Abdominal pain is a frequent symptom in patients with inflammatory bowel disease (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC). Pain can result from ongoing inflammation or functional disorders imitating irritable bowel syndrome (IBS). Several single-nucleotide polymorphisms (SNPs) have been associated with IBS. However, the impact of IBS genetics on the clinical course of IBD, especially pain levels of patients remains unclear.Data of 857 UC and 1206 CD patients from the Swiss IBD Cohort Study were analysed. We tested the association of the maximum of the abdominal pain item of disease activity indices in UC and CD over the study period with 16 IBS-associated SNPs, using multivariate ANOVA models.P = 0.044; P = 0.037, respectively). Abdominal pain was not associated with any markers of patient management in a model adjusted for confounders. In CD patients, higher levels of abdominal pain correlated with the number of physician contacts (P < 10–15), examinations (P < 10–12), medical therapies (P = 0.023) and weeks of hospitalisation (P = 0.0013) in a multivariate model.In UC patients, the SNPs rs1042713 (located on the ADRB2 gene) and rs4663866 (close to the HES6 gene) were associated with higher abdominal pain levels (We detected an association between maximal abdominal pain in UC patients and two IBS-associated SNPs. Abdominal pain levels had a pronounced impact on diagnostic and therapeutic procedures in CD but not in UC patients. Inflammatory bowel disease (IBD) comprise inflammatory conditions of the intestinal tract including Crohn’s disease (CD) and ulcerative colitis (UC). The clinical course of IBD is variable, ranging from very mild to severe and life-threatening disease or complications . IdentifGenetic predisposition plays a prominent role in IBD pathogenesis. Genome wide association studies (GWAS) identified more than 240 single-nucleotide polymorphisms (SNPs) associated with the risk for IBD . TherefoPain is a frequent problem in IBD, affecting approximately 70% of patients and it remains a long-standing problem for every second patient . It is mAbdominal pain in the absence of active inflammation is also characteristic for irritable bowel syndrome (IBS). IBS is a functional gastrointestinal disorder (FGID) and defined by the Rome IV criteria as recurrent abdominal pain at least once a week over the last three months and two or more of the following criteria: relation to defecation, association with changes in stool frequency or changes in stool form . In a meSeveral SNPs have been analysed in the context of IBS in large GWAS and meta-analyses –20. The Even though IBD and IBS are fundamentally different conditions, some pathways of pathogenesis including alterations in gut permeability, microbiota, inflammation, enteric nervous system, gut brain axis and psychological factors are partially shared . MoreoveIn the Swiss IBD cohort study (SIBDC) extensive clinical information and genetic information are available. The primary aim of this study is to test for a possible association of IBS-SNPs and the level of abdominal pain in patients with IBD. The second goal is to explore the effects of abdominal pain on the disease management.The SIBDC has been collecting longitudinal data of IBD patients from all parts of Switzerland since 2006. Patients are followed up yearly, using both a physician and a patient questionnaire. The design and goals of the SIBDC have been described elsewhere .In 2015, in a comprehensive effort, the genotype of 379 SNPs was determined in all SIBDC patients consenting to genetic analysis provided sufficient biomaterial was available. Selected SNPs comprise genetic markers associated with IBD risk, smoking, primary sclerosing cholangitis, anxiety, depression and pain after a thorough literature search. Genotyping of the SIBDC-SNPs was performed by Matrix-Assisted Laser Desorption/Ionisation–Time of Flight Mass Spectrometry (MALDI-TOF–MS) based SNP genotyping . The comOur selection of SNPs was based on SNPs previously identified in three GWAS –18 and tClinical, epidemiological, socio-demographic and psychosocial data were extracted in autumn 2015 from the SIBDC database. Patient characteristics include gender, age at diagnosis, disease duration, time interval between IBD diagnosis and SIBDC enrolment, ethnicity, smoking habits , educatimaximal abdominal pain, assessed with the abdominal pain item from the CDAI for CD patients and the MTWAI for UC patients, respectively. Both scores distinguish four levels of abdominal pain intensity: none, mild, moderate and severe. We selected the highest reported pain score  over the entire observation period. We favoured maximal abdominal pain since it is probably the measure closest associated with the main interest of our study: pain typical for IBD during a flare. During a flare, contacts to the health system is frequent and the likelihood of an assessment for SIBDC is high. During these episodes, the highest pain levels are expected. Using maximal abdominal therefore maximises the chances to focus the assessment on pain due to acute inflammation. Moreover, maximal abdominal pain has been identified in a previous study as having the strongest impact on quality of life [The primary endpoint of our study was  of life .disease activity, we calculated CDAI for CD and MTWAI for UC, according to SIBDC follow-up questionnaires.We also used median abdominal pain  as a secondary readout in a sensitivity analysis. This measure likely integrates assessments during a flare as well as during remission. During remission, abdominal pain might be absent (in the absence of an inflammatory stimulus) or due to post-inflammatory IBS, which is not the focus of our study. In further sensitivity analyses, we also tested pain ever  as outcomes. To assess number of physician contacts we calculated all visits to the primary care physician, gastroenterologist, hospital ambulatories and other doctors, starting three months before enrolment until data extraction.For the overall number of medical examinations  was used to characterize the vigour of diagnostic efforts. In an additional analysis, the overall number of medical examinations was adjusted for the number of visits.The number of medical therapies ever used during the observation period in each patient. The following six classes of drugs were considered: (1) oral/local prednisone or budesonide, (2) purine analogues , (3) sulfasalazine and oral/local 5-amino salicylic acid, (4) methotrexate, (5) TNF-inhibitors  and (6) calcineurin inhibitors . No SIBDC patient had received vedolizumab or golimumab at time of data extraction. Additionally, the use of TNF-inhibitors (yes or no) was analysed separately.As a simple summary measure for medical treatments, we added the duration of hospitalisation, all weeks spent hospitalised, from 12 months prior to enrolment until data extraction, were summarized. Endpoints for the quality of life were the inflammatory disease questionnaire (IBDQ) [To calculate the e (IBDQ) , 34 and e (IBDQ) , 36.Data were imported into the statistical program R version 3.3.3 . To asseFor our analysis, clinical, epidemiological and genetic data of 2063 individuals with IBD were available. 1206 of those patients were diagnosed with CD and 857 with UC. Table In the SIBDC data base, data relating to 379 SNPs are available . This association remained significant (q < 0.1) after the false-discovery rate was controlled by the Benjamini–Hochberg procedure .We tested the 16 IBS-associated SNPs Table  for effeP = 0.012, q = 0.09) and the maximal abdominal pain levels in UC patients . Details of the difference in outcome according to the genotype (contrast in pain level) of rs4663866 and rs1042713 are shown in Table Our analysis also showed a significant univariate association between rs1042713  but showed no significance for rs1042713 .In additional sensitivity analyses, we also tested the association of median abdominal pain  and the binary variable pain level (no or mild pain versus moderate or severe pain) with the selected SNPs. This yielded in similar results for rs4663866 , which was lost after applying the Benjamini–Hochberg correction (q > 0.1) .Maximal abdominal pain was also an independent and highly significant predictor for the number of examinations , but not in UC patients (data not shown).In a simplified assessment of the number of medical therapies in IBD patients, we considered six classes of drugs (see methods). For patients with UC and CD, in a univariate analysis, individuals with a higher degree of abdominal pain had been exposed to a higher number of different treatments .We used data of 2063 patients from the Swiss IBD cohort study to analyse pain in IBD patients. The risk alleles of two IBS-associated SNPs increased maximal pain intensity experienced by UC but not CD patients. IBD patients frequently experience abdominal pain; however, in UC patients pain did not significantly influence management of IBD after controlling for confounders. In contrast, in CD patients, pain was associated with a higher number of physician contacts, examinations, medical therapies and hospitalisation weeks in a multivariate analysis. Both IBS-associated SNPs did not influence patient management.Pain in IBD might be caused by inflammatory and non-inflammatory pathways. The genetic risk for IBD is mediated by a number of genetic regions –4. HowevSNP rs1042713 is located on the ADRB2 gene which encodes the beta-2-adrenergic receptor. This receptor plays an important role in pain signalling cascades , 40 and P = 5 × 10–6). SNP rs4663866 is located near the transcription factor HES6 gene but no studies addressing rs4663866 function could be found in literature and mechanistic aspects remain unclear.The second SNP associated with abdominal pain, rs4663866, was identified in a GWAS for IBS . rs46638We would like to emphasise that testing for post-inflammatory IBS in our study has not been possible for two reasons: First, Rome IV criteria for our patients were not available, preventing a formal diagnosis of IBS in our IBD cohort. Second, the inflammatory state (level of inflammation) has not been rigorously tested in our patients at the time of pain assessment.In our study, abdominal pain was a crucial predictor for the intensity of disease management in CD patients. Maximal abdominal pain was strongly associated with the number of visits and investigations, TNF-inhibitor usage and overall medical therapies as well as the length of time spent hospitalised. In other studies, patient management has also been associated with measures different from acute bowel inflammation: In a longitudinal study, IBS like symptoms in IBD increased the number of clinical visits and examinations during a follow up period of more than 2 years . FurtherIn our study, pain influenced clinical management in CD but only to a much lower degree in UC. A potential explanation could be the easier clinical assessment of disease activity in UC patients. The rectum is uniformly affected in UC and disease activity directly correlates with the number of bowel movements and bloody diarrhoea. The partial Mayo score  is an accepted and validated endpoint in clinical studies of UC . Of noteIn contrast, in CD, assessment of disease activity is complex and inflammation especially in the small intestine will not necessarily result in non-ambiguous symptoms, requiring usage of “softer” parameters such as the intensity of abdominal pain for treatment decisions.Besides pain, our study also identified well-known predictors of severe disease contributing to more intense disease management. EIM were uniformly associated with all endpoints of disease management in both, UC and CD. While abdominal pain was the single symptom most consistently associated with disease management in CD, in UC, the severity of diarrhoea predicted intense management better. Other clinical markers of disease activity such as bloody diarrhoea, abdominal mass and incontinence influenced some but not all outcomes.Our study has several strengths and limitations. To the best of our knowledge, this study is the first to analyse the association between abdominal pain, SNPs previously analysed in the context of IBS and management and disease course in IBD patients. Due to the extensive data of our cohort, we were able to test and control for many possible epidemiological, sociodemographic and clinical confounders. Limitations include lack of testing for Rome IV criteria (see above). Also, the number of IBS-related SNPs tested in the Swiss IBD cohort is limited and not all SNPs identified by GWAS and systematic reviews were available. If selection of SNPs would be limited to SNPs with an association to IBS identified by a GWAS, only rs4663866 would remain. For instance, none of the SNPs tested were associated with pain in CD and it is possible that pain in CD is mediated by other SNPs. Our study should therefore be considered as pilot study and additional analyses with more SNPs are warranted. Further, effects of rs1042713 and rs4663866 should be confirmed in an independent cohort. No validated pain questionnaires (such as the McGill Pain Questionnaire ) could bOur study shows an association between pain levels in UC patients and IBS-associated SNPs, providing genetic evidence for an overlap of some disease mechanisms in IBD and IBS. We did not find an significant association between abdominal pain and patient management in patients with UC. However, in CD patients, pain was a strong predictor for intense patient management with regard to clinical visits, investigations and medical therapies, indicating that physicians use pain levels as a surrogate for disease activity in CD.Additional file 1. Supplementary tables.Additional file 2. List of SNPs available in the SIBDC (2020).


Pain is one of the major symptoms complained about by patients in the prehospital setting, especially in the case of trauma. When there is mountainous topography, as in Switzerland, there may be a time delay between injury and arrival of professional rescuers, in particular on ski slopes. Administration of a safe opioid by first responders may improve overall treatment. We therefore assessed administration of nasal nalbuphine as an analgesic treatment for trauma patients in Switzerland.This observational cohort study examined 267 patients who were treated with nasal nalbuphine by first responders in six ski resorts in Switzerland. All first responders were instructed to begin treatment by assessing the feasibility of using nalbuphine to treat pain in the patient. A treatment algorithm was developed and distributed to assure that nalbuphine was only administered following a strict protocol. Data regarding pain scores and pain reduction after administration of nalbuphine were collected on-site. Refills were handed out to the first responders with the return of each completed questionnaire.p < 0.001). The multivariate regression model showed that pain reduction was more pronounced in patients with higher initial pain levels. Nalbuphine was more effective in adolsecents than in patients aged 20 to 60 years (p = 0.006). No major side effects were observed.Nalbuphine provided effective pain relief, with the median level of pain on the numeric rating scale for pain reduced by 3 units on average, from 8 points (Nasal administration of nalbuphine by first responders is a presumably safe and effective noninvasive pain management strategy for acutely injured patients in the prehospital setting. This may be an alternative, especially in the case of severe pain and prolonged time between arrival of the first responders and arrival of EMS/HEMS personnel on scene. Pain is one of the major prehospital symptoms and requires prompt management, in particular in trauma patients. Nevertheless, many colleagues report that analgesia in the field is insufficient for multiple reasons, one being the overly long response times of the emergency medical service (EMS) –5. In SwWinter sports such as downhill skiing and snowboarding attract > 2.5 million skiers annually in Switzerland, with about 76,000 injured skiers requiring treatment . First rThere are several approved routes of nalbuphine administration, including intravenous (IV), intramuscular (IM), subcutaneous (SC) , and nasThis observational cohort study examined data collected from patients given nalbuphine analgesia by first responders in the prehospital phase. Reporting of the study conforms to the STROBE statement for the reporting of observational cohort studies.This analytical observational cohort study was performed in six different ski resorts in the canton of Graubuenden, Switzerland . All interested first responders received mandatory theoretical and practical instruction about nasal nalbuphine using the Mucosal Atomization Device . Specifically, they were instructed about the mechanisms of action, indications and contraindications, as well as the potential side effects. Administration of nalbuphine according to an algorithm was required to assure patient safety Fig. . First rNalbuphine  in a dose of 10 mg/ml in vials containing 2 ml (20 mg) was used. The dosage was according to body weight, with a minimum dose of 5 mg for patients of 20-44 kg up to a maximum dose of 20 mg for adults > 75 kg with severe pain . Apart from age and sex, no further personal data were recorded in order to ensure de-identification of patients. Also, no personal data of the first responders on scene were collected, so no conclusions about the rescuers could be drawn during later analysis.Data collection was performed directly by first responders using an online questionnaire with predefined endpoints  were treated with nasal nalbuphine by first responders (Table p < 0.001) (Table p = 0.006). The same tendency was observed for the elderly population, (≥60 years of age); however, there were only 20 patients in this age group and the difference was not statistically significant. The level of pain reduction was similar for both sexes (Table The trauma victims reported a median pain level of 8 points (IQR 7 to 9) on the numeric rating scale at the initial assessment by first responders. Nalbuphine caused a statistically significant and clinically relevant decrease in the level of pain, by a median of 3 NRS units, p < 0.00 (Table 11) Table  & 3. The1) Table . Nalbuphn = 11) of patients. No major adverse events like intoxications which needed to be reversed by the intravenous administration of naloxon were observed.Mild side effects were reported in 5.6%  of the patients, which is to be expected in an observational study in the pre-hospital setting. There was also a predominance of the male sex, which could have had an influence on the described pain reduction. We observed only a few minor side effects with nalbuphine. However, we did not follow up on the patients, and we cannot prove that nalbuphine administration is always safe.Our study has some limitations. First, we could not follow up patients after handover to EMS/HEMS personnel. Second, we mainly observed traumatic shoulder and knee injuries, which is expected with the predominance of our study sites being in Swiss ski resorts . Third, In conclusion, nasal nalbuphine administered by first responders was a noninvasive pain management strategy that provided effective and presumably safe analgesia in prehospital, acutely injured patients in our studied environment. This method may provide an alternative, especially in situations involving severe pain and prolonged time between arrival of the first responders and arrival of EMS/HEMS personnel on scene. This conclusion is viable in the setting described, involving trained first responders. Further studies would be needed to include an overall recommendation for laypersons.


Background: The objective benefits of low dose radiotherapy (LDRT) for non-malignant joint disorders are controversial. This study evaluated changes in pain, quality of life (QoL) and function after LDRT for epicondylitis, plantar fasciitis, and finger osteoarthritis.Materials and Methods: Patients over 40 years old with epicondylitis, plantar fasciitis, and finger osteoarthritis were had pain following at least 6 months of conservative therapy. Patients received 0.5 Gy LDRT twice weekly for 4 weeks repeated once after 8 weeks in patients who failed to achieve complete pain relief. Patients assessed their pain according to the visual analog scale. Handgrip strength was measured with an isometric dynamometer and the fast self-paced walking test was used in patients with plantar fasciitis. QoL was evaluated according to the EQ-5D and HAQ-DI questionnaires.Results: Outcomes for 157 patients (204 sites) were documented at 2, 6, and 12 months after last LDRT. Pain reduction at rest (p < 0.001), during activity (p < 0.001) and increase in handgrip strength  were highly significant for patients with lateral epicondylitis. Patients with medial epicondylitis reported pain relief at rest (p = 0.041) and during activity (p = 0.041) and significant increase in handgrip strength (p = 0.022). Patients with plantar fasciitis reported pain reduction at rest (p < 0.001), during activity (p < 0.001) and faster walking times (p < 0.001). A trend toward improved QoL was observed. Patients with finger osteoarthritis reported significant pain relief during activity (p < 0.001) and a gain in handgrip strength (p = 0.004), with a trend to both pain relief at rest (p = 0.056) and stronger pinch grip (p = 0.099).Conclusions: LDRT achieved significant pain relief at rest and during activity and a corresponding objective improvement in handgrip strength in patients with epicondylitis. Pain relief at rest, during activity and improvement in walking time were demonstrated in patients with plantar fasciitis. LDRT achieved pain relief during activity, and handgrip strength was improved in patients with finger osteoarthritis. No significant effect was seen on quality of life measures for these conditions. The observed benefits were maintained 12 months after LDRT for all 3 indications and we recommend this low cost, safe intervention for patients over 40 who have failed prior conservative therapy. The Numerous retrospective series describe response rates of 63–89% following LDRT for non-malignant joint disorders . 7–70% oIn 2014 in Germany, 16,989 patients with non-malignant musculoskeletal conditions were irradiated to improve quality of life through pain relief and gain in function . PatientThe aim of this study was to assess objective changes in musculoskeletal function in addition to patient-reported outcome measures (PROMs) in patients with lateral and medial epicondylitis, plantar fasciitis, and finger osteoarthritis following LDRT as applied in our practice.The trial was approved by the institutional review board  and registered with the German Registry for Clinical Studies (No. DRK 500006288). Informed consent was obtained for inclusion of patients in the study. This prospective, uncontrolled interventional trial was performed in a single center setting and was conducted according to Good Clinical Practice and the declaration of Helsinki. The trial closed 12 months after the last patient was treated.Consecutive patients with persistent pain from lateral and medial epicondylitis, plantar fasciitis and finger osteoarthritis who were referred for LDRT for were recruited between 01/2013 and 10/2015. Inclusion criteria were (1) age >40, (2) Karnofsky performance status >70, (3) non-pregnant or non-lactating if female, (4) effective contraception for 12 months if relevant and (5) prior treatment with conservative measures  for at least 6 months. Exclusion criteria were previous radiotherapy to the site, radiosensitivity disorders or an inability to comply with the study protocol.®, USA)  for quality of life  and the ®, USA)  in elbow® dynamometer , which counts the time taken to walk 20 meters . This siPatients were irradiated with 8 x 0.5 Gy twice a week on non-consecutive days over 4 weeks to a total dose of 4.0 Gy with 200 kV orthovoltage direct fields . Non-target joints and, in the case of finger irradiation nail beds, were shielded with lead . The dosLDRT was repeated up to a dose of 8.0 Gy in patients who did not achieve a complete pain response with the first course . Follow-The study endpoints were VAS pain scores, handgrip and pinch grip strength (kg), walking time (seconds), EQ-5D score  and HAQ-DI score. Outcomes were evaluated per site and patients with lateral epicondylitis, medial epicondylitis, finger osteoarthritis and plantar fasciitis were analyzed separately.post hoc testing of median changes was performed (paired Wilcoxon signed rank test). The two-sided p-values were adjusted for multiple comparisons (Bonferroni-Holm method). An adjusted p-value of less than 0.05 was considered statistically significant. Spearman's rank correlation coefficient (rho) was calculated to assess the relationship between changes in pain scores and functional test outcomes for lateral epicondylitis and plantar fasciitis. A smoothing function was fitted to the EQ-5D and the HAQ-DI scores using locally weighted smoothing (LOESS) to allow an estimation of the overall time trend. All statistical analyses were conducted using the statistical software package R  are presented for each time point for each analysis set . The difackage R .One hundred and fifty-seven patients  with 204 sites were treated: lateral epicondylitis (39), medial epicondylitis (10), finger osteoarthritis (99) and plantar fasciitis (56). The low number of patients with medial epicondylitis reflects its incidence. All patients reported limitations in activities of daily living (ADL) due to pain at rest or during activity. Patient characteristics are summarized in Complete pain response (VAS 0) was achieved in 55/204 (27%) of sites after the first course of low dose radiotherapy and therefore the second course of LDRT was not given in these patients. The planned second course of LDRT was delivered in 149/204 (73%) sites after 2–12 months . Eighty percent (165/204) of treated sites could be assessed at 12 months . All patients who attended for follow-up at 2, 6, and 12 months returned the quality of life questionnaires.The data points for each set at 2, 6, and 12 months after last LDRT (12 months after the first course if one course was given or the second course in the event of 2 courses of irradiation) are shown in violin plots . The medp = 0.006), and during activity after 12 months (p = 0.002). This pattern was observed after the first and second course of LDRT. Median change in pain score 12 months after last LDRT was −2.5 (p < 0.001) at rest, and −6.0 (p < 0.001) during activity. At rest, 23/31 (74%) treated sites responded completely and 21/27 (78%) patients were pain free at 12 months. During activity, 13/30 (43%) treated sites and 11/28 (39%) patients were pain free at 12 months. Median change in handgrip strength 12 months after last LDRT was 5.2 kg (p = 0.002) in elbow flexion and 16.0 kg (p < 0.001) in elbow extension (p < 0.001) and pain during activity  . A median pain score of 0 at rest was reached 2 months after LDRT (xtension . There w< 0.001) . No tren< 0.001) .p = 0.331 and p = 0.249, respectively). At rest, 5/6 treated sites (83%) were pain free at 12 months. Median changes in pain 12 months after last LDRT were: −3.0 (p = 0.041) at rest and −4.0 (p = 0.041) during activity (p = 0.022). Quality of life seemed to increase after radiotherapy according to the EQ-5D but not the HAQ-DI score . At rest, 40/83 (48%) treated sites (27/48: 56% patients) were pain free at 12 months. In contrast, pain during activity was high at baseline (median: 5.0) and decreased significantly after last LDRT . During activity, 11/83 (13%) treated sites (9/48: 19% patients) had VAS scores of 0 at the same time point. A significant improvement was seen for handgrip strength  but not pinch grip  at 12 months. No clear trend was visible in either EQ-5D total score or HAQ-DI (Pain at rest due to finger osteoarthritis was low prior to therapy (median: 2.0) and did not decrease significantly after last LDRT . 38 of 41 (93%) sites evaluated at 12 months  were pain free. In comparison, pain scores during activity were higher before LDRT (VAS: 6.0) but decreased to a VAS of 0 after 6 months . 28 of 41 sites evaluated at 12 months  were pain free during activity. Median change in pain during activity 12 months after last LDRT was −6.0 (p < 0.001). Performance in the fSPWT also improved significantly. At 12 months after LDRT, the median walking time was 5.0 s quicker (p < 0.001) compared with before first LDRT. At 12 months, the correlation between walking time and pain during activity  was stronger than with pain at rest . There seemed to be a slight increase in EQ-5D total score) but not for the HAQ-DI  and was sustained for 12 months. Median change in pain at rest at 12 months was −4.0 , the data cannot be considered statistically meaningful, however the median 6.5 kg increase in handgrip strength 12 months after LDRT and pain reduction of 3–4 VAS points strongly suggest efficacy in both medial epicondylitis and lateral epicondylitis.Other than a dose finding study , this isPatients with finger osteoarthritis and pain during activity reported pain relief following LDRT, however, the reduction in pain relief at rest did not quite reach statistical significance, although there was a trend to improvement 12 months after LDRT as compared with prior to first LDRT. The low baseline VAS scores at rest-16/59 patients (27%) had median VAS 0 at rest but pain during activity-may have been a contributory factor. This pattern of pain during activity but not at rest is characteristic of osteoarthritis .This study confirms the effectiveness of LDRT for the pain relief of plantar fasciitis, consistent with complete response rates of up to 81% reported in a review of 11,909 patients from 22 studies . We usedWe showed a corresponding improvement in function after LDRT for plantar fasciitis. Guidelines from the American Physical Therapy Society recommend: “… easily reproducible activity limitation and participation restriction measures associated with their patient's heel pain/plantar fasciitis to assess the changes in the patient's level of function…” . The fSPThe improved pain and function test scores did not translate into significant improvements in quality of life or improvement in functional independence for any subgroup as evaluated by EQ-5D and HAQ-DI, respectively. Trends to increased function and decreased invalidity could be seen in 50% of the analysis sets , however the medial epicondylitis group contained only a small number of patients. It is possible that these questionnaires did not clearly show a corresponding benefit in quality of life as the questions address practical issues which are likely to be limited by chronic joint deformity  can bettThe main limitation of this study is that concomitant analgesia could not be interpreted as non-malignant musculoskeletal conditions such as osteoarthritis usually affect more than one anatomical site and dosage may be altered due to pain at a non-irradiated site. Although a transient pain flare may require additional medication, the subsequent sustained analgesic benefits of radiotherapy can reduce the need for long-term analgesia and the associated potential toxicities . Study pRandomized data for LDRT in non-malignant conditions are scarce , 55, 56 Two recent sham-controlled RCTs failed to demonstrate any beneficial effect of 1.0 Gy weekly for 6 weeks in patients with osteoarthritis of the hand  and kneeThe primary endpoint of the above sham-controlled RCT was “proportion of responders”  and this was not statistically different in the experimental  and the sham  groups. Patients received only one course of LDRT and the primary endpoint was assessed after only 3 months. In our study, two courses of LDRT were standard and received by 73% of patients who had an incomplete pain response after the first course. It has been observed that patients with plantar fasciitis, epicondylitis, and hand osteoarthritis benefit from a second course of LDRT after 8 weeks . A largeMany countries do not offer radiotherapy for benign conditions, mostly due to concerns about the potential for radiation-induced malignancy. As the population in many countries is aging and such disorders result in significant impairment in quality of life and costs, there is now a wider international interest in LDRT . As a prPatients with refractory pain from lateral epicondylitis, plantar fasciitis and finger osteoarthritis with pain during activity reported significant pain relief and demonstrated improved musculoskeletal function sustained after 12 months. The improved pain and functional test scores were not associated with improved quality of life as evaluated by the EQ-5D and HAQ-DI questionnaires. LDRT with 6 x 0.5 Gy, repeated after a minimum of 8 weeks in the absence of a complete pain response, may be offered to patients over 40 years old as a safe, non-toxic treatment modality which may achieve sustained pain relief and improved functional outcomes 12 months after the last treatment.The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by Aargau Ethikkommission (2012/069). The patients/participants provided their written informed consent to participate in this study. Informed consent to participate was obtained for all patients.BE, IT, EM, PH, and SB designed the trial. DV performed the statistical analysis. SR wrote the manuscript. OR and SB reviewed the manuscript. BE, EM, SD, SG, and LM collected data. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Sternal fractures are rare accounting for about 3–8% of traumatic chest. There are many lines of treatments for sternal fractures which can be classified as conservative or surgical. Surgical techniques include wire fixation and sternal plating. There are no standardization of indications for each line of management.We explore if sternal reconstruction using locking titanium plates and self-tapping screws provide the patient with the best chance of proper sternal healing avoiding chronic pain and its complications and allow the patient early mobilization and rapid restoring of his normal life at its maximum.Our inclusion criteria are patients of both gender from 20 to 60 years of age presented with traumatic sternal fracture at any site or pathological fracture due to metastatic or primary tumors infiltrating the sternum. High Associated Injury Scale scores were excluded. Exclusion criteria also included patients younger than 20 years or older than 60 years. Primary outcome is post-operative pain score and is measured using numerical pain scale ranging from zero to 10 where zero means there is no pain at all and ten is the worst imaginable pain ever.n = 5) with Median scores being 7 and 1.5 with range being from 7 to 9 and 1 to 3 respectively . Operative time range between 150 min and 90 min with median of 120 min. Extubation of patients was smooth with no events with median time of extubation being 120 min. From our experience, there were no observed wound complications except at the third patient who suffered a small wound hematoma that was resolved by gentle compressing only and needed no further intervention.Sternal reconstruction using titanium plates has proven to be an efficient method of stabilization with tremendous immediate relief of pain showed by the differences between pre-operative and post-operative pain scale scores in our patients (We recommend adopting sternal reconstruction using titanium plating systems more readily encouraging even larger clinical trials on the way to a clear guidelines. Plating systems show promising results with least pain, better stability, less complications and rapid, smooth recovery.NCT04092374 Sternal fractures are rare accounting for about 3–8% of traumatic chest injuries , 2. It nWe explore if sternal reconstruction using locking titanium plates and self-tapping screws provide the patient with the best chance of proper sternal healing avoiding chronic pain and its complications and allow the patient early mobilization and rapid restoring of his normal life at its maximum especially for those patients who depend on active lifestyle.This is a case series of patients who needed sternal reconstruction for traumatic and pathological causes. Our inclusion criteria are patients of both gender from 20 to 60 years of age presented with traumatic sternal fracture at any site or pathological fracture due to metastatic or primary tumors infiltrating the sternum. High Associated Injury Scale scores were excluded due to affection on our primary outcome acting as a confounder. Exclusion criteria also included patients younger than 20 years or older than 60 years. Primary outcome is post-operative pain score and is measured using numerical pain scale ranging from zero to 10 where zero means there is no pain at all and ten is the worst imaginable pain ever. Our secondary outcomes include hospital stay and period of bed recumbence. Sternal fracture is defined as discontinuity of sternal cortex at any part of the cortex palpated on examination and seen by imaging techniques such as CXR and CT chest. Planning is done based on prior assessment of patients’ general condition, their preferences and a written consent is signed. Choosing type and shape of plates is made based on site of fracture and mechanics of movement at this part to provide the most achievable stability. End state variables will be designated, such as, morbidity, or mortality. Morbidity will include wound infection, postoperative pain, delayed healing, sternal dehiscence & postoperative length of hospital stay at short term post-operative period. Analysis of post-operative pain will be done using numerical pain score system. Post-Operative sternal healing will be assessed by the standard suitable imaging modality, MSCT Chest with 3D Reconstruction is used in all casesWound healing will be assessed by close monitoring for signs of inflammation or infections such as redness, increasing pain, wound discharge or swelling.Titanium plates were used with different shapes and sizes according to site of fracture from BIOMET™ with 2.4*8 mm self-tapping screw.P-value (.034)} with early recovery and ambulation. Hospital stay was 2 days including the day of surgery. Early Post-operative follow-up showed excellent wound healing with no seroma nor surgical site infection , general condition was good with GCS 14, vitally stable. Examination showed bruising on chest with tenderness over upper chest. Primary survey showed suspicious appearance at manubrium at CXR so we proceeded with MSCT chest for further evaluation and it showed fracture of manubrium together with left sterno-clavicular joint fracture and no other abnormalities were detected. Planning for surgery is done after counselling the patient. We used 4-holes straight titanium plate for manubrial fracture and 4-holes orbital titanium plate with titanium 2.7 mm auto self-tapping screws for further stabilization at manubrio-sternal joint. Post-operative pain score was 1 compared with 7 pre-operatively {Male patient, 50 years old presented to trauma department with blunt trauma to chest because of motor vehicle accident. Patient was vitally stable, GCS 15 with agonizing pain. Appropriate analgesia is administrated together with primary survey which showed mid-sternal fracture at lateral CXR and no other abnormalities could be detected. MSCT chest was obtained for further evaluation of the fracture. It showed mid-sternal fracture. Counselling of the patient with planning for surgery is made. One orbital titanium plate is used for fixation of the fracture. Post-operative pain score was 1. Hospital stay was 2 days with early mobility and rapid recovery without any respiratory function complications.Male patient, 45 years presented to our trauma department with motor vehicle accident, GCS could not be assessed due to motor system affection. Patient presented vitally stable with BP 110/70, HR 85, SaO2 on Room air (RA) 97%. Primary survey showed abnormal sternal appearance on CXR together right radial fracture. MSCT chest showed manubrio-sternal joint fracture with mild lung contusion. MSCT spine showed cervical injury and patient needed collar for stabilization of cervical spine. Patient was unable to move both his legs and showed sensory level affection starting at T 10 dermatome (umbilicus). His right forearm was put in plaster of Pairs (POP) after orthopedics evaluation. Counselling of patient is done about options of fixation of his sternal fracture and planning for plate fixation is made after his choice and consenting. Although this patient has high associated injury scale (AIS) score, we were concerning about providing our patient with best options for better coping and faster recovery from his sternal fracture which was adding sever pain to his suffering. We used straight titanium plate with two orbital plates at each side for better stability of his sternum and pain recovery. His pain score was not reliable due to other confounding factors which are cervical agonizing pain and his sensory level loss. However, he showed excellent recovery post-operatively in the form of good wound healing, normal respiratory function tests without any deterioration which gives us a clue about stability and recovery of his sternum that caused no further pain which if persisted could lead to chest stitching pain with respiration leading to decrease inspiratory reserve volume, atelectasis and suppression of cough mechanisms with chest infections super-imposed. Hospital stay was 40 days due to orthopedics and neurosurgery follow-up Figs. , 4 and 5Male patient, 55 years, presented with blunt trauma to his chest of high velocity. Primary survey of the patient showed no abnormalities. Sever tenderness on his chest raised our suspicious so we proceeded with MSCT chest. It showed fracture at his manubrium. We used H-shaped titanium plate. His Pain score was 2. His hospital stay was 4 days Fig. .Fig. 6IMale patient, 42 years old, was diagnosed with chondrosarcoma at the body of the tumor. MSCT chest is done for staging and evaluation of the patient alluding its suitability for excision. After discussion with patient and consenting, surgical excision was the decision. At exploration the mass had infiltrated the whole body of the sternum and overlying pectoral muscle. Surgical excision of the body of the sternum together with the overlying pectoralis is done leaving a big gap. Titanium mesh 20*10 cm is used fixed by 2 mm titanium screws and sandwiched between 2 layers of prolene meshes. Post-operative pain score was 2 at third day and he was discharged successfully at that day with good recovery. At 1 week post-operative follow-up, there has been good stability of chest wall with perfect wound healing (Table n = 5) with Median scores being 7 and 1.5 with range being from 7 to 9 and 1 to 3 respectively . Operative time range between 150 min and 90 min with median of 120 min. Extubation of patients was smooth with no events with median time of extubation being 120 min. From our experience, there were no observed wound complications except at the third patient who suffered a small wound hematoma that was resolved by gentle compressing only and needed no further intervention. Indeed, wound seroma or hematoma was reported in many literature with a rate of 24% of cases [Sternal reconstruction using titanium plates has proven to be an efficient method of stabilization with tremendous immediate relief of pain showed by the differences between pre-operative and post-operative pain scale scores in our patients n =  with Medof cases . Bleedinof cases . We recoPlating stabilization of sternum shows mechanical superiority over other methods of stabilization taking into consideration the liability of this part of chest wall to motion with spontaneous ventilation and minor movement being an important point of muscle and ribs attachment and the complex mechanics of chest wall. Trivial movements are making shear forces which disrupt healing process needing absolute stability necessitating good stabilization , 10. ThiSmall number of cases –15 preseWe recommend exploring sternal reconstruction using titanium plating systems more readily encouraging even larger studies on the way to a clear guidelines. Giving our patients the best available curative options for sternal reconstruction with better Quality of Adjusted Life Years (QALY) should be our main consideration. Plating systems show promising results with least pain, better stability, less complications and rapid, smooth recovery.


Postoperative pain in children has always been inadequately evaluated. This study aims to evaluate the postoperative pain response using an additional dose of brachial plexus block (BPB) for younger children receiving elbow surgeries under general anesthesia (GA).This retrospective case-control study included pediatric patients (3–10 years) who underwent surgeries for elbow injuries between January 2015 and January 2019. Patients with previous history of surgeries around the elbow, neurological impairment of injured limb, polytrauma, undergoing pain management for different causes, and open or old fractures were excluded. Patients were dichotomized into the GA group and the GA + BPB group as per the presence or absence of BPB.P < 0.001). As for the pain response after medial epicondyle fracture of the humerus (MCFH), the FLACC pain scale was significantly higher for those in the GA group (6.0 ± 0.8) when compared to the GA + BPB group (1.5 ± 0.5) (P < 0.001). As for the pain response after supracondylar fracture of the humerus (SCFH), the FLACC pain scale was significantly higher for those in the GA group (6.0 ± 0.8) when compared to the GA + BPB group (1.6 ± 0.5) (P < 0.001). As for the pain response after cubitus varus correction, the FLACC pain scale was significantly higher for those in the GA group (6.7 ± 0.7) when compared to the GA + BPB group (2.1 ± 0.7) (P < 0.001).In all, 150 patients  in the GA and 150 patients  in the GA + BPB group were included. There existed no significant differences between the two groups in age, sex, fracture side, and types of elbow procedures. As for the pain response after lateral condyle fracture of the humerus (LCFH), the FLACC pain scale was significantly higher for those in the GA group (6.2 ± 0.8) when compared to the GA + BPB group (1.6 ± 0.5) (An additional shot of BPB for patients undergoing surgeries for elbow surgeries resulted in better postoperative pain response in younger children without significant BPB-related complications. Most of the orthopedic surgeries in the pediatric population, especially in younger children, are performed under general anesthesia (GA) . Age lesIn order to cope with postoperative pain, additional ultrasonography (US)-guided brachial plexus block (BPB) was implemented for pediatric patients under GA since 2017 at our institute. This study aims to compare the postoperative pain response under GA with or without BPB retrospectively.From January 2015 to January 2019, all patients who underwent elbow surgeries under GA were retrospectively reviewed. Since 2017, additional BPB was performed in younger children at our institute, and it was consented by the parents. The results are summarized according to the type of fractures that the patient had: lateral condylar fracture of the humerus (LCFH), medial epicondyle fracture of the humerus (MCFH), supracondylar fracture of the humerus (SCFH), and cubitus varus deformity.Inclusion criteria: (1) pediatric patients aged between 3 and 10 years who underwent surgeries for LCFH, MCFH, SCFH, and corrective osteotomy and fixation for cubitus varus deformity; (2) no previous history of surgeries around the same elbow; and (3) patients without neurological impairment. Exclusion criteria: (1) patients with polytrauma or open fractures, (2) patients with the underlying disease requiring regular pain management, (3) patients not having clear and complete medical records, and (4) delayed presentation of elbow fractures.The pain response at PACU after extubation was evaluated by the anesthetic nurse using Face, Legs, Activity, Cry, and Consolability (FLACC) pain scale . Pain reχ2) test, and the continuous data were analyzed using Student’s t test. Fisher exact test was used under those circumstances with fewer subjects in groups of interest. Data were presented as mean ± SD (range), median (range), or n (%). A P value of less than 0.05 was considered significantly different.SPSS statistical package program  was used for statistical analysis. The categorical data were analyzed using the chi-square (As shown in Table P < 0.001), and all patients in GA group were given additional analgesics in PACU. The pain response from the patient, caregiver, and HCW was significantly better in the GA + BPB group. The frequency of waking up from the sleep, calling nurse/doctor, and utilization of oral ibuprofen was significantly higher in the GA group than the GA + BPB group. Thirty-nine percent (17/44) of patients in the GA group required additional analgesics during the night shift, whereas only 8.9% (4/45) in the GA + BPB group required additional analgesics.As for the pain response after LCFH Table , there wP < 0.001), and all patients in the GA group required additional analgesics in PACU. The pain response from the patient, caregiver, and HCW was significantly better in the GA + BPB group. The frequency of waking up from the sleep, calling nurse/doctor, and utilization of oral ibuprofen was significantly higher in the GA than the GA + BPB. Fifty-two percent (12/23) of patients in the GA group required additional analgesics during the night shift, whereas only 13% (3/23) in the GA + BPB group required additional analgesics.As for the pain response after MCFH Table , there wP < 0.001), and 75.0% (45/60) patients in GA group required additional analgesics in PACU. The pain response from the patient, caregiver, and HCW was significantly better in the GA + BPB group. The frequency of waking up from the sleep, calling nurse/doctor, and utilization of oral ibuprofen was significantly higher in the GA group than the GA + BPB group. Twenty-five percent (15/60) of patients in the GA group required additional analgesics during the night shift, whereas no patients in the GA + BPB group required additional analgesics.As for the pain response after SCFH see Fig. , Table 4P < 0.001), and all patients in GA group required additional analgesics, whereas 54.5% (12/22) in the GA + BPB group required analgesics in PACU. The pain response from the patient, caregiver, and HCW was significantly better in the GA + BPB group. The frequency of waking up from the sleep, calling nurse/doctor, and utilization of oral ibuprofen was significantly higher in the GA group than the GA + BPB group. Seventy-four percent (17/23) of patients in the GA group required additional analgesics during the night shift, whereas only 27.3% (6/22) in the GA + BPB group required additional analgesics.As for the pain response after corrective osteotomy for cubitus varus deformity Table , there wNone of the patients reported BPB-related complications during the postoperative follow-up visit.Additional BPB for elbow surgeries resulted in better postoperative pain response without significant BPB-related complications.Elbow surgeries for fractures and cubitus varus deformity correction are common in the pediatric population , 17. AltIn displaced LCFH and MCFH, open reduction and internal fixation (ORIF) is our preferred choice and usually yields satisfactory outcomes , 28. WheAdditionally, the cost for BPB is about 120 US dollars at our institute, and it is affordable for most patients and their families. There have been reports regarding the complications, including pneumothorax and neuropathy, related to the BPB , 31; howAn additional BPB is recommended for patients undergoing ORIF for elbow fractures; however, it might not be necessary for patients requiring CRPP only. More attention should be paid for postoperative pain management for patients undergoing corrective osteotomy and fixation with the application of a tourniquet for cubitus varus deformity. It is because the corrective osteotomy and fixation usually takes longer surgical time and prolonged use of the tourniquet that might result in tourniquet-related pain , 33.There were certain limitations in our study. Firstly, it is a retrospective study with modest sample size; secondly, the cost of BPB is different in different countries, and cost-effective analysis remains to be investigated.An additional shot of BPB for patients undergoing surgeries for elbow surgeries resulted in better postoperative pain response in younger children without significant BPB-related complications. Those treated with GA + BPB had significantly less pain regardless of the fracture type. Patients treated with GA + BPB also woke up from sleep much less and utilized oral ibuprofen significantly less than those treated with GA alone regardless of fracture type.


Assessment of pain is critical to its optimal treatment. There is a high demand for accurate objective pain assessment for effectively optimizing pain management interventions. However, pain is a multivalent, dynamic, and ambiguous phenomenon that is difficult to quantify, particularly when the patient’s ability to communicate is limited. The criterion standard of pain intensity assessment is self-reporting. However, this unidimensional model is disparaged for its oversimplification and limited applicability in several vulnerable patient populations. Researchers have attempted to develop objective pain assessment tools through analysis of physiological pain indicators, such as electrocardiography, electromyography, photoplethysmography, and electrodermal activity. However, pain assessment by using only these signals can be unreliable, as various other factors alter these vital signs and the adaptation of vital signs to pain stimulation varies from person to person. Objective pain assessment using behavioral signs such as facial expressions has recently gained attention.Our objective is to further the development and research of a pain assessment tool for use with patients who are likely experiencing mild to moderate pain. We will collect observational data through wearable technologies, measuring facial electromyography, electrocardiography, photoplethysmography, and electrodermal activity.This protocol focuses on the second phase of a larger study of multimodal signal acquisition through facial muscle electrical activity, cardiac electrical activity, and electrodermal activity as indicators of pain and for building predictive models. We used state-of-the-art standard sensors to measure bioelectrical electromyographic signals and changes in heart rate, respiratory rate, and oxygen saturation. Based on the results, we further developed the pain assessment tool and reconstituted it with modern wearable sensors, devices, and algorithms. In this second phase, we will test the smart pain assessment tool in communicative patients after elective surgery in the recovery room.Our human research protections application for institutional review board review was approved for this part of the study. We expect to have the pain assessment tool developed and available for further research in early 2021. Preliminary results will be ready for publication during fall 2020.This study will help to further the development of and research on an objective pain assessment tool for monitoring patients likely experiencing mild to moderate pain.DERR1-10.2196/17783 Pain is the most common reason for patients to seek medical care and is associated with many illnesses . There iAutomated and continuous pain intensity assessment for poorly communicating patients can enable timely treatment, reduce the monitoring burden on clinicians, and contribute to optimizing the use of analgesics and managing side effects and complications . As painState-of-the-art automatic and objective pain intensity assessment techniques described in the literature use physiological data, obtained by monitoring the changes in patients’ physiological data, such as electromyography (EMG), electrocardiography (ECG), photoplethysmography (PPG), and electrodermal activity (EDA), to identify autonomic nervous system reactions to pain. One of the most well-known pain indicators is facial muscle activity. The facial nerve controls voluntary and involuntary activity of the facial muscles. The involuntary control of facial muscles is both protective and emotional, signaling the experience of pain. Other objective pain assessment tools include the surgical pleth index , based on analysis of the PPG waveform and heart rate. Similarly, analysis of skin conductance has been used as a surrogate for pain in clinical situations .Wearable technology is a promising paradigm to integrate several technologies and communication solutions ,13. The The main research project consists of 3 study phases, which Phase 2, described in this paper, involves the further development of and research on a pain assessment tool in patients likely experiencing mild to moderate pain. In phase 3, we will conduct a trial to assess the effectiveness of the whole platform in uncommunicative patients at 2 sites, both of which will have both intervention and control groups. In the intervention and control patients, continuous pain intensity assessments will be collected by the sensors embedded in a facial patch worn by all study patients.This protocol focuses on the second phase of a larger prospective observational data collection study to collect training data from patients likely experiencing mild to moderate pain . The IRB approved the recruitment of 30 participants selected from the Acute Pain Service patient list at University of California, Irvine Medical Center (UCIMC) in Irvine, CA, USA. The Acute Pain Service unit at UCIMC serves over 100 participants weekly, enabling the lead physician to recruit patients for this study. We will collect primary demographic data from each patient, including height, weight, body mass index, and sex.Approximately 30 minutes of continuous biosignals  data will be collected from the participants. We will separate this 30-minute period into 2 parts: control (baseline pain) and experimental. Each part will consist of 2 to 3 challenge intervals in an attempt to capture pain perception before, during, and after a stimulus, with appropriate rest periods to make the statistical analysis more powerful.In the control part, we will use a transcutaneous electrical nerve stimulation (TENS) unit  to obtaiIn the experimental part, patients will be engaged with soft activities  that may cause a pain sensation. The participant’s experience of pain will be recorded using NRS. The NRS for pain is a unidimensional measure of pain intensity and a segmented numeric version of the VAS, in which a respondent points to a number (integers from 0 to 10) on the NRS that best represents the intensity of their pain . The usuThe prospective study will be conducted at UCIMC. The primary study population will comprise adults ranging in age from 18 to 89 years. The maximum number of patients to be asked for their consent and data collection, including withdrawals, is 30. We expect 20 to complete the study.Participants who are enrolled on this UCIMC protocol must meet the following criteria: (1) are aged 18 years or older, (2) will be consulted by the APS, (3) have the ability to communicate, (4) have provided written informed consent, and (5) have healthy, intact facial skin. Participants will be excluded if they have (1) any diagnosed condition affecting cognitive functions , (2) hand deformities that prevent the sensor from being placed, (3) any diagnosed condition affecting the central nervous system, or facial nerves or muscles, or (4) significant facial hair growth in the area where the sensors will be attached.We must consider the natural variation in caseload (such as trauma and elective procedures) specific to both of our institutions’ regions, coupled with the fact that the recovery period is different for each patient. All candidates considered for enrollment universally will be experiencing postoperative pain during their hospitalization, and all will be receiving analgesic treatment. The study team ensures that patient safety will not be compromised while maintaining regulatory compliance, and future studies will be aimed at multicenter studies with a larger, diverse sample size to support generalizability.After IRB approval, we will screen the medical records at UCIMC, to which APS has access, to determine patient eligibility using the protocol inclusion and exclusion criteria. The anesthesiologist will approach their patients directly about study participation at the University of California Irvine Douglas Hospital, Orange, CA, USA. The study procedure will be continued if patients show interest and are suitable for the study (according to the inclusion and exclusion criteria). The study physician will explain the study in detail, providing both oral and written information. If a patient decides not to participate in the study, the study will be discontinued for this patient. If the patient is still willing to participate, the study participant enrollment log will be updated accordingly. During the study, participants’ experience of pain intensity will be recorded using the NRS.Eligible patients will be given a consent form to consider until the following day, when the study physician will follow up regarding their participation. We encourage all participants to discuss study participation with their family and friends before consenting. Patients will be enrolled in the study only after one of the investigators has reviewed the consent form with each patient, ensuring that the patient has understood the study, has answered all questions, and has provided written informed consent. Patients are also informed about their right to withdraw from the study at any time, that their participation is voluntary, and that withdrawal would not affect their patient care.iHURT is a system that tracks changes in the activity of facial muscles  developed at the University of Turku, Finland. It simultaneously uses physiological signs such as heart rate, heart rate variability, respiratory rate, and EDA as adjuvant measures as we attempt to develop an algorithm for pain assessment in hospitalized patients. The technology used in this study to capture the aforementioned signals includes the following components.EMG and ECG are both biopotential signals captured from the skin surface. We developed the system used to collect them in our previous work . The sysThe device is configured to work in single-ended mode, called a monopolar electrode configuration, where the potential in each channel is measured between the electrode on the target site and the common reference electrode. The common reference electrode is placed on a neutral bony area behind the ear. For this reason, 2 channels are used to collect the lead I ECG, as As a sensitive and convenient measure of indexing changes in sympathetic arousal associated with emotion, cognition, and attention, EDA has been widely used in psychological studies  and in sTo monitor EDA and PPG, we use the commercially available Empatica E4  wristband. The wristband will permit participants to maneuver more easily, as it will not impede their movements and will reduce the time of each patient encounter because it is considerably easier to position on the patient. The wristband has an internal memory that can record up to 36 hours of data and allows for wireless data transmission. The E4 wristband is rechargeable, with a charging time of less than 2 hours. It includes an EDA sensor, which measures the constantly fluctuating changes in certain electrical properties of the skin. This device can also noninvasively monitor blood volume pulse PPG in real time through green and red light-emitting diodes.The TENS device is a US Food and Drug Administration (FDA)–cleared Class II over-the-counter HealthmateForever YK15AB  electrotherapy device. The TENS unit works by delivering small electrical impulses through electrodes that have adhesive pads to attach them to a person’s skin.For patients who have consented to participate, a study team member will explain what will happen in the next 30 minutes, how to report their pain level, and what the NRS is. The team member will demonstrate how the TENS unit works on themselves with separate electrodes and explain that it is not harmful. Then, the following components will be placed on the participant: (1) the 8 leads of the EMG and ECG, (2) the Empatica E4 sensor, and (3) the TENS unit on the contralateral arm.The biopotential acquisition device will be connected to the study analyst’s laptop and the Empatica E4 will be connected to the study analyst’s iPhone, both over Bluetooth. Data recording will begin after the study participant, clinical researcher, and study analyst are ready. The start of the recording period will be marked on the computer. Data from the sensors will be collected for a maximum period of 30 minutes. In addition, patients will be asked to complete the following parts of the procedure.First, in the control part, after the study equipment is placed on the participant, a member of the study team will turn on the TENS device while the patient is sitting. Patients will be asked to slowly increase the TENS unit level on the contralateral arm to the highest tolerable level for them, rest for at least 10 seconds, and then decrease it to level 0, including an additional rest between TENS challenges. At each point the study team member will ask for the NRS pain score. During this period, the other devices will be simultaneously collecting physiological data.Second, during the experimental part, as the patient is resting in the transition between the control and experimental part, the TENS unit will be disconnected. Then, patients will be engaged with soft activities  that may cause a pain sensation wearing the noninvasive devices connected excluding the TENS device. At each point , the study team member will ask for the NRS pain score. During this period, the other devices will be simultaneously collecting physiological data.Each part will consist of 2 to 3 challenge intervals in an attempt to capture pain perception using NRS before, during, and after a stimulus with appropriate rest periods to make the statistical analysis more powerful. During this period, the other devices will be simultaneously collecting physiological data.We will use data acquisition software (LabVIEW version 14.0f2) to capture data from the device and sensors. As mentioned above, 2 devices will transmit data wirelessly through Bluetooth and 1 via a serial wired USB. The computer with Bluetooth USB adapters receives data from these sensor nodes. We developed a LabVIEW program in Windows for real-time waveform plotting, marking time stamps, and saving the raw data along with the time stamps. The waveform plotting function ensures checking of data validity during measurement. Raw data will be saved for offline processing and analysis.The pain intensity assessment algorithm will be developed after the data collection phase, including basic signal preprocessing and a machine learning algorithm. The designed algorithm will be built based on the preliminary algorithm from phase 1 of the study and will be verified and compared between the 2 databases.For phase 2, we will attempt to further improve the accuracy of the electronic health system and identify proper personalization methods based on the demographic data, the profile of the patient when admitted to hospital, and the biosignals collected from the patient. For the prospective study, we will recruit patients who meet the inclusion criteria. We will take into account the attrition rate and will have a maximum enrollment of 30 participants. We calculated this sample size taking into account the receiver operating characteristic analyses from the previous phase results ,20.We will design a multimodal software tool for signal processing, data fusion, and machine learning for pain assessment and classification based on the processing flow developed from study phase 1.The analysis of pain can be broken down into the following stages: data preprocessing, filtering, feature extraction, and classification . DiffereThe next step is to digitally filter out the noise produced during data collection. Noise can be caused by multiple sources. For example, motion artifacts, baseline wander, and power channels are all common sources of noise in a clinical setting. The low- and high-frequency noise is digitally filtered using a Butterworth filter and the necessary frequencies are allowed to pass through using a bandpass filter.For optimal classification performance, we will extract features from multiple signal domains and approaches, for example, statistical features and entropy extracted from the signal time domain and the frequency domain 0. We wilFinally, once we obtain these features and their corresponding pain labels, we can use machine learning techniques to train models based on these data. Furthermore, we will automatically classify and predict the pain levels of any future patients using this existing model.The final outcome of phase 2 is the prediction of patients’ pain levels based on metrics such as accuracy, sensitivity, specificity, and the area under curve with respect to patients’ self-reported NRS as the reference standard.We have started implementing the protocol, and we are in the process of data collection. We expect to complete the analyses in early fall 2020 and then publish them. The dataset will be available for further research in early 2021.This is, to our knowledge, the first protocol for collecting physiological signals from patients with postoperative pain for the development of an automatic pain assessment tool. Existing databases have targeted several types of pain, for example, chronic pain , neonataThe proposed data collection protocol is for multimodal development, similar to some of the aforementioned databases ,24-26. HAlthough the data collection focuses on postoperative pain, we included a controllable experimental pain stimulus, which was induced separate from the movement inductions. The benefit of this design is twofold. First, the physiological responses to each stimulation can be compared with each other in terms of similarity and difference within the database. Second, this design connects this study to previous studies using experimental pain stimulation only, where pain threshold (the stimulus intensity at which pain begins to be felt) and pain tolerance (the maximum pain intensity a person is able to tolerate) were mainly used as pain self-reports.The main limitation is the presence of noise (or incorrect labels), making machine learning difficult. Although a certain level of noise has been shown to be positive in order to obtain a more tolerant and robust algorithm, given the real day-to-day data, the noise ratio must be low so that this does not interfere with machine learning. In our case, noise comes mainly from the cognitive difference in pain levels and motion artifacts. These artifacts can be from several sources, such as the movement of the electrodes on the face while the patient is talking.Another limitation of this protocol is that some physiological parameter changes  can result from a compound reaction to both pain stimulus and the motion itself. However, these two factors cannot be separated within the same patient, that is, moving without causing any pain. One solution could be recruiting healthy controls to make the same motions and to observe the physiological parameter response difference from postoperative patients.This study will help to further the development of and research on an objective and self-aware pain assessment tool for monitoring patients in clinical settings using both behavioral and physiological indicators. The resultant solution will be an automatic, user-centered, and versatile pain assessment system, based on the internet of things.


Prolonged immobilization after transfemoral coronary angiography (TFA) may cause pain and vascular complications in patients. This study aimed to evaluate the effectiveness of a change in position to decrease pain and vascular complications for patients after TFA.This randomized clinical trial was conducted in 2020. Purposive sampling of 72 eligible patients undergoing TFA were selected and randomly assigned to either an experimental or control group. Patients in the experimental group (EG) were placed in a supine position for 2 h after angiography, followed by a semi-seated position with the bed angle gradually increased to 45° over 4 h. Patients in the control group (CG) remained in the supine position for 6 h. Vital signs, groin, back and leg pain, hematoma, hemorrhage, and urinary retention were assessed in both groups before, immediately after, and over 6 h after angiography. The Visual Analogue Scale was used to measure pain, the Christensen scale to measure hematoma, counting bloody gases to measure hemorrhage, and patient self-rating to determine urinary retention.There was no significant difference between EG and CG on score of groin , back , and leg pain  before the TFA. However, from the second hour to the sixth hour after the TFA, the pain in the EG was significantly less than the CG (P < 0.001). So that pain in the groin (1.36 ± 0.48 vs. 3.28 ± 0.81), back (1.25 ± 0.50 vs. 3.81 ± 1.06), and leg (1.44 ± 0.55 vs. 3.28 ± 0.81) for the EG patients was significantly less than the CG in the sixth hour after TFA (P < 0.001). No patients experienced hematoma. No differences were noted between groups in hemorrhage and urinary retention.Position change to a semi-seated position in patients after TFA is effective and safe for reduction of pain without increasing vascular complications.Iranian Registry of Clinical Trials: IRCT registration number: IRCT20200410047011N1, Registration date: 30/04/2020 Cardiovascular diseases (CVD) and vascular disorders account for more than 12% of all diseases around the world  and 78% Early and accurate diagnosis is imperative in patients with CAD. Coronary angiography is considered the gold standard for the diagnosis of significant CAD . HoweverTransradial and transfemoral are the two main approaches to angiography which are used for diagnostic and therapeutic purposes in catheterization. Transfemoral coronary angiography (TFA) is often preferred over transradial due to the unlimited repetition of puncturing, easy access, less radiation, and less contrast . HoweverThis study was planned and carried out according to CONSORT guideline for randomized clinical trials on the angiography and post-angiography wards of 502 Hospital, Tehran, Iran and registered in the Iranian Registry of Clinical Trials . Eligible patients included those admitted to the cardiovascular ward between May and June, 2020 with CAD who underwent TFA. Patients were randomly assigned to either the experimental group (EG) or the control group (CG) by tossing a coin. This study was a double blinded trial. The researcher assistant enrolled patients and assigned them to interventions. Outcome evaluator, the patients, and statistical analyst were blinded to group allocation.Based on a previous study , the appThe inclusion criteria encompassed: (1) willingness to participate in the study, (2) conscious, (3) lack of hemophilia and other coagulation disorders, (4) normal prothrombin time (PT) and international normalized ratio (INR) tests, (5) candidate for TFA, (6) no past treatment with streptokinase, (7) no history of previous low back pain, (8) no history of severe hemorrhage, extensive hematoma or pain intensity greater than 4.5 based on the Visual Analog Scale (VAS), and (9) no history of analgesic or opioid use before, during, and after TFA. Exclusion criteria included: (1) withdrawal to continue in the study and (2) worsening of the patient's condition such as pain more than 7, active hemorrhage, and unstable vital signs. In this study, all patients used tablet aspirin 80 mg, Plavix 300 mg single dose, ampule diazepam 5 mg, and ampule promethazine 25 mg for prophylaxis according to the physician order before TFA.Demographic and medical history data were collected from the patients’ medical records. Individual characteristics included age, sex, and previous history of angiography, and history of cardiac surgery.Primary outcomes including pain scores, size of hematoma, and amount of hemorrhage were collected eight times in 1-h intervals starting at 1 h before the TFA, immediately after the TFA, and every hour for the next 6 h following the TFA. Urinary retention was assessed before, during, and 10 min after the TFA.Secondary outcomes including vital signs such as pulse rate, respiratory rate, body temperature, and systolic and diastolic blood pressure were recorded throughout the study, starting at 1 h before and up to 6 h after TFA. Vital signs were measured using telemetry based vital sign monitoring.Pain was measured using the VAS, a subjective, validated measure to assess acute and chronic pain with high reliability . The VAS2 and a large hematoma was equal to or greater than 5 cm2. In an irregularly shaped hematoma, the largest and smallest diameters of the hematoma are measured and the area of the hematoma is calculated by multiplying the diameters by each other [Hematoma was measured using the Christensen scale. On the Christensen scale, a small hematoma was noted as measuring between 2 and 5 cmch other . Cohen'sch other . The intAll variables were collected by the researchers. Quality assurance and validity of data collection were provided by 12 nursing professors from Aja, Tehran, Mashhad, and Tarbiat Modares University of Medical Sciences.All the beds used in this study were electric intensive care unit (ICU)/cardiac care unit (CCU) beds and the angle of the bed could be adjusted easily to the precise angle required of the study protocol. Beds were equipped with four motors, resistant to water and dust penetration, and were adjustable by four actuators without disturbing the patient.Patients in the CG received the standard care provided at the study institution following TFA which included positioning in supine for 6 h after the TFA and the affected leg was straight and immobilized. Patients were asked not to move their legs during this time and a sandbag weighing about 4 kg , 32 was All interventions in the EG were performed by one of the researchers, under the supervision of a physician, who was a master’s student of emergency nursing with 19 years of experience in ICU care. Patients in the EG were kept in the supine position for 2 h after angiography. The affected leg was straight and immobile. After 2 h of immobility, the EG patient was transitioned to a semi-seated position. Over the next 4 h, the bed angle gradually increased from 0° to 45°. For example, in the second, third, and fourth hour, the bed was placed at an angle of 15°, 30°, 45°, respectively. It should be noted that in all stages of the intervention for the EG, a sandbag was located on the dressing area of the arterial access and the patients' leg was straight. From the third hour onwards, a small pillow was placed under the patients' waist area for comfort. Throughout the intervention in the EG, specialist physicians and experienced nurses were available in case of serious complications such as active hemorrhage, severe pain, or patient dissatisfaction.Data were analyzed using SPSS software version 22  and descriptive and analytical tests. Kolmogorov–Smirnov test was used to check the normality of the data. The homogeneity of groups for demographic and clinical characteristics of the patients was assessed using independent sample t-test and Fisher's exact test. Also, homogeneity of groups for baseline condition was investigated by the independent sample t-test. To compare the mean changes of the outcome variables immediately after TFA, 1st, 2nd, 3rd, 4th, 5th, and 6th hours after TFA compared to the baseline between groups, the researchers employed repeated measures analysis of variance (RM-ANOVA). The significance level was considered less than 0.05.The mean age of patients was 62.21 ± 12.22 (range 21–88) years. Forty-two (58.3%) of the patients were male, 64 (88.9%) patients had no incidence of cardiac surgery, and 43 (59.7%) patients had previous angiography experience. There was no significant difference between the two groups in terms of any of the individual baseline characteristics (P < 0.05). See Table None of the patients had severe pain and/or hemorrhage. There was no significant difference between groin P = 0.74), back P = 0.21), and leg pain (P = 0.27) in the two study groups before the TFA. However, from the second hour to the sixth hour after the TFA, the pain in the EG was significantly less than the CG (P < 0.001 for each hour segment). See Table 1, and le, back P Before and after the TFA there was no indication of hematoma for any of the patients in either the EG or CG. Fisher's exact test showed that patients in both groups had no significant hemorrhage before (P = 0.18), immediately after (P = 0.08), in the first hour (P = 0.62), or any time up to the sixth hour after TFA (P = 0.90). After the TFA, patients in two groups did not experience significant hemorrhage. Fisher's exact test showed that none of the patients complained of urinary retention before the TFA and urinary retention in patients immediately, ten minutes after TFA was not statistically different (P > 0.05).There was no significant difference between the mean pulse rate, respiration rate, body temperature, or systolic and diastolic blood pressure in the two groups before the TFA. But the mean respiratory rate of the patients in the two groups immediately after TFA (P = 0.042) and 1 h after TFA (P = 0.021) was significantly different with the EG showing the most optimal respiratory rate. There was a significant difference in body temperature in the 6th and final hour after the trial (P = 0.018). The RM-ANOVA test showed an almost constant trend of pulse rate, respiratory rate, body temperature, and systolic and diastolic blood pressure in the EG and CG in all hours before and after TFA (P > 0.05). See Table The current study demonstrated the effectiveness of changing a patients' position to decrease pain and vascular complications after TFA. Patients that were positioned with the head of bed significantly inclined and were supported into a semi-seated position reported less pain in the groin, leg, and back. Similar to previous researches, this study provides additional evidence that changing the position of patients after angiography reduced the severity of pain , 23, 33.The current study demonstrated safety in changing the patient’s position to a semi-sitting position with angles of 15°–45° for up to 6 h after TFA as no patients experienced significant hematoma, hemorrhage, or urinary retention before or after the TFA. Other studies have reported similar results in terms of hematoma incidence , 34, 35,Similar to other research where the position following TFA was adjusted, this study showed that there was no significant difference between mean pulse rate, respiration rate, body temperature, or systolic and diastolic blood pressure in the two groups before and after TFA when the patient position was altered , 17, 26.Limitations of this study include variable pain thresholds for patients which could not be adequately measured, variable duration of angiography, and variable physician implemented pressure on the femoral access site after TFA. Also, the current study used the Christensen scale to measure the hematoma in the patients. The researchers suggest that more accurate methods such as Doppler ultrasound be used in future studies to assess hematoma.Overall, change in the position of patient (head of bed elevated from 15° to 45° and supported into semi-seated positioning) after TFA is an effective and safe procedure to reduce pain without changes to vital signs or complications such as hematoma, hemorrhage, and urinary retention that can cause to reduce the time of hospitalization. The current study showed that a simple, cost free, and safe nursing intervention can effectively improve the patients’ outcome after TFA. Further studies are recommended to investigate the possibility of increased patient movement directly after TFA to further support patient comfort and healing.


Monitoring the pain intensity in critically ill patients is crucial because intense pain can cause adverse events, including poor survival rates; however, continuous pain evaluation is difficult. Vital signs have traditionally been considered ineffective in pain assessment; nevertheless, the use of machine learning may automate pain assessment using vital signs. This retrospective observational study was performed at a university hospital in Sendai, Japan. Objective pain assessments were performed in eligible patients using the Critical-Care Pain Observation Tool (CPOT). Three machine-learning methods—random forest (RF), support vector machine (SVM), and logistic regression (LR)—were employed to predict pain using parameters, such as vital signs, age group, and sedation levels. Prediction accuracy was calculated as the harmonic mean of sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). Furthermore, 117,190 CPOT assessments were performed in 11,507 eligible patients . We found that pain prediction was possible with all three machine-learning methods. RF demonstrated the highest AUROC for the test data . With this method, pain can be objectively, continuously, and semi-automatically evaluated in critically ill patients. It has been reported that 33% of intubated patients experience pain at rest4, while an additional 56% experience pain during the procedure5. The primary source of pain in surgical patients is the surgical site, whereas that in medical patients includes the back and extremities; notably, the incidence was reported to be no different between surgical and medical patients1. Stress caused by pain generally has a detrimental effect on ICU patients. Increased catecholamine levels cause arteriole vasoconstriction and decrease tissue oxygen tension, thus, resulting in tissue perfusion failure6. Other reactions caused by pain include increased catabolism, such as lipolysis to provide protein substrates, and muscle loss7. Increased catabolism associated with tissue hypoxia delays wound healing and increases the risk of infections. Pain suppresses the activity of natural killer cells9 and lowers the number of cytotoxic T-cells and phagocytic neutrophils10. Furthermore, acute pain is a major risk factor for subsequent chronic neuropathic pain.Patients in intensive care units (ICUs) experience a high incidence of pain, which requires detailed assessments11 and Behavioral Pain Scale12 are recommended when patients cannot communicate due to sedatives, intubation, or tracheostomy14. Regular use of pain assessment scales has been reported to improve the clinical outcomes in ICU patients17; however, these methods are cumbersome and do not facilitate continuous monitoring of pain. Therefore, a method for continuous and easy assessment of patients that can enable healthcare professionals to perform interventions sooner is highly necessary.In the ICU, objective methods of pain assessment, such as the Critical-Care Pain Observation Tool (CPOT)20. Notably, the studies that concluded the latter employed time-series data of vital signs at specific points rather than using continuous data because of computational complexity. Such data may not fully reflect the information available from vital signs because they cannot account for continuous changes in the pain.Vital signs are considered indicators of pain; however, changes in vital signs have been reported to be nonreliable indicators of the extent of pain21. Notably, AI-based tools have the potential to provide continuous and automated pain assessments that can eliminate the effects of uncertainty caused by discrete decision-making, such as that based on pain assessment scales25. However, only a few studies have actively employed continuous data, such as vital signs, in pain analysis. Adjei et al. predicted pain by quantifying pain sensitivity by analyzing the electrocardiogram (ECG) waveforms of 17 patients who underwent varicose vein surgery; however, the small number of patients and the use of questionnaires in pain assessment made it difficult to apply this method in unconscious patients26. There have also been attempts to detect pain through machine-learning analysis of electroencephalogram (EEG) and images30; however, they are difficult to interpret and cannot be used for continuous assessment. To the best of our knowledge, no studies have performed objective, continuous, and semi-automatic evaluation of pain in ICU patients. Therefore, this study aimed to investigate if AI analysis of vital signs could be used to automate the assessment of pain.In contrast, artificial intelligence (AI)-based predictive tools are increasingly resulting in automation of diagnostics through comprehensive monitoring of patient health, which is traditionally done by physicians and nurses, based on real-time and continuous recordings, processing, monitoring, and intelligent diagnosisIn 11,527 eligible patients, CPOT assessment was performed 117,190 times and 3,925 patients (3.3%) were determined to experience pain with a score of ≥ 3. Although the level of sedation  was assessed almost simultaneously, 42.8% of the patients were determined to be calm (0 points), 8.3% aggressive (≥ 1 point), and 48.9% sedated (≤ − 1 point). Furthermore, 21.7% of the ratings indicated delirium . Patients who met the following inclusion criteria were enrolled at ICU admission between October 2016 and October 2019: (1) age ≥ 20 years; (2) CPOT, RASS, and confusion assessment method for the intensive care unit (CAM-ICU) were evaluated at least five times per patient; and (3) ECG and arterial pressure were monitored for ≥ 30 min before employing CAM-ICU. Data of the following patients whose vital signs differed significantly from those of the general adult population were excluded: (1) pregnant patients; (2) cardiopulmonary bypass recipients; and (3) those with organ transplants (i.e. organ recipients), ventricular assist devices, extracorporeal membrane oxygenation, intra-aortic balloon pumps, or do-not-resuscitate orders. The final dataset included 11,527 patients. The commonest analgesic and sedative were fentanyl and dexmedetomidine. All data were retrieved from the institution’s electronic medical record system . No patient-identifying information was recorded.This retrospective observational study was performed in the ICU of Tohoku University Hospital, Sendai, Japan. Ethical approval was obtained from the Ethics Committee of the Tohoku University Graduate School of Medicine (reference number 2018–1–650). The requirement for informed consent was waived due to the retrospective design by the Ethics Committee of Tohoku University Graduate School of Medicine. All methods were performed in accordance with the relevant guidelines and regulations as per the Declaration of Helsinki. The patients’ data will be deleted as soon as the current paper is published. The study was registered in a database in advance . RASS42 was used to assess the sedation level. Delirium was assessed using CAM-ICU43. Furthermore, RASS and CAM-ICU assessments were performed concurrently with CPOT assessment. CPOT, RASS, and CAM-ICU evaluations were performed by multiple nurses to ensure agreement between them. If there was a difference in opinion, the intensivist made the final decision and approved the evaluations.To assess the pain levels of all eligible patients, we used CPOTAll patients were managed using a pain management protocol of the hospital  as vital signs as well as the patient’s sex, age group , and RASS score in the last 3 h. Figure First, the noise was removed from the data of the vital signs according to the noise requirements in Supplementary Table For predicting pain, CPOT values from 0 to 2 were considered negative and scores of ≥ 3 were considered positive. Since these data were unbalanced, oversampling was performed on the positive group. In terms of the oversampling method, Synthetic Minority Over-sampling Technique (SMOTE), Borderline SMOTE, and Adaptive Synthetic Sampling (ADASYN) were verified, and ADASYN, which showed the highest accuracy, was adopted. In machine learning, precision was compared between random forest (RF), support vector machine (SVM), and logistic regression (LR) models. To evaluate the generalization performance, the data were randomly classified between the training and validation data in a ratio of 9:1 and 10 cross-validations were performed. A grid search was performed on the training data to select the hyperparameter that derived the highest accuracy in each of the models. Furthermore, the harmonic means of the sensitivity, specificity, and AUROC were calculated.Data analysis was performed using JMP v15 . Normally distributed data were reported as mean ± standard deviation and non-normally distributed data as median and interquartile range. AUROC was used to compare the accuracy, which was evaluated as low (0.5–0.7), moderate (0.7–0.8), and high (≥ 0.8).Supplementary Information