severe pain in terms of pain-related interference with functioning in patients with chronic musculoskeletal pain, to measure the variability of the optimal cut-off points, and to determine the influence of patients’ catastrophizing and their sex on these cut-off points.Methods: 2854 patients were included. Pain was assessed by the NRS, functioning by the Pain Disability Index (PDI) and catastrophizing by the Pain Catastrophizing Scale (PCS). Cut-off point schemes were tested using ANOVAs with and without using the PSC scores or sex as co-variates and with the interaction between CP scheme and PCS score and sex, respectively. The variability of the optimal cut-off point schemes was quantified using bootstrapping procedure.Results and conclusion: The study showed that NRS scores ≤ 5 correspond to mild, scores of 6–7 to moderate and scores ≥8 to severe pain in terms of pain-related interference with functioning. Bootstrapping analysis identified this optimal NRS cut-off point scheme in 90% of the bootstrapping samples. The interpretation of the NRS is independent of sex, but seems to depend on catastrophizing. In patients with high catastrophizing tendency, the optimal cut-off point scheme equals that for the total study sample, but in patients with a low catastrophizing tendency, NRS scores ≤ 3 correspond to mild, scores of 4–6 to moderate and scores ≥7 to severe pain in terms of interference with functioning. In these optimal cut-off schemes, NRS scores of 4 and 5 correspond to moderate interference with functioning for patients with low catastrophizing tendency and to mild interference for patients with high catastrophizing tendency. Theoretically one would therefore expect that among the patients with NRS scores 4 and 5 there would be a higher average PDI score for those with low catastrophizing than for those with high catastrophizing. However, we found the opposite. The fact that we did not find the same optimal CP scheme in the subgroups with lower and higher catastrophizing tendency may be due to chance variability. Assessment of pain intensity is considered one of the core outcome domains in clinical pain research  is associated with pain severity and disability in patients with several chronic pain conditions , two (rehabilitation center d), or five (rehabilitation center c) treatment sites in the Netherlands. Some of these centers were departments of a university or general hospital, others were stand-alone rehabilitation centers. The centers are located in different parts of the Netherlands, with patients from rural or semi-industrialized areas, living in villages or medium-sized to large towns and cities. Patients were included between the early months of 2012 and mid-2014; the exact time of inclusion differed between the participating rehabilitation centers. Inclusion criteria were: age over 18 years and having had musculoskeletal pain for longer than 3 months. Exclusion criteria were inability to understand Dutch, current major psychiatric disorder , unwillingness to provide data for research purposes, a score of “no pain” or missing data on the NRS and more than 3 missing values on the Pain Disability Index .All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2000. The data were collected in a setting of usual care, in order to measure the outcome of the treatment. The patients were asked to indicate if they did not allow their anonymous data to be used for the nationwide survey and/or for scientific studies. Because the data were collected during usual care, no approval of a Medical Ethics Committee was needed.Cross-sectional study in the context of care as usual.The following background characteristics were assessed: age, sex, marital status, duration of current pain period, and localization of pain .The NRS for pain is an 11-point numeric rating scale, with 0 representing “no pain” and 10 “unbearable pain.” The patients were asked to assign a number to their average pain in the last week. We decided to ask the patients to report their average pain, as two studies found no differences in the cut-off point schemes of the NRS for average and worst pain . In this procedure the distribution is estimated using the information based on a number of resamples from the total sample. One thousand (1000) repetitions of samples of the patients were used to yield sufficiently stable estimates for the variability of the optimal cut-off points. The optimal CP scheme for each of the 1000 randomly chosen samples was determined, using the above-mentioned method introduced by Serlin et al. .F-values of the CP schemes were used to determine which scheme fitted best. In these two (median split method) and three (quartile split method) patient subgroups we also conducted the bootstrap resampling procedure described above.The associations between the cut-off point schemes and the patients' catastrophizing tendency and sex were determined by once again conducting ANOVAs  for each of the 28 CP schemes. In the two series of additional analyses , the NRS (recoded as 1–3) was again used as the independent variable and the PDI-DV score as the dependent variable, while the total score on the PSC and the patient's sex were respectively included as co-variates, as was the interaction between CP scheme and PCS score and sex, respectively. In view of the results of the analyses with the PCS score, we decided to conduct separate analyses, firstly for the patients with a PCS score equal to or lower than the median of the PCS scores and the patients with a PCS score higher than the median of the PCS scores (dividing the population into two groups by the median split method), and secondly for patients in the lower and higher quartiles and the middle group of scores (dividing the population into three groups by the quartile split method). In total, therefore, 7 times 28 (196) ANOVAs were conducted. Again, the F-values of the CP schemes not presented here were lower than the F-value with ranking 6 as indicated in Table F-value, indicating that this scheme provided the best fit for distinguishing pain into three categories, i.e., mild, moderate, or severe pain, in terms of interference with functioning. This means that an NRS score in the 1–5 range corresponds to mild interference with functioning, while scores of 6 and 7 represent moderate interference and a score in the 8–10 range corresponds to severe interference with functioning. The mean PDI scores of the patients with NRS scores in the range of 1–5, 6–7, and 8–10 were 30.3 (SD 11.8), 39.7 (SD 10.6), and 45.4 (11.5), respectively.A total of 2854 patients enrolled in the study. Patient characteristics are presented in Table Bootstrapping analysis identified the optimal CP scheme  in 90.2% of the bootstrapping samples. The 3,6 scheme was identified as the optimal CP scheme in 3.4% of the samples and the 4,6 scheme in 3.3%.*CP scheme were entered as co-variates, neither of these covariates contributed significantly to the model. In the analyses in which the PCS score and the interaction variable PCS score*CP scheme were entered as co-variates in catastrophizing, the PCS score contributed significantly to the model in all analyses, while the interaction variable PCS score*CP scheme contributed sometimes . The latter finding was explained as chance variation because only 2 of the analyses found a significant contribution. To explore the finding of the significant contribution of the PCS scores to the models, we conducted more analyses, as described above. First we split the total group into patients with low and with high catastrophizing tendency, and since the median of the PCS score was 29, we performed the analyses separately for patients with a PCS score equal or lower than 29 and for those with a PCS score higher than 29. For the patients with low catastrophizing tendency, i.e., a PCS score ≤ 29, the optimal CP scheme proved to be 3,6 and for the patients with high catastrophizing tendency, i.e., a PCS score > 29, the optimal CP scheme was 5,7  of 5 and 7  were found to provide the best model fit, indicating that an NRS score ≤ 5 corresponds to mild interference of pain with functioning, 6 and 7 to moderate interference and 8–10 to severe interference. The variability of the optimal CP scheme was low, as bootstrapping found the 5,7 CP scheme to be optimal in ~90% of the samples. This makes it unlikely that our findings were due to chance fluctuations.No clear association was found between the cut-off points and patients' sex. In clinical practice, therefore, interpreting the NRS as mild, moderate or severe pain in terms of interference with functioning is independent of the patient's sex. By contrast, the level of catastrophizing influenced the optimal CP scheme: the optimal scheme for patients with low catastrophizing tendency was 3,6, indicating that an NRS score ≤ 3 corresponds to mild interference of pain with functioning, 4–6 to moderate interference, and 7–10 to severe interference, whereas the optimal scheme for patients with high catastrophizing tendency was the same as for the total patient sample, i.e., 5,7, indicating that an NRS score ≤ 5 corresponds to mild interference of pain with functioning, 6 and 7 to moderate interference and 8–10 to severe interference. In terms of the cut-off points between mild and moderate, this finding implies the following: among patients with low catastrophizing tendency, the interpretation of an NRS score of 4 or 5 is that the patients with these scores experience moderate interference of their pain with functioning, while among patients with high catastrophizing tendency, the interpretation of the NRS score 4 or 5 is that the patients with these scores experience mild interference of their pain with functioning.F-value to indicate the classification scheme that maximizes the differences between the groups and is therefore the most useful for distinguishing between mild, moderate, and severe pain-related interference, may not be the best method for finding the optimal CP scheme.Moderate interference with functioning would theoretically imply a higher PDI score than mild interference. However, as can be seen in Figure Optimal cut-off points of 5 and 7 were only mentioned in the literature by Zelman et al. , for patThe association between catastrophizing and cut-off points has not been studied before, so no comparison with other studies is possible. As far as we are aware, only Fejer et al.  studied The main strength of our study was the large study sample, the largest sample used until now in studies of this topic. It was also the first study taking patient's catastrophizing into account and the second to examine the influence of sex on the CP schemes.One weakness of our study is the way the patients were included, i.e., using data from a nationwide survey, which meant that response rate and hence selection bias were unknown. In some rehabilitation centers, the localization of pain complaints was not recorded in the survey questionnaire for most patients (see Table Secondly, our study used the PDI to measure interference with functioning. It is possible that other instruments, such as the BPI, would have given different results. Finally, we explored the effect of catastrophizing by splitting the population using the median split and quartile split methods. Although these are common methods to split a population, they may have influenced the results.In conclusion, we found that NRS scores ≤ 5 correspond to mild pain-related interference with functioning, scores of 6 and 7 to moderate interference and scores ≥8 to severe interference. This interpretation of the NRS in terms of mild, moderate and severe interference with functioning is independent of the patient's sex, but seems to be influenced by their catastrophizing tendency. However, the difference in CP schemes we found for patients with lower and higher catastrophizing tendencies contradicts what is theoretically plausible. The reason why we did not find the same optimal CP scheme in the subgroups of patients with lower and higher catastrophizing tendencies may be chance variability.AB, contributed to the design of the work; and the acquisition, analysis, and interpretation of data; drafted the work, approves final version to be published; agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. RS contributed to design of the work; analysis, and interpretation of data for the work; revised the work critically for important intellectual content; approved final version to be published; agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. HS, AK, RO, JS, KS, contributed to design of the work; and interpretation of data for the work; revised the work critically for important intellectual content; approved final version to be published; and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.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.