Persistent pain and disability following rib fractures result in a large psycho-socio-economic impact for health-care system. Benefits of rib osteosynthesis are well documented in patients with flail chest that necessitates invasive ventilation. In patients with uncomplicated and simple rib fractures, indication for rib osteosynthesis is not clear. The aim of this trial is to compare pain at 2 months after rib osteosynthesis versus medical therapy.This trial is a pragmatic multicenter, randomized, superiority, controlled, two-arm, not-blinded, trial that compares pain evolution between rib fixation and standard pain medication versus standard pain medication alone in patients with uncomplicated rib fractures. The study takes place in three hospitals of Thoracic Surgery of Western Switzerland. Primary outcome is pain measured by the brief pain inventory (BPI) questionnaire at 2 months post-surgery. The study includes follow-up assessments at 1, 2, 3, 6, and 12 months after discharge. To be able to detect at least 2 point-difference on the BPI between both groups (standard deviation 2) with 90% power and two-sided 5% type I error, 46 patients per group are required. Adjusting for 10% drop-outs leads to 51 patients per group.Uncomplicated rib fractures have a significant medico-economic impact. Surgical treatment with rib fixation could result in better clinical recovery of patients with uncomplicated rib fractures. These improved outcomes could include less acute and chronic pain, improved pulmonary function and quality of life, and shorter return to work. Finally, surgical treatment could then result in less financial costs.ClinicalTrials.govNCT04745520. Registered on 8 February 2021. Until recently, persistent pain and disability after uncomplicated rib fractures have been poorly documented . A recenThe only predictive factor for persistent pain and disability is the pain intensity within the first few days after injury , 3. SimiWhile a recent meta-analysis concluded that operative fixation of complicated flail chest provided a better outcome , the impWe aim at bringing further knowledge to improve care of trauma patients with uncomplicated rib fractures. Indeed, no previous studies have provided definitive evidence for recommending rib fixation over simple pain medication to control pain in these patients. Given the high prevalence of chronic pain in patients with isolated rib fractures , there iThe PAROS (Pain After Rib OSteosynthesis) trial is a pragmatic multicenter, randomized, superiority, controlled, two-arm, not-blinded trial that compares pain evolution between rib fixation and standard pain medication to standard pain medication alone in patients with uncomplicated rib fractures.Hôpitaux Universitaires de Genève (HUG) is the public hospital of the Canton of Geneva. The Centre Hospitalier Universitaire Vaudois (CHUV) is the main public hospital of the Canton de Vaud. The hospital of Sion, which is part of the Centre Hospitalier du Valais Romand, is the main public hospital of the Canton du Valais . Tertiary care units specialized in thoracic surgery will host the study. Each center hospitalizes approximately 60–120 patients per year with uncomplicated rib fractures. These units are used to working together through an inter-hospital structure (Center for Thoracic Surgery of Western Switzerland).The study will take place in three hospitals of Western Switzerland (French-speaking part). The Study’s participants will be recruited among patients admitted at the local emergency room with uncomplicated rib fractures. To optimize enrolment, the staff of emergency departments of each study site will receive information and regular updates about the trial. Initial care management for rib fractures in the emergency department will not be modified to reflect the current situation. The screening process and the selection of participants will be performed by an attending surgeon from local surgical thoracic unit, under the responsibility of the local principal investigator. Reasons for exclusion, as well as the number of subjects who decline participation, will be documented.Demographic data and comorbidities (Charlson Comorbidity Index ) will beblockrand [The R package lockrand  will be lockrand ) hosted lockrand . PracticMatrixRIB™, De Puy Synthes Companies, Zuchwill, SwitzerlandSTRATOS™, MedXpert GmbH, Heitersheim, GermanyTM, IAWAI, Yandzhou, ChinaNiTi Fixing PlatesSurgical procedures (rib fixation) are carried out during a maximum of five days after hospitalization. It is thought that surgery performed as soon as possible would have more impact on initial pain. To control the infectious risk, an antibiotic prophylaxis (Cefuroxime 1.5g IV) will be administered 30 min before surgery. Rib fixation will be performed by a senior surgeon under general anesthesia. A thoracotomy focused on the fracture will be performed to optimize the access to the broken rib. Video-assisted thoracic surgery (VATS) can be performed before the osteosynthesis to better localize rib fractures. During thoracotomy, significant muscle division is avoided. Removal of the periosteum is not required. The broken rib segments are approximated with forceps and the medical devices are used to fix the fracture. The medical devices are implemented according to the manufacturers’ recommendations. The goal is to stabilize the chest wall. It is not useful to fix all fractures to stabilize the wall. A chest tube can be placed at the end of the operation. The following medical devices can be used:They are already used in the three study centers in patients with rib fractures. However, there is no evidence that the intervention being tested will be superior to medical therapy. The choice of the type of medical devices will be let to the appreciation of the surgeon. MatrixRIB is usually used. However, Stratos system and NiTi Fixing Plates appear to be easier to apply behind the scapula. The devices will be sterilized before use following standard surgical procedures and packaged by the sterilization unit at each hospital. The supply of the product is managed by the hospitals according to the standard procedures. The type, batch number, and length of the implanted materials will be documented.After inclusion and until discharge, the study’s participants will continue to be taken in charge in the surgical thoracic units at each center. Medical treatment and analgesia used after the randomization will be applied following the written procedure. Epidural analgesia will be continued for 1 to 7 days post-randomization to maximize outcome benefits. Afterwards, paracetamol, NSAID , and/or opioid treatment will be prescribed according to pain severity. In the case of opioid use, morphine treatment will be preferred. However, other opioid drugs or doses can be considered to better customize the treatment. Patients allocated to the control group will be monitored until discharge. Discharge criteria are no thoracic drain, acceptable pain level, and no intravenous medication.The primary outcome is pain level, assessed via the first part of the French version of the brief pain inventory (BPI) questionnaire measured at 2 months post-surgery. The BPI has become one of the most widely used measurement tools for assessing clinical pain , 19. PaiAmount and type of analgesic medication. During hospitalization, each day since the enrolment, amount and type of analgesic medication will be recorded from the computerized patient record system. After discharge, analgesic medication will be tracked using a custom questionnaire. If any, the opioid amount will be recorded in equivalent dose of analgesics.Anxiety and depression. In order to highlight anxiety and depression symptoms, the Hospital Anxiety and Depression Scale (HADS) questionnaire will be applied at baseline and at 2 months [2 months . HADS scNeuropathic pain. The French questionnaire “Douleur Neuropathique en 4 Questions (DN4)” will be completed by the clinical research assistant or the surgeon during the follow-up visit at 2 months. The DN4 questionnaire was developed to diagnose polyneuropathy. Three items are linked with neuropathic pain examination, and seven items to pain symptoms, with a final score between 0 and 10. A score higher than four indicates neuropathic pain. The DN4 questionnaire has been broadly used and validated [alidated .Pain interference and quality of life. The last items of the BPI questionnaires measure how much pain has interfered with seven daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others and sleep. BPI pain interference is scored as the mean of the seven items coded on a 0-10 scale. To assess quality of life, health, and wellbeing, the short-form health survey (SF-36 [y (SF-36 ) will bey (SF-36 .Productivity impairment and return to work. The work productivity and activity impairment (WPAI) questionnaire is an instrument to measure impairments in both paid work and unpaid work. It measures absenteeism, presenteeism as well as the impairments in unpaid activity because of health problems during the past 7 days [t 7 days . The finPulmonary function and respiratory muscle function. Forced vital capacity , peak expiratory flow , and sniff nasal inspiratory pressure and maximum inspiratory pressure (in cmH2O) will be measured according to the recommendations of the European Respiratory Society [ Society . The besLength of hospital stay. Length of hospital stay will be reported in days from the day of hospitalization until hospital discharge.Medical direct costs. Costs are reported for each patient at the end of the follow-up period (12 months) in Swiss francs and will include costs for hospital care, surgery, and all related medications and drugs.Adverse events. We will collect safety outcomes in accordance with international standards (ISO 14155 [SO 14155  and ICH-SO 14155 ).Secondary outcomes will be:The schedule for recording the study’s outcomes is shown in Table After discharge, web surveys will be used to collect questionnaires. Phone calls can replace web surveys for participants without an internet connection. During visits (at 2 and 6 months after injury), pulmonary function and respiratory muscle function will be measured.Baseline characteristics will be described by randomization group: continuous variables by their mean and standard deviation (SD), and median ; categorical variables by their frequencies and relative percentages. Primary outcome will be compared between intervention and comparator groups using analysis of covariance ANCOVA  with BPIPrimary analysis will be performed on the intention-to-treat population (as-randomized) and completed by per-protocol analysis after exclusion of major deviations from the protocol . Secondary analyses which consist in longitudinal modeling will be performed using mixed linear models to assess the evolution of pain (BPI) over time then anxiety and depression (HADS) score, quality of life, and finally productivity impairment (WPAI); an interaction between the time-points and the randomization group will be investigated. For secondary outcomes measured once , we will perform non-parametric Mann-Whitney tests comparing both randomization groups, due to expected skewed distributions of those measurements. Finally, adverse event occurrence will be described according to the randomization groups. In addition, subgroup analyses will be performed to report the treatment effect by investigation sites and then by types of medical devices.The sample size was calculated for an ANCOVA, according to results of previous studies , 29. We Medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited. All electronic files and databases are secured with password-protected access systems. Participant’s records in the eCRF are identified by code number. On each study site, written forms, or any other listings, are stored in a locked file with limited access. The project principal investigator (sponsor-investigator) will have direct access to his own site data sets and will have access to other site data only through the eCRF. Data communicated to project team members are blinded of identifying participant information.For data verification purposes, authorized representatives of the sponsor-investigator, a competent authority, or the ethics committee may require direct access to parts of the medical records relevant to the study, including participants’ medical history.Independent monitoring is performed by the CRC  of the University Hospitals of Geneva. Monitoring activities are performed according to ISO 14155 . The monThe ethics committee may wish to conduct an audit during the study or even after its completion. The sponsor-investigator and the investigators in the participating sites will support the inspectors in their activities.Modifications to the protocol affecting important aspects of the study , or affecting patient safety will require a formal amendment approved by the ethics committee. Minor changes, such as minor corrections and/or clarifications that have no effect on the way the study is conducted are documented and notified to the ethics committee.The sponsor-investigator assures that all results of this study will be published in a peer-reviewed journal. All results relate to all outcomes as defined in this protocol regardless of statistical significance. The present article and other future articles follow the principles of the SPIRIT  and CONSThe PAROS trial compares pain control at 2 months after surgical versus non-surgical treatment among patients with uncomplicated rib fractures. Uncomplicated rib fractures have a significant medico-economic impact. Surgical treatment with rib fixation could result in better clinical recovery of patients with uncomplicated rib fractures. These improved outcomes could include less acute and chronic pain, improved pulmonary function and quality of life, and quicker return to work. Finally, surgical treatment could then result in less financial costs.To the best of our knowledge, this is the first multicenter randomized controlled trial to evaluate pain at 2 months as a primary outcome in patients suffering from uncomplicated rib fractures. Three hospitals in Switzerland participate in this trial.Rib fixation is a low-risk procedure. A known adverse effect after rib fixation is hardware infection. A retrospective study among 122 patients operated for rib fractures with a MatrixRIB™ system and RibLoc® plating System showed 4.1% of hardware infection . OutcomeRegarding selection biases, criteria of eligibility are clearly defined Table  and wereRegarding other biases, validated questionnaires will be used to minimize interviewer bias. In addition, during follow-up, questionnaires will be collected at home via a web survey system. An intention-to-treat analysis allows to minimize bias introduced by exclusions or group changes.For minimizing the introduction of biases due to missing data, a secure web application (REDCap) will be used for building and managing online surveys and study databases. Furthermore, data monitoring procedures  and regular contact with the study’s participants  will be carried out.This study is built as a pragmatic trial to perform it under normal conditions with the intention of providing results that are more applicable to clinical practice and decision-making. The use of three materials in the intervention group, the multiple possibilities to stabilize the chest wall and the use of a relevant primary outcome meaningful for participants are consistent to be generalizable.The PAROS trial began recruiting in April 2021. The first patient was included in June 2021. The recruitment continues until April 2023.The PAROS trial will be the first clinical trial to compare pain in long term between surgical fixation and non-surgical treatment for uncomplicated rib fractures.


This paper describes the research protocol for a randomized controlled trial of a self-management intervention for adults diagnosed with sickle cell disease (SCD). People living with SCD experience lifelong recurrent episodes of acute and chronic pain, which are exacerbated by stress.This study aims to decrease stress and improve SCD pain control with reduced opioid use through an intervention with self-management relaxation exercises, named You Cope, We Support (YCWS). Building on our previous findings from formative studies, this study is designed to test the efficacy of YCWS on stress intensity, pain intensity, and opioid use in adults with SCD.A randomized controlled trial of the short-term (8 weeks) and long-term (6 months) effects of YCWS on stress, pain, and opioid use will be conducted with 170 adults with SCD. Patients will be randomized based on 1:1 ratio (stratified on pain intensity [≤5 or >5]) to be either in the experimental  or control  group. Patients will be asked to report outcomes daily. During weeks 1 to 8, patients in both groups will receive system-generated alerts or reminders via phone call, text, or email to facilitate data entry (both groups) and intervention use support . If the participant does not enter data after 24 hours, the study support staff will contact them for data entry troubleshooting (both groups) and YCWS use . We will time stamp and track patients’ web-based activities to understand the study context and conduct exit interviews on the acceptability of system-generated and staff support. This study was approved by our institutional review board.This study was funded by the National Institute of Nursing Research of the National Institutes of Health in 2020. The study began in March 2021 and will be completed in June 2025. As of April 2022, we have enrolled 45.9% (78/170) of patients. We will analyze the data using mixed effects regression models (short term and long term) to account for the repeated measurements over time and use machine learning to construct and evaluate prediction models. Owing to the COVID-19 pandemic, the study was modified to allow for mail-in consent process, internet-based consent process via email or Zoom videoconference, devices delivered by FedEx, and training via Zoom videoconference.We expect the intervention group to report reductions in pain intensity  and in stress intensity  and opioid use (Wisepill event medication monitoring system), which are secondary outcomes. Our study will contribute to advancing the use of nonopioid therapy such as guided relaxation and distraction techniques for managing SCD pain.ClinicalTrials.gov NCT04484272; https://clinicaltrials.gov/ct2/show/NCT04484272PRR1-10.2196/33818 In the United States, the incident rate of SCD has remained constant . However9) years . Evidenc9) years .The chronic pain associated with SCD is often rated as more intense than childbirth pain and persists for years . RecurreOther studies report strong positive relationship between the frequency and severity of pain and death ,19-22. CP<.001) and pain (P=.002) [P<.001 and pain: P=.02) [Stress, associated with pain in patients with SCD, is correlated with overactivation of the hypothalamic-pituitary-adrenal axis hormones or neurotransmitters , which trigger the fight-or-flight responses and intensify responses to nociceptive pain  -28. Stre(P=.002) . Results: P=.02) . Others : P=.02) , and inc: P=.02) . CumulatThe use of pain self-management in SCD has gained much attention in recent years. Pain self-management techniques can include deep breathing exercises, progressive relaxation, and guided imagery . PatientThe use of opioids as the mainstay of therapy for both acute and persistent SCD is not ideal. Opioid analgesics are known to cause severe side effects, including death from overdose. They are frequently prescribed for SCD pain; however, accumulating evidence suggests the need to incorporate nondrug therapies as strategies for managing SCD pain systematically . A recenPatients who use high opioid doses were more likely to use nonsteroidal anti‐inflammatory drugs, visit acute health care facilities, and indicate that they experienced pain on most days . The opiProviding behavior change strategies via mobile health  apps or internet-delivered interventions aligns with the Federal Pain Research Strategy to promote and enable pain self-management . In a prThe focus of this study is to evaluate the effectiveness of a self-management intervention that promotes the use of relaxation and distraction exercises (RDEs) in reducing pain, stress, and opioid dependency among adult outpatients with SCD. Specifically, the aims of this study are the following:short-term effects of You Cope, We Support (YCWS). Hypothesis: In the first 8 weeks, compared with the control group, the experimental group will report reductions in the primary outcome—pain intensity  and in the secondary outcomes—stress intensity  and opioid use (OME).Determine the long-term effects of YCWS. Hypothesis: During months 3 to 6, compared with the control group, the experimental group will report reductions in the primary outcome—pain intensity  and in the secondary outcomes—stress intensity  and opioid use (OME).Determine the Use machine learning to develop and evaluate models that predict patient outcomes based on their group assignment and their personal  and environmental characteristics . The results will provide insight into the heterogeneity of intervention’s effects and the patients most likely to benefit from YCWS.The study is a randomized controlled trial (RCT) of the short-term (8 weeks) and long-term (6 months) effects of YCWS on efficacy outcomes , designed to determine the short-term and long-term effects of the YCWS intervention and to evaluate models that predict patient outcomes based on their group assignment and their personal and environmental characteristics.We are recruiting patients both in person and internet-based throughout the state of Florida, including the University of Florida (UF) Health-Shands in Gainesville and UF Health-Shands in Jacksonville. Thus, data collection and intervention delivery occur throughout Florida, with UF Health-Shands in Gainesville as the primary site for data collection, intervention delivery, and data analysis.The UF institutional review board (IRB) is the approving IRB of record and has approved all the recruitment and study procedures (IRB202000984).We will recruit from the UF Health-Gainesville and UF Health-Jacksonville hematology clinics and the UF Health-Jacksonville transition program. The UF Health-Shands Hospital, Gainesville, adult sickle cell program has a clinic panel of 497 adult patients with SCD. Of the 497 patients,  are women and  are African American individuals. The adult SCD program consists of a multidisciplinary team including 5 medical hematologists, 2 advanced registered nurse practitioners, 1 physician assistant, and 1 registered nurse. The UF Health-Jacksonville adult sickle cell program has a clinic panel of 569 adult patients with SCD. Of the 569 patients, 318 (56%) are women and 540 (95%) are African American individuals. The UF Health-Jacksonville adult SCD program consists of a multidisciplinary team including 1 medical hematologist and 1 advanced registered nurse practitioner.The study is registered on ClinicalTrials.gov. We will use web-based recruitment processes, including posting recruitment information on the UF study Facebook page and various internet listservs to identify and recruit adults with SCD from across Florida. We will also use colorful posters, flyers, and brochures developed for this study and distribute them in sickle cell clinics and health fairs and through university bulletin boards. In addition, we will work directly with sickle cell organizations, community-based organizations, health care networks, and churches to post recruitment flyers aimed at encouraging adults to participate in and advertise the study within their networks throughout Florida.0 thalassemia, and HbSβ+ thalassemia), report moderate to severe level of pain  related to SCD within previous 24 hours, use opioid analgesics on as-needed or continuous basis, speak and read English, and be ≥18 years.To be included in the study, patients must be adults with a diagnosis of SCD  participants with complete data at 8 weeks, based on a 13% attrition rate observed in our previous longitudinal studies in which follow-up was more than a year. We will strive for a sample in which 95% participants have African descent and approximately 50% are women. Our team has been exceptionally successful in conducting longitudinal studies using tablet technology with this vulnerable population and recruiting and retaining patients with SCD for pain research ,47-50.This is an internet-based study, with all screening and consent processes completed by the research specialist (RS) or the community health worker either in person, internet-based, through email, or through US postal service, depending on the patient’s needs. The RS or community health worker will explain the study to the patients and ascertain their willingness to participate. Patients will be informed that their participation is voluntary and that a decision to decline participation will not affect their care. Patients who choose to participate will be asked to sign a written consent form. We will use one of the following methods: (1) patient will sign the consent form in person and will be given a copy, which they may keep for their record; (2) we will email the consent form for the patient to sign and email back to the RS; or (3) we will send 2 copies of the consent form with a self-addressed envelope with paid postage to the patient using the address provided. The patient will sign the consent form, keep a copy for their record, and mail a copy back to us. Patients recruited via phone or email will sign the written consent form on the day of their first study visit, if occurring in person. Otherwise, patients will sign the consent form electronically or via the other consenting methods described previously. The RS who will assist individuals in these screening and consent processes will be trained in good clinical practices for research and IRB and Health Insurance Portability and Accountability Act procedures. The training includes role-playing with the principal investigator (PI) and retraining if the staff deviate from the proper processes.We will use permuted block randomization with stratification based on worst pain intensity (≤5 or >5) to assign the 195 consecutively selected patients to the 2 study groups. The assignment will be blind until a sealed electronic envelope is opened after the patient completes the pretest data collection procedures.An important retention strategy is to engage the patients as active partners in the study by explaining the importance of their contribution. We have built trusting relationships with the clinic staff and patient panel, which facilitated the success of our feasibility study and an 18-month longitudinal study (1R01HL124945) that have resulted in several publications -55. OtheThe experimental arm includes self-monitoring of pain and stress, electronic monitoring of opioid use, alerts or reminders, and use of YCWS (3 video banks of RDE and support). The YCWS app features self-monitoring, video banks, and support elements, which comprise the YCWS intervention  and 2.Set your plans . The patient can use this auxiliary icon to revise optimal and tolerable pain goals and time of day to complete study activities including support and to set alerts or reminders. When patients click video banks  and pain intensity scale (0-10), set plans, or video banks subtabs that display on the screen consecutively . Patienteo banks , 3 subicIndividuals can click on any of the 3 banks to choose a video to watch. The YCWS intervention can be customized by choosing video clips based on female or male voice, type of nature images, background sound, or lengths and by finding their own video clips. Patients can watch as many video clips as needed. Patients would be able to discern whether they received stress or pain relief after using the videos and determine which of the videos provided them with the most stress or pain relief. According to individual preference, we will send system-generated alerts or reminders to patients or a research staff will call, text, or email the patients to facilitate data entry and intervention use every 24 hours. The patient can also connect with our support staff about issues related to YCWS intervention use  and technical difficulties with study device or app for advice on what to do (both groups). Our support staff will monitor our database daily. If the patient does not enter data after 24 hours of system-generated alerts or reminders or messages via staff cell phone, the study support staff will contact them for data entry troubleshooting and, for the experimental group, for YCWS use as they indicated in their goals. During the short-term trial (weeks 1-8), patients will monitor their stress and pain daily, as described previously.Breathing out worry, breathing in light guides the patients to “Notice the cloud-like formations on the screen. Observe how the images drift and change. As you breathe deeply, let your concerns and tensions (which worry you go) out into the atmosphere where they can dissolve just as the cloud-like formations on the screen dissolve and vanish from view. It is all right to let go of your worries. In fact, it is important to your health that you do so. Just breathe out problems and worries. See them drift off, walking by, and off the screen, no longer a part of you. Now, breathe in sunshine and healing energy.” This requirement is critical and supported by recent evidence showing that the respiratory control center communicates directly with and controls a brain center linked to attention, arousal, and panic [We will provide experimental group members access to 3 video banks from which they can choose their daily intervention. Patients will use only basic videos during week 1 to become familiar with the intervention and learn deep breathing and relaxation exercises through instructions. For example, one of the basic video clips entitled nd panic . Corlessnd panic -60 . Patients with SCD report a preference for active remote support as opposed to face-to-face peer or social support because of weather, travel, and parking issues involved with receiving the support at an academic health center. Remote support also empowers them to participate in the study without the additional burden of traveling to the location of any peer or social support as recommended by the Chronic Disease Self-Management Program . We specfavorite videos for personal use, and recommend them via the investigators to other patients with SCD. We will vet these recommendations before releasing them to other patients. Throughout the study period, we will time stamp and track the patients’ YCWS web-based activities to capture data on system use.During the long-term period (months 3-6), only system-generated alerts or reminders via messaging service or staff cell phone will be available. Patients will have the ability to find their favorite video clips on the web, add them to The control arm includes self-monitoring of pain and stress, electronic monitoring of opioid use, and alerts or reminders. During the efficacy trial (weeks 1-8), similar to patients in the experimental group, patients will monitor their stress, pain, and opioid use daily. We will send system-generated alerts or reminders every 24 hours to patients via phone call, text, or email to facilitate data entry. If the patient does not enter the data after 24 hours of alerts or reminders, the study support staff will contact them for data entry troubleshooting. During the long-term period (months 3-6), patients will continue to self-monitor their daily stress and pain and use the electronic opioid use monitoring device. Patients will also continue to receive system-generated alerts or reminders via messaging service or staff cell phone. Throughout the study period, we will time stamp and track patients’ web-based activities to capture data on system use and outcome variables.The PI will conduct reliability assessments for the RS’s implementation of the protocol on a random sample of 20% of the study measures. Although this assessment cannot be blinded, the RS will not be informed of the reliability check until the baseline data collection procedure is underway. If there are any deviations from the protocol, the RS will undergo additional training and supervised data collection to ensure protocol adherence.To improve fidelity, we will ensure that participants use the YCWS intervention as intended by monitoring the participants’ YCWS system use on the web. During the first 8 weeks, we will call or text participants 2 hours before the next data collection time if the patient does not enter data after 24 hours of system-generated alerts or reminders and has missed the period they indicated for completing the study, to encourage the use of YCWS. We will also ascertain if they are having trouble with accessing the program and will troubleshoot with the participants to resolve any issues. We will also monitor the participants’ self-monitoring of stress, pain, and opioid use in both groups. As a measure of intervention fidelity, the use of the system and measures will be documented by the app software that automatically writes time-stamped data to a SQL database. The fidelity of our pilot feasibility protocol is rigorous as the program is computerized and consistently implemented. In addition, we will monitor mobile device use, and time of use will be documented in the database to determine the intervention dose.Pain, the primary outcome, will be measured using the pain intensity scale. This 3-item scale asks patients to report their current, least, and worst pain intensity in the past 24 hours on a scale of 0 (no pain) to 10 (pain as bad as it could be). We will calculate the average of the 3 scores to obtain an average pain intensity score, which has an internal consistency (α) of .85 [) of .85  and predStress will be measured using the stress intensity scale. This 3-item scale asks patients to report their current, least, and worst stress intensity in the past 24 hours on a scale of 0 (no stress) to 10 (stress as bad as it could be). We will calculate the average of the 3 scores to obtain an average stress intensity score. The internal consistency (α) of the stress intensity in the SCD sample was .82 [r=0.41; P=.07) with the participants’ Perceived Stress Questionnaire (PSQ)-Recent score, demonstrating fair construct validity [ was .82 . It showvalidity .We will use PAINReportIt -65 softwr=0.73) [α) reliability of the PSQ-Recent in our SCD sample was .94 [PSQ-Recent  is a 30-r=0.73) . The intWe will collect data on patients’ daily activities, such as the time spent on the YCWS intervention, including the time spent in using the video banks of RDE. The software will capture these activities by time-stamped data in the SQL database.Questions regarding demographic characteristics and analgesics are also included in PAINReportIt -65. Patiα) of .87 in the population with SCD [The Sickle Cell Self-Efficacy Scale is a 9-item tool that measures patients’ beliefs in their ability to engage in daily activities despite having SCD and coping with obstacles or setbacks associated with SCD. For example, one of the items asks patients, “How sure are you that you can reduce your SCD pain by using methods other than taking extra pain medication?” The response options are 1  to 4 (very sure). The total self-efficacy score is the sum of the 9 items, with scores ranging from 9 to 36. High scores indicate great self-efficacy. The Sickle Cell Self-Efficacy Scale has been validated in patients with SCD who are ≥11 years and has an internal consistency  and opinions  about the YCWS video clips and how they can be improved (3 questions). We will conduct an exit interview about staff support’s acceptability (1 question) and system-generated support (1 question). We will conduct the exit interview at week 8  and month 6 . The exit interview will be audiotaped and transcribed verbatim. We used this measure in our feasibility study. We will use patients’ feedback to modify and improve our protocol for future studies.The research data will be collected electronically using laptop and pen tablet computers. All the study surveys may be completed via the web using an app developed for this study. This application will contain PAINReportIt, a computer program developed by DJW to collect participants’ pain information and other surveys in electronic format. Participants’ data will be written directly to that server and will not reside, even temporarily, on the laptop or pen tablet computer. We will use HTTPS for encrypted data transfer to the College of Nursing server. The data will be stored in a secure College of Nursing server with access restricted to the immediate study personnel. All patients will be assigned a code number, and the research team will identify their data only with that code number. The link of the code numbers to the participant identifiers will be kept separate from the study data. Only the investigators and key personnel will have access to the code or master key. Any hard data collected will be stored in a locked office at the College of Nursing.The software design will make every effort to reduce user errors; all data will be entered directly by the participant using an interface tested with cognitive interview methods that informed the final interface design. Consistency checks are built into the software so that inconsistent data  are flagged immediately to inform the users and assess their intent. In addition, there will be more comprehensive consistency checks before data analysis. Inconsistent data points will be treated as missing. On the basis of our previous studies with this web application, we expect the percentage of inconsistent data values to be very low (<0.5%).P<.025 as statistically significant for intervention efficacy tests (short term and long term) on the primary outcome of pain intensity. For other inferences, we will consider P<.05 to be statistically significant. We will compute descriptive statistics  of baseline patient characteristics data, including demographics, pain, stress, and analgesic use before the test and compare the control group and the experimental group using chi-square tests or 2-tailed t tests. We expect no significant difference between the 2 randomly generated groups.The study biostatistician will perform data management and analysis in collaboration with the PI and coinvestigators. The data will be stored in an SQL database and exported to the statistical software R for analysis. We will use an intention-to-treat approach, which includes all randomized participants in our analysis. We will consider To study the short-term effect of the intervention on the primary outcome (pain intensity) and secondary outcomes (stress intensity and opioid use), all of which are measured daily, we will use linear mixed effects models. Fixed effect terms in the models include the group variable to represent the treatment effect and baseline outcome measurement. Participant-specific random effect terms will be used to account for within-participant correlation in repeat measures. Note that we do not include the time variable in our models because we are primarily interested in the treatment effect on the average pain, stress, and opioid use over time. We do not anticipate significant time trends, but will explore them in the secondary analysis.To estimate the long-term effects of the intervention, we will again use linear mixed effects models. Fixed effect terms in the models include the group variable to represent the treatment effect and baseline outcome measurement. Participant-specific random effect terms will be used to account for within-participant correlation in repeat measures.We will construct machine learning models, in particular, random forest models, to predict outcomes based on patient group assigned, patient’s personal characteristics , and environmental factors . A random forest model consists of a large ensemble of regression trees and the average prediction of these trees will be output as the prediction of the model. Regression trees can accommodate nonlinearity and complex interaction without manual specification by researchers, but have the disadvantage of noisiness. Random forest retains the advantage of tree, while reducing noise by introducing randomness in the form of training each component tree with a bootstrap sample of the original training data and randomly selecting a subset of predictors as candidate for splitting at each split of the tree, to reduce the correlation between the trees and the variance of average prediction. We will use a random 70/30 partition (stratified by group and baseline pain) to reserve 30% of the patient sample as the test set, with the remaining 70% as the training set. We will use cross validation to optimize the parameters  for the random forest prediction models. The models, trained and optimized on the training data set, will be assessed using the reserved test data set to obtain an unbiased estimate of its performance when applied to new data. These models will allow us to identify individuals most likely to benefit from the proposed intervention and the modifiable environmental factors to improve the effects of the intervention.Random effect models can accommodate longitudinal data with missing visits. For visits with partial data (item-level missing data), we will use multiple imputation by fully conditional specification to generate multiple completed data sets, on each of which statistical inference will be performed separately and then aggregated using Rubin rule . This alThe success of this study lies on its short-term and long-term efficacy on the primary outcome of pain intensity. We conservatively assume an SD of 3 for pain intensity based on values we observed in earlier studies. With a 2-sided type I error of 0.025, the proposed sample of 170 patients provides 80% power to detect a pain reduction of 1.5, below the minimal pain reduction of 2, which is considered as clinically meaningful.The project was funded by the National Institutes of Health and National Institute of Nursing Research. Our IRB approved the study on May 14, 2020.Study recruitment started on March 29, 2021. As of April 2022, we had enrolled 45.9% (78/170) participants in the study. Of the 78 participants, 65 (83%) participants have completed baseline, 53 (68%) have completed the postintervention assessment after 8 weeks, and 28 (36%) have completed the 6-month study.As technology advances, the use of mHealth apps is becoming an integral part of daily life, including for self-management of chronic conditions. Web-based interventions and technologies are reported to have high usability and acceptability as a tool to monitor and self-report daily pain -75, moniThis protocol paper presents the design of the RADIANCE study, an RCT with the long-term goal to reduce stress and improve pain control in patients with SCD with less opioid use. The intervention with self-management RDEs, YCWS, can offer interactive learning that allows sustained or repeated sessions. Although the intervention may have no direct benefit to individual participants, it may provide individuals with previously unrecognized insights about their stress, pain, and opioid use and options for self-management of these symptoms.A strength of this guided relaxation study is its web-based design and implementation that provides patients with the ability to interact with the program at their convenience in real-world settings. By providing the tools to reduce their pain, it may help patients with SCD to feel empowered. Given that the guided relaxation is web-based, the patients may have a sense of control and empowerment. However, the web-based design can also be a limitation if internet connection becomes an issue. We attempt to mitigate this potential effect by making the intervention platform independent and allowing patients to go to the library and use the library computer or use their other smart devices for the study. Furthermore, the findings of this study will be generalized only to the state of Florida and not nationwide.Although recruiting patients from health care networks and churches is a new strategy for us in Gainesville, Florida, this will likely be an opportunity for access to affected communities . We will report on the patients’ YCWS web-based activities, data on system use, and pain and stress intensity. The study has the potential for assisting people to develop the confidence necessary to self-manage stress that could intensify their acute or persistent SCD pain. If demonstrated to be effective, this internet-based and web-based intervention could be made available nationwide and, eventually, worldwide.To maximize the dissemination of this study, we will share methodological approaches, data, and results generated from this study by publishing our findings in research journals that are indexed by PubMed and generally accessible to the research community. We will also present the findings and methodologies at national and international research and health care conferences in accordance with the proposed study time line.


To assess the effectiveness of a single application of 2% sodium hyaluronate (SH) in controlling pain after pterygium excision as compared with that of a control group.  We performed a prospective randomized controlled trial in the patients who underwent pterygium excision. The outcome of topical application of 2.0% SH was measured using the visual analogue scale (VAS), in comparison with that observed in a control group (without SH). The area of ocular surface defects was assessed by ImageJ freeware. Analysis of pain scores and ocular surface defects were observed from both groups immediately after the operation, Day 0, and 3 subsequent days. p=0.242). The medians of pain score assessed by the VAS on Days 0, 1, and 2 were 5, 3, and 0 for the SH group and 6, 5, and 3 for the control group, respectively. The pain score was statistically significantly decreased in the SH group compared to the control group on Day 1 (p < 0.001) and Day 2 (p < 0.001). The pain level of both groups was nearly the same on Day 3 (p=0.141). The area of ocular surface defects was significantly different between two groups on Day 1 (p < 0.001) and Day 2 (p < 0.001). Postoperative complications were not observed.  Thirty patients were randomly divided into control group and SH treatment group. The initial area of the ocular surface defect on Day 0 was approximately the same for both groups ( A single topical application of 2% SH in pterygium excision was effective in relieving pain in the early postoperative period without any adverse effects. This innovation may provide alternative pain control in pterygium surgery. Pterygium, an ocular surface disorder, is a winged-like fibrovascular growth of the limbus and conjunctiva towards the cornea . A positSeveral surgical modalities have been described as methods of treating pterygium, including simple excision  and bareSodium hyaluronate (SH) is a polysaccharide consisting of disaccharide units of glucuronic acid and N-acetyl-glucosamine . It playhttps://www.thaiclinicaltrials.org/ with the following identification number: TCTR 20210928002. Informed consent was obtained from all participants prior to the study. The treatment outcome of a single immediate postoperative topical application of 2.0% SH  was measured by postoperative pain using the visual analogue scale (VAS) . Th. Th19]. t-test, and Chi-square test were analyzed based on the demographic and clinical characteristics of participants at baseline. The comparison of pain scores between the SH group and the control group was carried out using the Mann–Whitney U test and median (range). The t-test was utilized to compare the area of corneal and conjunctival epithelial defects between the two groups. Statistical significance was considered as a p value less than 0.05.This study was designed as a prospective randomized control trial. A sample size of 30 eyes in this prospective study was calculated based on the mean pain score in the study of Oksuz H and Tamer C . AnalysiThirty-five patients were enrolled in this study. Five patients were excluded because three patients declined to participate in the protocol, one patient had rheumatoid arthritis, and another had diabetes mellitus. Therefore, 30 patients were randomized into one of the two groups, resulting in the SH group of 15 patients in total and 15 patients in the control group. The CONSORT flow diagram is illustrated in The baseline characteristics of the study patients included in the analysis are summarized in p < 0.001) and Day 2 (p < 0.001). On postoperative Day 3, 6.7% (1/15) of the patients in each group had a small corneal defect. However, these two patients had complete epithelialization by Day 4. p < 0.001) and Day 2 (p < 0.001). It showed that pain and ocular surface defects were decreased significantly on Day 1 and Day 2.Pain scores are summarized in No serious adverse events were detected in the SH and control groups.The ocular surface, including the conjunctiva and cornea, is densely supplied by corneal sensory nerves predominantly from the ophthalmic division of the trigeminal nerve , making Ocular pain is one of the most common postoperative complaints following pterygium excision . Adequat6 Da) SH is inhibition of inflammation by its interaction with the cluster of differentiation 44 cell surface receptor and the SH-mediated motility receptor [SH is a natural high molecular weight and linear polysaccharide with several hydrophilic functional groups. The biological function of high-molecular-weight  were induced by UV irradiation in a pterygium patient . Visiol®A single topical application of 2% SH in pterygium excision was effective for pain relief in the early postoperative period without any adverse effects. This innovation may provide alternative pain control in pterygium surgery. However, the cost-effectiveness analysis is an essential consideration for clinical application.


Pain is frequently encountered in the prehospital setting. The treatment of pain is one of the priority activities for paramedics.  1048576 patients under the care of EMS over a 7-month period were included in this study. Data included using pain scale and pain score, the initial diagnosis, analgesic treatment and the given drug obtained from the Ambulance Emergency Procedure Cards.  The complete absence of pain was detected in 43.9% (95% CI 43.8–44.0) of patients, mild pain in 17.0% (95% CI 16.9–17.1), moderate pain in 11.6% (95% CI 11.5–11.7), and severe pain in 4.9% (95% CI 4.9–4.9) of cases. In 22.5% (95% CI 22.4–22.6), no pain rating scale was used. 98.0% (95% CI 97.9–98.1) of patients with mild, 96.1% (95% CI 96.0–96.2) with moderate, and 94.0% (95% CI 93.9–94.1) with severe pain did not receive any pain medication. The most commonly used drugs in all groups were metamizole and ketoprofen. The greatest analgesic effect was observed in the group of patients with severe pain. Pain decreased by an average of 3.2 NRS points in the drug-free group and 3.1 NRS points in the treated group. The most commonly documented diagnoses in all groups of patients were signs and diseases not classified in other groups (ICD-10 R00-R99), injuries and consequences of external causes (ICD-10 S00-T98), and diseases of the circulatory system (ICD-10 I00–I99).  Paramedics may use a variety of medications but use them rarely. Adding metamizole to the list of medications used by paramedics has made it one of the most commonly used drugs. Regardless of whether the drug was used or not, the analgesic effect was similar. Pain is a subjective complex phenomenon caused by illnesses or injuries. The extension of paramedic's competences in legal regulations in Poland in the beginning of 2016 provoked broad discussion among clinical emergency doctors, researchers in the area of pain, and paramedics themselves. One of the main causes of doubt was the possibility of self-administration of analgesic drugs  crew), such as ibuprofen, metamizole, paracetamol, and fentanyl. Paramedics could earlier use only acetylsalicylic acid (ASA), ketoprofen, and morphine. The National Medical Rescue System in Poland is based mainly on the so-called primary ambulance emergency teams without a medical doctor that consist of two or three paramedics or emergency nurses. Paramedics ensure the professional care and implementation of rescue procedures at the Advanced Life Support (ALS) level. They can now independently administer 47 drugs, including analgesic agents. The following analgesic drugs are nonopioids: ibuprofen (tablets), ketoprofen (tablets and intravenous), sodium metamizole (intravenous), paracetamol/acetaminophen , and acetylsalicylic acid (tablets), as well as opioids: morphine and fentanyl (both intravenous). Finally, they are entitled to administer drotaverine and papaverine which (together with ASA) were not taken into consideration in this study. Paramedics most often use the numeric rating scale (NRS) or similar  or Faces Pain Scale (FPS), also in the range of 0–10 points) to assess pain. In most cases, the assessment is made twice—before and after the treatment procedures (taking into account the pharmacokinetics of various drugs and the condition of the patient). Only some rare reports on prehospital pain management by paramedics in Poland were available and they focused on regional research material and their results were not optimistic . The majThis research is a register-based observational study of patients with acute pain transported by emergency medical services (EMSs) to hospital or left at the call place in Poland over a 7-month period from January 1, 2020 to July 31, 2020 (1048576 patients). The research material consisted of data gathered from Ambulance Emergency Procedure Cards collected in the System of Management Assistance for the National Medical Rescue Service. The authors applied to the Ministry of Health for access to data concerning several actions and procedures implemented by EMS in the whole area of Poland. It was information about using pain scale, patient assessment with the NRS and the score , the initial diagnosis made by paramedics (according to ICD-10 classification code and description), analgesic treatment and the given drug and, finally, using nonpharmacological techniques . The latter information was not complete, so it was not considered in the final analysis. The material received from the National Monitoring Center of Medical Rescue System did not include any demographic data such as age and gender of the patients, either due to very strict legal regulation about personal data protection. The records with at least one application of numerical pain assessment scale were selected first. They were subsequently divided into subgroups according to the document “Good Practices of Pain Treatment by Emergency Medical Services,” such as: mild pain (1–4 pts.), moderate pain (5–7 pts.), and severe/extreme pain (8–10 pts.). In each subgroup, we analyzed applied analgesic drugs, indications for their use, and also diagnoses in which no pharmacological agents were given. The groups were also created in which the NRS score was zero. Moreover, the authors analyzed the frequency of each drug application depending on pain intensity and initial diagnosis according to ICD-10 classification. The key to the list of diagnoses compatible with ICD-10 classification is shown in Additional Statistical analysis was performed using GraphPad Prism ver. 8.4.0, GraphPad Software, San Diego, California USA. Categorical data were reported as numbers/percentages (%) with 95% confidence intervals (CI). The means were reported as mean ± standard deviation (SD). Due to extremely large study material, no standard statistical tests were used in order to compare the pain in different groups of patients, because they might show statistical relevance with negligible change in the NRS, so their clinical importance would be minimal. In such cases, the data were shown in a descriptive and illustrative manner.n = 460569) of patients, mild pain in 17.0% , moderate pain in 11.6% , and severe/unbearable pain in 4.9%  of cases. In 22.5%  of people, no pain rating scale was used. In less than 0.01%  of patients, it was not possible to unequivocally determine the use of the NRS or whether the assessment was repeated. Analgesic drugs were used in 1.0%  of all analyzed interventions of EMS.In total, 1048576 interventions of primary EMS were analyzed. The complete absence of pain (0 pts. in the NRS) was detected in 43.9%  of patients with mild pain did not receive any pain medication. Patients with 3 pts. in the first and 2 pts. in the second assessment were the largest group  of patients with mild pain. The medications were as follows: ibuprofen, 2.4% , ketoprofen, 38.4% , metamizole, 43.0% , paracetamol, 11.3% , fentanyl, 2.1% , and morphine, 2.8%  (The pain intensity in the pharmacotherapy group ranged from 1 to 4 pts. during the first assessment and the majority of patients (41.3%) graded their pain as 4 pts. In the second examination, the most frequent result (33.0%) was only 2 pts . Analges n = 95) . The secn = 116433) of patients with moderate pain did not receive any analgesic treatment. The pain score range in this group was 5–7 pts. and the most common score was 5 pts. in 45.3% patients. The second pain assessment was made in 92.2% patients  of cases. The first examination showed that the majority of the patients rated the pain as 5 pts. (39.6%). In the second assessment, the score ranged from 0 to 10 (n = 14), ketoprofen, 28.9% , metamizole, 4.3% , paracetamol, 7.7% , fentanyl, 8.1% , and morphine, 8.7%  of cases  of patients with severe pain were not given any drugs. The largest group of people (62.0%) had the 8-pt pain score (n = 47466) of patients. 8-pt pain decreased from 62.0% to 17.3% of patients and in case of 10 pts. decreased from 19.2% to 3.3%. The details are given in Additional As many as 94.0%  of patients with severe/extreme pain. The pain severity in the first examination ranged from 8 to 10 pts. In the repeated assessment, the pain score ranged from 0 to 10 pts., with the mean of 5.4 ± 2.3 points which shows a considerable pain reduction , metamizole, 43.9% , paracetamol, 5.2% , fentanyl, 17.0% , and morphine, 15.5% . The second examination was made in at least 96.1% of patients. Additional Analgesic drugs were administered in only 4.8%  of patients with mild pain, 2.6%  with moderate pain, and 8.4%  with severe pain were given more than one analgesic drug. Detailed data are shown in As many as 1.5%  in 17% of cases, including 1.9% of patients who were given analgesic drugs; moderate pain (5–7 points) in 11.6% of cases in whom 3.9% obtained analgesics; and extreme pain (8–10 points) in 4.9% of patients, including only 4.8% with applied pain medications. Berben et al. carried out a study to assess the conduct of Dutch national EMS staff in terms of using analgesia protocols in trauma patients and noticed that local paramedics applied pain medications in 42% of cases in all pain intensity scores . Data weWe have shown that the application of specific analgesic agents depends on the pain severity and ICD-compliant diagnoses. Nonopioid drugs were used more frequently. Most common states and disorders (code S00-T98), independently on the pain severity, were treated with fentanyl (about 62–70% of cases), morphine, and ketoprofen (30% each). Regarding disorders with R00-R99 code metamizole was used in 58–65% of cases and paracetamol in 54–61% of patients. The third in frequency order ICD-compliant codes I00-I99 were related to the administration of morphine (most often–18–20% of cases) and considerably more rarely ibuprofen (0–12.2%) and paracetamol (4.1–7.0%). It is not surprising that morphine is more often used in patients with cardiac diseases. As expected, opioids were prescribed more often in patients with more severe pain in all groups. These observations follow good pain management practices. However, the quite frequent use of ketoprofen is noteworthy.The results indicate that paramedics actually realize the recommendations called “Good Practices of Pain Treatment” in most cases of application of analgesic drugs in patients. Analgesic agents are used in pain treatment regardless of its intensity appropriately according to recommendations: metamizole, paracetamol, ketoprofen, ibuprofen, and morphine in nontraumatic pain and fentanyl and morphine in pain causes by injury .Multimodal analgesia was used relatively rarely (1.5–8.4% of cases), most often in patients with severe pain. Cases with more than two drugs practically did not occur in any group of patients. The synergistic effect of drugs and the reduction of their dose is important. The most common drug combinations were fentanyl with metamizole. It is in line with the practice of combining analgesics from two or more drug classes.According to “good practices,” paramedics should reduce the pain severity by at least 50% . BesidesInterestingly, patients with mild pain who were not given drugs declared complete pain resolution in 6.9% of cases which is not true for patients who obtained pharmacological treatment. In the groups of patients with moderate and severe pain, the authors did not report cases of complete relief of pain regardless of application of drugs. Interestingly, both patients without drug treatment and those who were given analgesic agents show similar distribution of pain score in the first and repeated pain severity assessment. This indicates that apart from the pharmacotherapy, it is also very important to use other medical procedures. It is possible that some instrumented techniques were used to alleviate the pain instead of drugs, for example Kramer's splint in limb fractures, triangular bandage, placing the patient in a comfortable position or cold pads in case of burns. The similar phenomenon was observed in Sweden where 80% of patients declared a reduction of pain severity without getting any pain medications or obtaining any injury protection procedures . One of Our study shows that the enhancement of paramedic competences, publication of “Good practices of pain treatment,” and implementation of digital medical documentation  had an impact on pain management by EMS. In our opinion especially introduction of obligatory pain assessment and documentation in the digital form contributed to the frequent use of pain rating scales. Unfortunately, the frequency of pain treatment is still low. We support the idea that education courses for paramedics covering pain assessment and treatment should be planned and implemented in practice. The changes in legal acts may not be enough.Our study has some serious limitations. The method of access to data contained in the emergency medical command support system (electronic documentation) in Poland and the form of these data often make it completely impossible to obtain detailed information about the patient's condition, treatment, or pain assessment scale. The timing of the second pain assessment is also problematic. Despite the fact that it should take into account the pharmacokinetics of drugs, it is often selected subjectively by paramedics. We also have no information why a pain assessment was not performed or what scale was used. There is also no certain method of assessing whether the change in pain intensity depended on the implemented medical procedures in a group of patients who did not receive pain medications.


VAS pain scores were assessed before and after the laser PBM, the day after, and on the 7th and 30th days after the treatment. No adverse effects occurred within 30 days after treatment. The mean VAS-pain score was 3.8 (SD 2.3) before PBM; 2.6 (SD 2.0) after PBM; 1.9 (SD 2.2) on day 1; 2.0 (SD 2.3) on day 7; and 1.5 (SD 2.2) on day 30. VAS pain decreased significantly over time (p < 0.0001). A single session of laser PBM may be safe and effective in reducing pain for symptomatic OLP patients. Further investigations are required to include placebo or topical corticosteroids as comparators.This study aimed to evaluate the effectiveness of a single session of laser photobiomodulation (PBM) with flat top handpiece in reducing painful symptoms in patients with Oral Lichen Planus (OLP). The clinical charts of 20 patients of the Dental Clinic of University of Padua  who underwent a single laser PBM to manage OLP symptomatology were retrospectively analyzed. A 980 nm diode laser and a flat top handpiece with a 1-cm Oral lichen planus (OLP) is a chronic non-infective inflammatory disease that affects oral mucosa –3. This 2; 3 = white striae with an atrophic area more than 1 cm2; 4 = white striae with a erosive area less than 1cm2; 5 = white striae with a erosive area more than 1cm2” [OLP is generally classified into reticular and erosive form . Reticulan 1cm2” .Fig. 1ReThere are controversies about the exact etiology and pathogenesis of OLP –9. An imThe therapy is required only in case of symptomatic OLP , 17. TheThis study aimed to evaluate the effectiveness of a single session of laser photobiomodulation with diode laser in reducing painful symptoms in patients with OLP.This is a retrospective study including all 20 consecutive patients who were treated with a single session laser PBM to manage OLP symptomatology at the Dental Clinic of University of Padua from January to June 2021. Inclusion criteria were as follows: (1) patients followed for OLP in the Oral Pathology Unit; (2) clinical and histopathological diagnosis of OLP according to Van Der Meij 2003 ; (3) ageThe following data were collected from the clinical charts: age, sex, OLP lesion localization, Thongprasom score , treatme2 spot area (Doctor-Smile® AB2799) were employed to perform a single session of laser PBM. Laser energy was delivered with a spot-technique in non-contact mode, with a variable number of spots to cover all the size of the lesion and the area over the border for 5 mm. Some patients presented symptomatic and asymptomatic lesions, and both were treated. To ensure a fluence of 10 J/cm2, the diode laser was set as follows: output power of 0.5 W with continuous wave  and time of application 20 s per point.A 980-nm diode laser (Doctor-Smile® Wiser L A 8D0 001.3) and a flat top handpiece with a 1-cmVAS pain scores were assessed before and after the laser PBM, the day after, and on the 7th and 30th days after the treatment. The patient recorded the VAS pain score by using a score collection form and communicated the data by telephone due to COVID-19 restrictions. If VAS pain score was ≥ 4 before PBM, a therapy based on corticosteroids and antifungals  was also prescribed. In case of persistence of symptoms, patients could take this medication and record the VAS pain score before starting the therapy. These patients were considered as dropouts.t test with Benjamini–Hochberg correction for multiple tests . The association between the change of VAS pain scores over time and some clinically relevant parameters  was investigated with additional mixed regression models including time and one parameter in each model (due to the limited sample size). As two subjects dropped out the follow-up before 15-day and 30-day assessments, a sensitivity analysis was performed by reasonably imputing the missing VAS pain score with the baseline VAS pain score (to represent the increase in pain experienced by the subject if the drug was not taken). All tests were 2-sided, and a p value of less than 0.05 was considered statistically significant.The statistical analysis was carried out with R 4.1 . We estThe analysis included 20 patients  who were treated with a single session laser PBM to manage OLP symptomatology during the study period. Patient characteristics are reported in Table No adverse effects occurred after the treatment with laser PBM. Six patients (30%) spontaneously requested further laser PBM sessions in the future. Two patients (10%) dropped out from follow-up at 8 and 15 days after PBM because they started the fluocinonide/miconazole therapy due to lack of pain relief .p < 0.0001; Table padj = 0.01), day 1 (padj = 0.005), day 7 (padj = 0.003), and day 30 (padj = 0.004). No statistically significant associations were found between VAS over time and age (p = 0.61), sex (p = 0.37), number of spots (p = 0.48), and Thongprasom score (p = 0.09).VAS pain scores decreased significantly over time , at day 1 (padj = 0.008), day 7 (padj = 0.003), and day 30 (padj = 0.02). Patients with higher Thongprasom score reported higher VAS pain scores over time (p = 0.04), while no statistically significant associations were found between VAS over time and age (p = 0.36), sex (p = 0.33), and number of spot (p = 0.44).In the sensitivity analysis, VAS pain scores decreased significantly over time p = 0.00; Table 2Our findings suggest that a single session of laser PBM may provide some advantages in the reduction of pain for symptomatic OLP.The literature offers several trials and systematic reviews supporting the efficacy of laser PBM in reducing symptoms and clinical signs in OLP , 29–34, Our study investigated the effectiveness of a single laser PBM session during the COVID-19 pandemic, where the choice of a single PBM session was mandatory to reduce visits at the hospital. However, a single laser administration  would allow an easier and more suitable treatment to a higher number of patients suffering from OLP.2, in accordance with the Clinical Recommendations in Dentistry of the Italian Ministry of Health of 2017 [This study differs from current scientific literature for the use of a flat top handpiece in the treatment of OLP. According to the literature, PBM performed with a flat top handpiece would be more effective, predictable and reproducible . The use of 2017 . This va of 2017 . However of 2017 .Although limited to a single session, our findings confirm the data in the literature about the absence of side effects after laser PBM, which is a very relevant data for the treatment of a chronic disease such as OLP . Indeed,Our study has some limitations that should be considered by the reader. The retrospective design and the limited sample size suggest caution in the interpretation of the findings. In addition, the absence of a control group or treatment does not allow to exclude any placebo effect in the reduction of painful symptoms , 40, whiOur findings suggest that a single session of laser PBM may provide some advantages in the reduction of pain for symptomatic OLP, with no undesirable effects. Randomized controlled trials including placebo or topical corticosteroids as comparator would be required to assess the efficacy of the single session laser PBM with a higher level of evidence.


Carotenoids are organic, liposoluble pigments found in nature, which are responsible for the characteristic colors of ripe tomatoes, carrots, peppers, and crustaceans, among others. Palliative care provided to patients with an incurable disease is aimed at improving the patient’s quality of life through appropriate treatment of symptoms accompanying the disease. Palliative care patients with burdensome symptoms related to advanced-stage cancers are especially interested in the use of natural dietary supplements and herbal remedies to reduce symptoms’ intensity and ameliorate the quality of life. Carotenoids seem to be a group of natural compounds with particularly promising properties in relieving symptoms, mainly due to their strong antioxidant, anti-inflammatory, and neuroprotective properties. Moreover, carotenoids have been used in folk medicine to treat various diseases and alleviate the accompanying symptoms. In this narrative review, the authors decided to determine whether there is any scientific evidence supporting the rationale for carotenoid supplementation in advanced-stage cancer patients, with particular emphasis on the adjuvant treatment of cancer-related symptoms, such as neuropathic pain and cancer-related cachexia. Carotenoids are organic, liposoluble pigments distributed in colored fruits, vegetables, photosynthetic bacteria, fungi, algae, and some fish . CarotenThe consumption of a diet rich in fruits and vegetables significantly affects the risk for various chronic diseases. Donaldson , in a rePalliative care is an approach that improves the quality of life of patients (and their families) facing the burden of life-threatening illness through prevention and relief of suffering using early identification and adequate assessment and treatment of pain as well as other problems  . PalliatAlthough the scale of the use of diet supplements and herbal remedies among palliative-care patients remains unknown, it seems to enjoy unflagging interest from patients with advanced-stage cancer disease refractory to standard therapy. One of the most frequent questions asked by patients and their families to palliative medicine specialists concerns the effectiveness of various natural compounds, carotenoids among them, as a therapy that can improve prognosis or relieve refractory and distressing symptoms. In this narrative review, the authors deal with this issue, trying to determine whether there is any scientific evidence supporting the rationale for carotenoid supplementation in advanced-stage cancer patients, with particular emphasis on the adjuvant treatment of cancer-related symptoms. The chemical structures of the key carotenoids discussed in the manuscript are shown in Neuropathic pain is defined as pain caused by lesion or disease of the somatosensory system, a part of the nervous system responsible for sensing touch, temperature, posture, and limb position, among others . In patiA special role in the pathogenesis of chronic neuropathic pain is played by the cascade of immune responses and oxidative stress induced by nerve injury . While sThus, carotenoids with both anti-inflammatory and antioxidant properties seem to be an excellent example of naturally occurring active substances capable of alleviating neuropathic pain. Additional carotenoid supplementation in parallel with standard analgesic treatment may not only contribute to better pain control and alleviation of side effects of treatment, but also due to additional properties may improve other inflammation-related symptoms, such as cancer-related cachexia, anorexia, or asthenia. In the following subsections, the authors will try to determine whether the results of the studies conducted so far support the benefits of additional supplementation of carotenoids such as crocetin/crocin, astaxanthin, β-cryptoxanthin, fucoxanthin, bixin, and lycopene in the treatment of neuropathic pain.Crocus sativus L. Saffron extracts and tinctures have been used for ages in traditional medicine for the treatment of different symptoms and diseases, due to its antispasmodic, sedative, diaphoretic, expectorant, and analgesic properties [Crocetin and its glycosidic ester crocin are the water-soluble carotenoids responsible for the unique color of saffron, a spice sourced from the dried stigmas of operties . Saffronoperties . In vitroperties . What isoperties . As mentioned above, neuroinflammation and oxidative stress have been identified as factors playing a crucial role in the pathogenesis of neuropathic pain . Data ob2 histaminergic and alpha-2 adrenergic receptors might be involved in crocetin-induced antinociception. Wang et al. [α and IL-1β through the Wnt5a/β-catenin pathway, as Wnt Family Member 5A (Wnt5a) plays an important role in central sensitization and neuronal plasticity in both acute and chronic pain. On the other hand, Vafaei et al. [Experimental studies conducted on animal models of neuropathic pain have shown that parenterally and centrally administered crocetin and crocin possess the ability to alleviate pain sensitization; however, no consistent data on the analgesic mechanism have been established. The results of a study by Erfanparast et al.  suggesteg et al.  proposedi et al.  suggestei et al.  postulati et al.  in turn In a mouse model of neuropathic pain induced by spared nerve injury (SNI), intrathecally perfused crocetin dose-dependently reduced mechanical and thermal allodynia . MoreoveCentrally administered crocin at a dose of 6 µg significantly decreased thermal hyperalgesia and mechanical allodynia in a chronic constriction injury (CCI)-induced model of neuropathic pain in laboratory rats . IntrapeA neuroprotective effect of crocin was also observed in the streptozocin (STZ)-induced model of diabetic neuropathy. Farshid and Tamaddonfard  proved tThe analgesic effect induced by centrally and peripherally administered crocin has also been demonstrated in other pain models. Tamaddonfard et al.  showed tAs shown above, crocin has been demonstrated to attenuate neuropathic pain in animal models . In the Astaxanthin is considered to be the carotenoid with the strongest antioxidant capacity when compared to other carotenoids  and commonly used antioxidants, such as α-tocopherol (vitamin E) ,34. ThisHaematococcus pluvialis and Chlorella vulgaris and the red yeast Phaffia rhodozyma are considered rich sources of astaxanthin. However, it also can be ingested with crustaceans  and Salmonidae species , containing natural sources of astaxanthin in their diet [Marine microalgae such as eir diet . In recent years astaxanthin has been widely studied in in vitro tests, in animal models, and in human clinical trials, due to its antioxidant, anti-inflammatory, anti-apoptotic, neuroprotective, cardioprotective, hepatoprotective, anti-cancer, anti-diabetic, and immuno-modulatory properties ,35. Asta+) channels (L-arginine/NO/cGMP/KATP) playing the modulatory role in the perception of pain. In the promising study by Zhao et al. , astaxanMoreover, it has been proven that the trans-isomer of astaxanthin exerts an anti-depressant-like effect by influencing the serotonergic system, and it may be of particular interest in the treatment of chronic neuropathic pain in cases with pain-related depressive disorders coexisting . In the Unfortunately, the authors did not find in the literature data from human studies that would confirm the analgesic efficacy of astaxanthin. Despite the promising results of studies conducted so far in silico, in vitro, and in vivo on animal models, it is impossible to properly assess the usefulness of astaxanthin in the treatment of neuropathic pain in cancer patients. Further research in humans should be conducted in this area. A summary of preclinical studies on the antinociceptive effect of astaxanthin on animal models of neuropathic pain is presented in The only experimental study to evaluate the use of β-cryptoxanthin, a major xanthophyll carotenoid routinely found in human serum, in the relief of symptoms associated with neuropathic pain was carried out by Park et al.  on a mouFucoxanthin is a carotenoid with many pharmaceutical properties that is found in brown seaweed . Chen etAs shown above, the analgesic properties of both β-cryptoxanthin and fucoxanthin have not been tested in clinical trials. In addition, studies on animal models are few, and so far do not allow for consistent conclusions about the analgesic properties of these xanthophylls. A summary of preclinical studies on the antinociceptive effect of β-cryptoxanthin and fucoxanthin on animal models of neuropathic pain is presented in Bixa orellana seeds. This natural pigment is commonly used as a cosmetic and textile colorant and in the food industry as well, in the coloring of products such as margarine, yellow cheese, etc. The potential anti-inflammatory and antinociceptive effects of bixin in daily doses of 15 or 30 mg/kg body mass orally were investigated in a preclinical model of inflammation and acute pain in a study by Pacheco et al. [Bixin is a natural apocarotenoid extracted from o et al. . In thato et al. . In the o et al.  observedIn a partial sciatic nerve ligation-induced mouse model of neuropathic pain, Zhang et al.  observedThe authors identified only two human intervention studies that tested the effectiveness of lycopene supplementation on cancer-related pain. However, none of these studies have evaluated the effectiveness of lycopene in relieving neuropathic pain. In the clinical trial conducted in 2003 by Ansari and Gupta , patientCancer cachexia was defined in 2011 by international consensus statement as “a multifactorial syndrome characterized by ongoing loss of skeletal muscle mass, with or without loss of fat mass, that cannot be fully reversed by conventional nutritional support and leads to a progressive functional impairment” . As the A systemic inflammation is the main pathogenetic factor of cancer cachexia, which affects the function of several tissues such as skeletal muscle, fat tissue, liver, and brain , leadingThe most effective way to treat or slow down the progression of cancer cachexia is optimal anti-cancer therapy. However, in many patients with advanced neoplastic disease under palliative care, that procedure has been terminated earlier by the oncologists, mainly due to its ineffectiveness, side effects, or disease progression. In these cases, the symptomatic treatment of cancer cachexia should be aimed at improving quality of life without creating additional disadvantages unacceptable to the patient. Unfortunately, mentioned above, the therapeutic options are limited and, in many cases, not effective Nutrition adequate to the patient’s condition and needs, considering the appropriate feeding route, is the fundamental factor in the management of cancer cachexia. Reliable and insightful assessment of a patient’s current diet and consultation with a nutritional healthcare professional to improve the quantity and quality of food consumed is essential. A first-line approach includes oral nutritional supplements providing macro- and micronutrients for those who are unable to meet their caloric and nutritional needs by the oral route . In someOrexigenic drugs as well as drugs leading to cytokine inhibition, such as corticosteroids and progestogens (megestrol acetate) have shown positive results in clinical trials, but undesirable side effects leading to muscle atrophy and enhanced risk of thromboembolism may limit their prolonged use . New theAs the anabolic deficit may be partially compensated by maintaining physical activity, the introduction of a motor intervention optimized in terms of the individual’s exercise tolerance may be an important intervention improving the overall state and quality of life of patients with cancer cachexia. Especially since a systematic review of 16 randomized controlled trials (RCT) conducted in cancer patients has shown that aerobic and resistance exercises improved body muscle strength more than usual care . MoreoveSince an excessive inflammatory state underlies the disturbances leading to cancer cachexia, the inclusion of naturally occurring anti-inflammatory substances in the daily diet may be able to significantly improve the patient’s cancer-related symptoms, general condition, and prognosis. That assumption seems to be confirmed by data from the pilot randomized trial conducted by Zick et al. , where iCarotenoids are a group of naturally occurring chemical compounds whose anti-inflammatory properties have been known for centuries and have been used in folk medicine in the management of inflammation-related symptoms and diseases. Hajizadeh-Sharafabad et al. , in a meThe anti-inflammatory properties of carotenoids have been confirmed in experimental studies conducted under various conditions, both in vitro and in preclinical and clinical studies as well. Widespread access to food products containing carotenoids, as well as the increasing amount of synthetically produced carotenoids available in various forms on the market, make this group of micronutrients particularly interesting in terms of supportive treatment of cancer cachexia. Below, the authors present an overview of carotenoids with the most proven anti-inflammatory properties that may be beneficial if added to the daily diet for prophylaxis and slowing down the progress of cancer cachexia. The studies conducted so far indicate that the anti-inflammatory properties of astaxanthin result from its ability to regulate the genes of inflammatory biomarkers, such as acute-phase proteins and abnormal activation of specific inducible enzymes, and to influence some signaling pathways . As postIn the experimental in vitro study by Choi et al.  astaxantHelicobacterpylori-positive patients a significant decrease in gastric inflammation and elevated CD4/CD8 response after astaxanthin supplementation (40 mg daily) was observed [In a preclinical study Part et al.  revealedobserved . However, the most important premise confirming the possible effectiveness of astaxanthin in cancer cachexia are the results of preclinical studies conducted by Cremades et al.  and NishLycopene is an acyclic isomer of β-carotene, however, unlike β-carotene lycopene is devoid of the β-ionic ring structure, therefore it does not possess provitamin A activity . LycopenIn a study by Huang et al. , lycopenBurton-Freeman et al.  proved tIn the RCT conducted among healthy men by Kim et al.  highly sData from a study by Thies et al.  indicateLycopene-rich tomato juice reduced systemic inflammation in overweight and obese females consuming 330 mL/d of tomato juice for 20 days in the RCT by Ghavipour et al. . Serum cOn the other hand, in the clinical trial conducted by Upritchard et al. , the incDespite the promising data obtained from preclinical studies, the results of the abovementioned clinical trials are inconsistent. Data from the systematic review of 17 intervention studies conducted by van Steenwijk et al.  showed tIn an in vitro study, Liu et al.  examinedheme oxygenase 1 (HO-1), peroxisome proliferator-activated receptor alpha (PPAR-α), and phosphorylated insulin receptor substrate 1 (p-IRS-1) expression after β-cryptoxanthin supplementation in laboratory rats. Data from a preclinical study by Liu et al.  indicateDespite the promising results of animal studies, due to the lack of data from clinical trials on the benefits of β-cryptoxanthin supplementation in preventing and slowing down the progression of cancer cachexia, no unequivocal conclusions can be made regarding beta-cryptoxanthin supplementation in palliative-care cancer patients.The studies conducted so far have shown that higher fruit and vegetable intake as well as a Mediterranean diet were associated with a lower risk for frailty—a geriatric syndrome observed in the population above 65 years old. Conversely, a suboptimal consumption of vitamins A, E, D, and carotenoids was shown to be related with low physical activity, weakness, reduced muscle mass, and poor physical performance in the abovementioned population . There aIn many studies the association of frailty syndrome with the elevated parameters of the inflammatory state, such as CRP, factor VII, fibrinogen, D-dimers, interleukins IL-6, IL-8 and IL-2, TNFα, and interferon gamma (IFN-γ), and with reduced albumin plasma concentration were shown ,92,93. SThe above hypothesis has been supported by data obtained from the FRAILOMIC study conducted by Kochlik et al. . In thatThe effect of carotenoids on exercise-related parameters was analyzed by the authors of this publication, as the inclusion of appropriate physical activity in patients with cancer cachexia and cancer-related fatigue may also be of benefit. We found the results of the study carried out by Liu et al.  particulThe authors of this article did not find in the literature data from human studies that would confirm the efficacy of astaxanthin in cancer cachexia. Despite the promising results of animal studies, no conclusions can be drawn about the effectiveness of such treatment in the population of palliative care patients. We know a little more about the possible influence of astaxanthin on the improvement of physical exertion, however, these studies were not conducted in a study group with cancer-related fatigue, so these data are also too weak to unequivocally draw a conclusion on this subject. Further research in humans should be conducted in this area.There is a great interest in natural compounds used in the treatment of many symptoms and diseases nowadays. Palliative care patients with burdensome symptoms related to advanced-stage cancers, disqualified from anti-cancer treatment, are especially interested in the use of dietary supplements and herbal remedies to improve prognosis, to reduce symptom intensity, and to ameliorate quality of life. Carotenoids seem to be a group of natural chemical compounds with particularly promising properties, mainly due to their strong antioxidant, anti-inflammatory, and neuroprotective properties . They arOne of the particularly bothersome symptoms observed in palliative care patients with advanced cancers is neuropathic pain. Due to the unsatisfactory effectiveness of treatment of neuropathic pain with analgesics and adjuvant drugs whose antinociceptive properties have been proved in clinical trials so far, the search for new substances with analgesic properties is still at the center of interest of both researchers and practicing physicians. Despite the promising results of studies on the analgesic properties of carotenoids that have been conducted so far in vitro and in vivo on animal models, it is impossible to unequivocally confirm the usefulness of carotenoids in the treatment of neuropathic pain in cancer patients. As was shown above, crocetin/crocin, xanthophylls , as well as bixin and lycopene have been demonstrated to attenuate neuropathic pain in animal models. However, the authors identified only one RCT  that posFurther clinical trials should be conducted, first of all on the effectiveness of carotenoids as co-analgesics that reduce pain intensity when taken simultaneously with opioids and reduce the need for opioids. It is well known that opioids such as morphine, are highly effective and recommended in the treatment of neuropathic pain. However, the tolerance and side effects observed with its chronic administration may limit its use in clinical practice ,99. SafaCancer cachexia, with coexisting cancer-related fatigue, is the second symptom with limited therapeutic options that causes enormous distress in palliative-care cancer patients and their caregivers. Considering the pathogenesis of neoplastic cachexia and the proinflammatory factors involved, in this case carotenoids also seem to be a beneficial treatment, due to their strong antioxidant and anti-inflammatory properties that have been proven in clinical trials conducted so far. And again, despite the promising data obtained from preclinical studies which have demonstrated the anti-inflammatory effect of selected carotenoids , the results of the clinical trials evaluating the effect of carotenoid consumption on the concentration of inflammatory markers presented in this review are inconsistent. Moreover, the abovementioned studies may not reflect the effect of carotenoids on systemic inflammation in cancer patients. Most clinical trials that investigate the anti-inflammatory properties of carotenoids involve young, healthy people or those with high cardiovascular risk or type 2 diabetes. In these study groups a beneficial effect of both astaxanthin, lycopene, and beta-cryptoxanthin on markers of inflammation was observed. It is worth mentioning that none of the analyzed studies assessed the impact of carotenoid supplementation on the markers of inflammation in cancer patients, with particular emphasis on patients with cancer cachexia. In patients with advanced neoplastic disease, generalized inflammation may be much more severe , and the beneficial anti-inflammatory effect of carotenoids may be weaker or nonexistent. On the other hand, there is no data on the absorption and bioavailability of carotenoids in patients with cancer cachexia. Without high-quality data from clinical trials in palliative care patients, no meaningful conclusions can be drawn. Keeping in mind the fact that prevention of micronutrient deficiency may counteract progressive deterioration in functioning, the inclusion of fruits and vegetables in the patient’s daily diet, in an acceptable form, may be a part of a potential multilevel intervention to prevent and better manage a patient’s disability connected to anorexia-cachexia-asthenia syndrome . DetailsThere are not any recommendations for daily supplementation of carotenoids available for cancer patients. Because of the wide variety in bioavailability among various carotenoids and individual host factors depending on age, sex, diseases, and genetics, such dietary intake recommendations are difficult to establish . TherefoTo sum up, despite the promising data obtained from studies conducted on animal models of neuropathic pain, the number of good-quality clinical trials confirming the analgesic properties of carotenoids in cancer-related neuropathic pain is lacking. Thus, it is impossible to establish the usefulness of carotenoids as the adjuvant therapy for neuropathic and other types of pain in palliative-care cancer patients. Similarly, despite the promising data obtained from in vitro and preclinical studies confirming the anti-inflammatory effect of selected carotenoids, the results of clinical trials evaluating the effect of carotenoid consumption on inflammatory markers are inconsistent. So far, no clinical trials have evaluated the effect of carotenoid consumption on inflammatory markers in cancer patients. Moreover, there is a lack of good-quality clinical trials confirming the effectiveness of dietary carotenoids in alleviating or slowing down cancer cachexia and related symptoms such as anorexia and asthenia. Therefore, it is impossible to establish the usefulness of carotenoids as the adjuvant therapy for cancer-related cachexia in palliative care. However, the inclusion of carotenoid-rich fruits and vegetables in the daily diet in a form acceptable to the patient may be a part of a multilevel nutritional intervention to prevent and better manage disability connected with anorexia-cachexia-asthenia syndrome.