Esketamine is dextrorotatory ketamine, which is an enantiomer of ketamine. Compared with ketamine, it has the advantages of a fast metabolism, fewer side effects, and strong pharmacological effects, so it is more suitable for clinical use. Esketamine has a powerful analgesic effect and has little effect on breathing. It has a wide range of applications in the fields of pediatric anesthesia, conscious sedation anesthesia, and emergency analgesia. In addition, it is also used for pain that is difficult to relieve with conventional drugs and to prevent postoperative pain. Various routes of administration are also suitable for patients who need short‐term analgesia and sedation. As a drug, esketamine inevitably brings some side effects when it is used clinically. In this article, by introducing the mechanism of action and pharmacological characteristics of esketamine, its clinical application is reviewed, and it provides a reference for the more reasonable and safe clinical application of esketamine. This article describes esketamine from four aspects, namely the mechanism, common clinical applications, common side effects, and prospects for esketamine. It describes the advantages of esketamine at the current stage, its unique role in some special fields, and compares it with ketamine. Therefore, its analgesic and anesthetic effects are about two to three times that of ketamine.R‐Ketamine and S‐Ketamine are optical enantiomers of the ketamine. Esketamine, which was recently approved for the treatment of depression, is essentially S‐ketamine. Esketamine is approved by the U.S. Food and Drug Administration for the treatment of depression in which two or more antidepressants are ineffective. The nasal administration of esketamine spray can significantly improve the symptoms of depression patients who are at risk of suicide. Depressive symptoms have a long‐lasting effect and delay recurrence, so it has attracted the attention of researchers.22+ binds to NMDA receptors to prevent Ca2+ from entering cells. When glutamate and glycine bind to NMDA receptors at the same time, NMDA receptors are activated and releases Mg2+, and a large amount of Ca2+ enters neuronal cells, activates secondary messengers, and produces NO, prostaglandins, and other substances. Excessive production of NO can directly inhibit GABA receptor activity, which reduces presynaptic inhibition. NO can also promote the release of presynaptic glutamate and other ways to participate in the regulation of nociceptionS‐ketamine inhibits NMDA receptors and exerts anesthesia, amnesia, analgesia, anti‐hyperalgesia, antidepression and other effects. When neuronal cells are in a resting state, MgBlocking the spinal cord reticular pathway at the level of the spinal cord: The sensory input generated by nociceptors activates the secondary neurons in the spinal cord, and the secondary neurons project to the somatosensory cortex through the intermediate relay area , which ultimately triggers pain perception. Ketamine blocks the incoming pain signals from the spinal cord reticular pathway and exerts analgesic effects.Blocking the hyperpolarization‐activated cyclic nucleotide‐gated channel‐1 (HCN‐1) produce a hypnotic effect .2+ channel can relax smooth muscleInhibition of cation channels: Blocking voltage‐gated sodium channels exertlocal anesthesia; restrainng potassium channels in spinal dorsal horn neurons can reduces neuronal excitability2+‐activated potassium channels (BK channels) can treat neuropathic pain: The excessive activation of spinal cord microglia after peripheral nerve injury is involved in the development of neuropathic pain. S‐ketamine inhibits the excessive activation of microglia by blocking BK channels to relieve neuropathic pain.Inhibiting the large‐conductance CaS‐Ketamine also acts on opioid receptors, and its affinity for opioid receptors is about twice that of ketamine, but opioid receptor antagonists cannot reverse the analgesic effect of ketamine, indicating that opioid receptors may not participate in ketamine's analgesic effectCurrent research suggests that ketamine acts on multiple receptors and channels causing different effects. The mechanism of action of S‐ketamine is similar to that of ketamine. There are several hypotheses regarding the mechanism of action of S‐ketamine:However, different channels are not isolated, but are part of a complete nervous system, with countless interactions at all levels. This is obvious in terms of antidepressant: molecular design based solely on NMDA receptor inhibition is not success that because pure NMDA receptor antagonists cannot show rapid and sustained antidepressant effect.33.1After esketamine was approved by the U.S. Food and Drug Administration for the treatment of refractory depression, there have been many clinical studies on its efficacy. Subcutaneous injection (0.5–1 mg/kg) of esketamine, once a week for six weeks, can improve anhedonia symptoms in patients with unipolar and bipolar depression.3.2n = 37 in the morphine group, n = 20 in the esketamine group). The results show that esketamine can improve the success rate of reduction, and shows a trend of reducing recurrence, shortening the time of operation and hospital stay. A small number of patients experienced vomiting events, which did not cause serious adverse events and was not statistically significant. Ketamine has many advantages in clinical pediatrics. It retains upper respiratory tract muscle tone and protective airway reflex. The common adverse reactions for ketamine in adults are less common and milder in children and adolescents.3.3At present, esketamine has been used in adult anesthesia. After sevoflurane is used to induce anesthesia, a laryngeal mask is inserted, and esketamine 0.5 mg/kg (or 1 mg/kg) is injected intravenously. After that, the dose of 0.5 mg/kg/h (or 1 mg/kg/h) was given by continuous intravenous infusion. Studies have confirmed that esketamine reduces the minimum alveolar concentration of sevoflurane in a dose‐dependent manner, indicating that esketamine has a coordinated effect with volatile anesthetics. However, patients taking esketamine 1 mg/kg have postoperative nausea.3.4Patients who use opioids to control pain may be more sensitive to pain. Unlike drug resistance and addiction, it is another side effect of opioid therapy, called hyperalgesia caused by opioids.3.5In some specific operations, compared with general anesthesia, conscious sedation anesthesia can avoid tracheal intubation, reduce the physiological interference to the patient, and be more conducive to some specific surgical operations and patient recovery. High‐intensity focused ultrasound ablation (HIFU) is a therapeutic modality that induces thermal necrosis of biological tissues by focusing high‐energy ultrasound waves at one specific target.3.6Endoscopy has been widely used in the diagnosis and treatment of gastrointestinal diseases. Due to limited medical resources, anesthesiologists must consider the safety and comfort of the patient as well as the recovery time. Therefore, the use of analgesic and sedative drugs must be reasonable and precise. Recent studies have confirmed that a single dose of esketamine/ketamine combined with propofol for painless gastroscopy is generally safe and tolerable. The patients were randomized to receive esketamine 0.5 mg/kg or ketamine 1 mg/kg while the propofol administration method and relative dose are the same for all patients. Both methods can provide satisfactory analgesia. The esketamine group had a shorter recovery time, and the incidence of adverse events, such as dizziness, restlessness, nausea, vomiting, headache, fatigue, and so forth, was also lower than that of the ketamine group.3.7Studies have confirmed that the use of esketamine in emergency situations is reliable and effective. In pre‐hospital emergency operations, patients often need analgesia, and sometimes it is difficult to open vascular access, and the way of administration is limited. Instillation of esketamine into the nasal cavity  can effectively control pain, and the administration is convenient and fast. Under the condition of providing satisfactory analgesia, only a few patients have dizziness, and other adverse reactions are relatively rare.3.8There are often different degrees of pain after surgery. Severe postoperative pain will affect the patient's recovery. It is related to the treatment result and brings more pain to the patient. Therefore, controlling postoperative pain is also a key part of the treatment process and cannot be ignored. Intraoperative opioid analgesia is the core part of general anesthesia. Intravenous or oral opioids are also one of the most common postoperative analgesia, clinically.3.9According to the definition of the International Association for the Study of Pain, neuropathic pain can be caused by a variety of causes that affect the peripheral or central nervous system. Various pathologies or diseases involving the somatosensory nervous system will not only increase pain sensitivity but also cause spontaneous pain.42+ channel, inhibiting Ca2+ influx and urinary dysfunction caused by smooth muscle contraction.S‐ketamine can increase cerebral blood flow, causing increased intracranial pressure.5Ketamine has been used clinically for many years. Due to its many side effects, it has been gradually replaced by other drugs. Recently, it was discovered that esketamine may have an antidepressant effect, and it has reappeared in the public eye. A large number of clinical studies are currently underway for its antidepressant effect, which hopefully will bring a new and effective treatment method for patients with depression. Esketamine has a stronger analgesic effect than ketamine, and has pharmacological effects such as anesthesia and sedation. Compared with opioid analgesics, esketamine has less effect on breathing that is an advantage in anesthesia where spontaneous breathing needs to be preserved. In terms of complex pain treatment and prevention of postoperative pain, the current clinical research results are quite different, and a large number of clinical studies are needed to confirm. The author believes that the focus of future research is still on the mechanism of action of esketamine and its effects in areas such as depression and complex pain. At present, there are also some urgent problems in these areas. To clarify the mechanism of action of esketamine can make more rational use of the drug, maximize its value, and better serve patients.The authors declare that there are no conflicts of interest.The ethics statement is not available.Xiao‐Xi Zhang conceived and wrote the article under the guidance of Yi‐Nan Zhang, while Zhao‐Qiong Zhu, Nai‐Xin Zhang, De‐Xing Liu, and Jun‐Ding guided and assisted in the writing of the article and completed the final draft with the efforts of all authors. Zhao‐Qiong Zhu and Yi‐Nan Zhang is the corresponding author.All the authors affirm that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.


The choice of a specific technique for surgical treatment of neuromas remains a problem. The purpose of this study is to determine the overall effectiveness of surgery as well as to find out whether certain surgical procedures are more effective than others. Twenty-nine patients operated between 1998 and 2018 and followed for at least 12 months were reviewed. Clinical assessment included the identification of a pre- and postoperative Tinel sign, pain visual analog score, two-point discrimination (2PD), and grip strength. Mechanisms of injury included clean lacerations (11), crush injuries (11), and other trauma or surgery (7). Mean time from presentation to surgery was 9 months. Seven surgical procedures involving excision in 10 patients and excision and nerve repair in 19 patients were performed. Pain score improved from an average of 7.1 ± 2.3 to 1.8 ± 1.7 with 27 patients (93%) reporting mild or no postoperative pain. Nine patients complained of residual scar hypersensitivity and six patients had residual positive Tinel. No patient required an additional surgical procedure. 2PD improved from an average of 9.6 ± 4.0 to 6.8 ± 1.0. The improvement of pain score and 2PD was statistically significant. Nerve repair resulted in marginally better outcomes, in terms of 2PD and grip strength recovery, than excision alone. The mechanism of injury, zone of involvement, time to intervention, or length of follow-up did not have an impact on the outcomes. Although patient numbers in this study are large in comparison to previous studies, larger patient numbers will allow for a multivariate analysis, which can be possible with a prospective multicenter trial. Neuromas are globular swellings that form as a result of abnormal and disorganized regeneration of unmyelinated nerve endings.Over 150 treatment methods have been reported to control pain caused by neuroma formation; however, comparative outcome studies are scarce.This retrospective review was initiated after obtaining approval from the institutional review board. Patients at our institute diagnosed with a peripheral neuroma between 1998 and 2018 were identified from their medical records and were reviewed. Inclusion criteria included patients who were operated upon for their painful neuroma in the hand or forearm. Exclusion criteria included patients with neuromas occurring at or proximal to the elbow, those who were managed with nonsurgical methods, and those followed for less than 1 year.Patient demographics, injury mechanism, hand dominance, associated symptoms, and repair type data were collected. Neuromas were classified according to where they occurred within the hand and forearm, as has been previously described in the literature.t-test . Ap-value ≤ 0.05 was considered significant.Clinical assessment included the identification of a pre- and postoperative Tinel sign, pain visual analog score (VAS), two-point discrimination (2PD), and grip strength, which were obtained from the medical records. The power grip may be affected in neuroma patients secondary to painful inhibition caused by mechanical irritation during grasp. The power grip was evaluated pre- and postoperatively on the same involved side to avoid the variability caused by hand dominance. The power grip was measured using Jamar dynamometer and the results recorded in pounds. Comparison between the pre- and postoperative variables was performed using the two-tailed Student'sForty-six patients who met the inclusion criteria were identified. Sixteen patients were lost to follow-up, leaving 29 patients who were treated for 29 individual neuromas. The study population consisted of 11 females (38%) and 18 males (62%) with a mean age of 36 years . Mean follow-up period was 19.07 ± 8.9 months . Mechanisms of injury included clean lacerations (11), crush injuries with finger amputation (11), tumor excision (3), and other trauma or surgery (4). Sixteen neuromas (55%) occurred in the right upper limb. Mean time from initial presentation to the patient's first surgery was 9 months . Preoperative pain evaluations revealed an average rating of severe pain (VAS = 7.4); 3 patients (10%) reported mild pain (VAS = 1–3), 4 patients (14%) reported moderate pain (VAS = 4–6), 20 patients (69%) reported severe pain (VAS = 7–9), and 2 patients (7%) reported intolerable pain (VAS = 10).All the cases included in this study were symptomatic sensory neuromas. All neuromas, except for one, were end neuromas. Sixteen neuromas occurred in zone I, nine in zone II, and four in zone III. All 16 neuromas in zone I involved the digital nerves. Operative procedures were performed by one surgeon, the senior author (T. M. T.). The surgical policy was dependent on the presence or absence of a distal nerve stump. If a distal nerve stump was present, either primary neurorrhaphy or reconstruction using autogenous nerve grafts, vein conduits, and allografts was performed depending on the defect size. If the distal stump is not retrievable, simple excision, excision and coverage with rotational flap, or excision and transposition of the remaining nerve stump into muscle or bone was performed depending on location of the neuroma and scar condition. Surgical procedures included excision of the neuromas in 10 patients and excision and nerve repair in 19 patients. Of the 10 excised neuromas, simple excision only was performed in 2 patients, excision and coverage with rotational flap in 1 patient, and excision and transposition of the remaining nerve stump into muscle or bone in 6 patients. Of the 19 nerves repaired, 3 underwent primary neurorrhaphy and 4 were reconstructed with autogenous nerve grafts, 9 with vein conduits, and 3 with Axogen graft weave .p≤ 0.05). Nine patients complained of residual scar hypersensitivity and six patients had residual positive Tinel. 2PD improved from an average of 9.6 ± 4.0 to 6.8 ± 1.0. The improvement in the 2PD was statistically significant (p < 0.05). The 2PD significantly improved only in the excision and reconstruction group from an average of 10.9 to 6.6 mm. The 2PD in the excision-only group did not improve as the difference between the preoperative and postoperative values (1 mm) is negligible and can be attributed to measurement variability  reported mild or no pain, and 2 patients (7%) reported moderate pain. The improvement in postoperative pain score was statistically significant (ability . The tyability . Both tability and3.% reporteAnalysis of our results revealed two findings. The first is that surgical management of painful neuromas led to clinically meaningful improvement of pain, with 93% of patients reporting no or mild postoperative pain regardless of surgical technique employed. This is supported by a recent comparative meta-analysis, which concluded that 77% of patients with neuroma had meaningful improvement of pain regardless of the surgical method used.The timing of presentation of symptomatic neuroma can vary. It has been proposed that painful symptoms tend to develop within 12 weeks of nerve injury or neuroma treatment.In a study designed to characterize morphologic stages during neuroma development following amputation, Oliveira et al speculated that neuroma treatment and/or prevention strategies might be more successful if targeted at the initial stages of development and not after 28 days following amputation.The location of the neuroma has been suggested as a factor affecting the selection of the treatment method,Previous studies have determined the magnitude of the injury bears no relationship to the development of pain.The principal drawbacks of this study were the retrospective nature and lack of long-term follow-up information. Although patient numbers in this study are large in comparison to those of other studies, larger patient numbers will allow for a multivariate analysis. This will be possible with a prospective multicenter trial.In conclusion, surgical treatment of hand and forearm neuromas results in significant pain relief and sensory recovery. Nerve repair produces marginally better outcomes compared with neuroma excision only. The mechanism of injury, zone of involvement, time from clinical presentation to surgical intervention, or length of follow-up did not have any impact on functional or sensory outcomes. Further prospective studies are warranted.


We hypothesized that the combined use of ELF and a soft elastic knee brace may provide better results. Thirty-five patients  were analyzed. The rehabilitative protocol consisted of 10 sessions of antiphlogistic and antiedema programs (first cycle) for 2 weeks, followed by twelve sessions of bone repair and connective tissue repair programs (second cycle) in patients with knee osteoarthritis (KOA) for 4 weeks. Patient evaluations were conducted at baseline (T0) and after 2 (T1) and 4 (T2) weeks of treatment. A follow-up evaluation was conducted 6 weeks after treatment (T3). The LIMFA© Therapy System was used to create multifrequency magnetoelectric fields with an intensity of 100 µT and a low-frequency field. The Incrediwear Cred 40 knee sleeve (Incred) was used for alleviating knee pain. The Visual Analogue Scale (VAS), the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Lysholm score (Ls) were used as outcome measures. The results showed that pain at rest (Vr), pain in motion (Vm), KOOS, and Ls were significantly affected by ELF over time. In conclusion, Group 2 had a better response in terms of pain resolution at rest ( Osteoarthritis (OA) is a chronic degenerative joint disease that occurs most commonly in people over 45 years of age. It is characterized by articular cartilage loss, synovial inflammation, and the remodeling of subchondral bone. OA has been shown to be associated with joint pain, stiffness, loss of function, reduced quality of life (QOL), and mortality. The treatment of OA traditionally comprises nonpharmacological and pharmacological management; however, if symptoms persist, surgery may be considered. Current treatments are limited by small effect sizes and adverse side effects. In recent years, there has been much emphasis on nonpharmacological management such as education, physiotherapy, and exercise therapy to relieve symptoms and improve function in those with OA .Magnetotherapy provides a non-invasive, safe, and easy method to directly treat the site of injury, the source of pain and inflammation, and it is widely used in rehabilitation in OA ,3. BriefThere are different rehabilitative electromagnetic field programs used in KOA based on short protocols, such as the program by Nelson et al., which consists of 2 weeks of treatment  with 6.8 MHz and an intensity of 30 Gauss . Ay et aThe difficulty often encountered in rehabilitation is the choice of a unique and shared physical therapy magnetic fields protocol in the treatment of symptomatic KOA. Therefore, the choice is entrusted to the physiatrist and physical therapists based on the characteristics and needs of the patient. Surely, short protocols allow better compliance by the patient  and an eTo reduce pain, improve physical function, and, possibly, slow disease progression in KOA, the use of knee braces has often been suggested . These aConsidering these premises and the evidence of the literature, we hypothesized that the combined use of magnetic fields and a soft elastic knee brace may have a better response in the resolution of pain in KOA patients compared to magnetic fields alone.The aim of the study was to evaluate the effect of the combined treatment of ELF and the soft elastic knee brace compared to ELF alone, with pain reduction as the primary outcome and functional recovery as the secondary outcome.An observational case–control study was conducted per the Strobe Guidelines  to deterPatients with acute pain in KOA were screened at the physical medicine and rehabilitation outpatient clinic of Don Orione Institute of Pescara  from December 2020 to February 2022 by a physician skilled in physical and rehabilitation medicine. The study was brought to the attention of the Department of Oral Medical Sciences and Biotechnologies of the G. D’Annunzio University of Chieti  and was approved by the National Ethics Committee of the Don Orione Board. Informed consent was obtained from all individual patients included in the study. The patients were treated in accordance with the World Medical Association Declaration of Helsinki.All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.The inclusion criteria were age between 40 and 70 years, diagnosis of acute pain in KOS < than 1 month, VAS > 3 according to the American College of Rheumatology Criteria , and staFinally, patients were included consecutively and formed two groups that are indicated as LIMFA therapy without (Group 1) or with (Group 2) Incred.The Visual Analogue Scale (VAS) was used to measure knee pain outcomes: patients were asked to mark the point that corresponded to their perceived pain intensity on a 10 cm line, with 0 indicating the absence of pain and 10 reflecting the most severe pain . The patThe Knee Injury and Osteoarthritis Outcome Score (KOOS) is a questionnaire designed to assess short-term and long-term patient-relevant outcomes following a knee injury or OA ,27. The Lysholm score (Ls), which measures the ability to manage in everyday life ,29, was The LIMFA © Therapy System   was used to create multifrequency magnetoelectric fields with an intensity of 100 µT and a low-frequency field. The Limfa’s patented ELF pre-set sequences are complex magnetic fields, pulsed and bipolar, that target specific ion channels in order to obtain the desired biological reaction. Depending on the ion channel, the frequencies vary from 2 to 80 Hz with a variable field intensity (lower than 100 µT) and variable waveform. The abovementioned parameters are not random but are pre-defined for each stimulation program.Patients participated in ten (n = 10) sessions of antiphlogistic and antiedema programs (first cycle) (15 min each) for 2 weeks, 5 days/week, followed by, without interruption, twelve (n = 12) sessions (20 min each) of bone repair and connective tissue repair programs (second cycle) for 4 weeks, 3 days/week .The Incrediwear Cred 40 knee sleeve (Incred)  is embedThe questionnaires were given to patients when they first received the knee sleeve, before starting magnetic field therapy (T0 = at baseline). They were also given to patients at the end of the first cycle of magnetotherapy (T1 = after 2 weeks), at the end of the second cycle of magnetotherapy (T2 = after 4 weeks), and 6 weeks after the end of all treatment (T3 = follow-up). Each patient was observed and received the treatment for a total of three months. The sample size was calculated, considering pain intensity per the VAS as the primary outcome. A power analysis of 90% and an alpha level = 0.05 was considered with a difference of 2 points (cm), assuming a standard deviation of ±1.5 for the VAS in relation to the minimal clinically important difference between the groups after treatment. Thus, the analysis would yield a minimum of 16 patients per group, and, based on a 20% potential dropout rate, we included 22 patients per group .Data were checked for normality and homogeneity of variance, which were analyzed with parametric and non-parametric data, respectively. The outcome scales for Vm, Vr, KOOS, KOOS-functional, and Ls differences during treatment, both for those who used and did not use Incred, were analyzed by two-way ANOVA for repeated measures  followed by the Bonferroni post hoc test.p < 0.05.Statistical analyses were performed using SPSS 22.0 statistic  for Windows (IBM). Results are described as means ± SD for each assessment. The level of a statistically significant difference was defined as Out of the thirty-five patients  ), sixtee7, 245 = 35.41, p < 0.001), Vm , KOOS , and Ls  were significantly affected by the ELFs over time  showed that Vr , with a significantly better functional recovery at T2 (the end of the second rehabilitative cycle) for KOOS, as reported in p for VAS at rest = 0.011).Considering the aim of the study, the results appeared interesting. Above all, compared to the primary outcome of pain reduction, Group 2, who carried out the two treatments in combination, showed a more rapid reduction in knee pain and a better response at rest, which were well maintained at follow-up  pulsed sub-sensory threshold electrical stimulation produced is effective in improving physical function but not pain intensity at treatment completion in adults with KOA . SimilarIn terms of the length of the treatment period, we have adopted a protocol similar to that used by Thamsborg and colleagues , reportiPhysiotherapy and, in particular, instrumental physical therapies in the treatment of KOA are often associated with the use of orthoses to contain pain more quickly and promote better function recovery, but the scientific evidence regarding the use of soft discharge braces attributable to Incred or similar devices is still limited.Lee et al.  showed tp = 0.011), and that they probably had a concurrent better response at T3 in functional recovery (for KOOS) compared to Group 1. Considering that the study was conducted using a non-randomized design, these results need further investigation. As reported in the literature [The data from our study would suggest that, in Group 2, patients had a better response in pain resolution, especially at rest  combined with the germanium-embedded knee sleeve in the rehabilitation treatment of patients suffering from KOA.The dropout of patients remained below 20%, and these interruptions to treatment were mainly for personal and organizational or work reasons. Patients reported no side effects during the sessions or complications, as proof of the safety of the proposed rehabilitative treatment.Furthermore, comparative studies that consider different rehabilitation protocols with randomized controlled trial (RCT) models would be desirable to contain the selection bias related to the lack of randomization of the sample. A study that considers the inclusion of a third group treated only with the soft knee brace would be particularly desirable. In addition, despite being an observational study, to contain the interview bias, the operator who administered the scales was kept unaware of the patient group, and to ensure adherence to the rehabilitation treatment, two expert physiotherapists were selected who followed the patients from the beginning to the end of the treatment.Our results showed that the association of Incred (from 6 h to 8 h a day) with ELF-EMF therapy seems to enhance its positive effect on KOA in short-term pain reduction at rest, with a short follow-up and good maintenance favoring a more rapid recovery of function after six weeks of treatment. Furthermore, in future RCT research developments the combined use of ELF-EMF and other models of soft elastic knee braces should be conducted.


The other types of TMDs were not associated with DFDs. Comorbidities, habits, and psychosocial variables were not associated with DFDs at a level of 0.05. (p > 0.05). In analyzing the participants with arthralgia, the ones with this condition presented higher frequencies of sleep bruxism (p = 0.046). Conclusions: Participants with DFDs presented a significantly higher frequency of arthralgia when compared to no DFDs ones. Sleep bruxism was associated with the occurrence of joint TMDs in these participants.Individuals seeking orthodontic treatment combined with orthognathic surgery (OS) have a high prevalence of temporomandibular disorders (TMDs), but the relationship between TMD diagnoses and dentofacial deformities (DFDs) is still controversial. Therefore, this cross-sectional study with a comparison group aimed to analyze the association between dentofacial deformities and TMDs. Methodology: Eighty patients undergoing OS were consecutively selected from the stomatology department of the Federal University of Paraná between July 2021 and July 2022. Forty patients who would undergo OS composed the group of participants with DFD, and forty who received other types of attention and did not present changes in the dental bone bases formed the group without DFDs (DFDs and no DFDs groups). The groups were matched for sex, age, and self-reported ethnicity. The diagnostic criteria for TMDs (DC/TMDs) were used to diagnose TMD based on the Axis I criteria. The psychosocial aspects, oral behaviors in wakefulness, and sleep bruxism were evaluated through the Axis II criteria. The data were analyzed with a 5% significance level. Results: The presence of DFDs was significantly associated with arthralgia ( Dentofacial deformities (DFD) correspond to dental malocclusion that is associated with skeletal pattern alterations . Such deThe moderate and severe cases of DFDs require a combined treatment between orthodontics and orthognathic surgery (OS). Orthognathic surgery consists of repositioning the bone bases through osteotomies to align and correct the jaw’s position, thereby improving function and facial aesthetics. Pain management in orthognathic surgery is essential to enhance recovery, reduce hospital stay, and improve the whole experience of the patient . The posAmong the reasons for performing OS, aesthetic purposes are frequently reported, as are functional improvements, including complaints related to temporomandibular dysfunction ,6,7. AltTemporomandibular disorders (TMDs) encompass heterogeneous conditions involving the masticatory muscles, the temporomandibular joint (TMJ), or both, as well as their associated structures. Several studies have investigated TMDs in orthosurgical patients ,13; howeThis study aimed to compare orthosurgical patients with dentofacial deformity (DFD group) and individuals without dentofacial deformity (no DFD group) regarding TMD diagnoses. This is an observational cross-sectional study with a comparison group, which was developed in the Oral and Maxillofacial Surgery and Traumatology Service (OMSTS) facilities and the dental clinics of the Department of Stomatology at Federal University of Paraná (UFPR), Jardim Botânico campus, located in Curitiba in south of Brazil. The study went on for 36 months. Calibration within the examiners was performed using the kappa coefficient. To assess the inter-rater reliability, the Kappa coefficient was used (k:095/95% CI).The longitudinal study was approved by the Research Ethics Committee under protocol CAAE number: 52207821.9.0000.0102. In addition, the study followed all the recommendations of the Declaration of Helsinki  regardinThe study included a total of 80 participants. The Open Epi Software, updated version 6 April 2013, calculated the sample size. The calculation was based on a previous study in which a prevalence of 31% was found in the general adult population . For theThe sample selection was performed as follows: for the group with DFDs, all individuals who would undergo OS by the OMSTS Service of UFPR and who met the inclusion criteria were invited to participate. The participants were recruited when they went through the clinical examination stage before OS. The inclusion criteria for the group with DFDs were the following: have dentofacial deformities not associated with cleft lip and palate or syndromes, requiring treatment through OS, over 18 years of age, accepted to participate in the research, and having signed the ICF. For each individual selected to the DFDs group, we looked for an individual matching the sex, age, and self-reported race in another dentistry clinic at the UFPR to maintain a more homogeneous sample and to eliminate potential biases. These individuals were approached in the first evaluation in other dental clinics of the UFPR. The individuals who agreed to participate and who met the inclusion and exclusion criteria were selected. The inclusion criteria for the group without DFDs comprised patients over 18 years of age, who were undergoing maintenance dental treatment, such as cleaning, bleaching, replacement of restorations, who signed the ICF, and who did not present dentofacial deformities. An experienced professional conducted a dentofacial deformity analysis.The exclusion criteria for both groups were the presence of previous surgeries in the cervicofacial region, cognitive and neurological alterations, the diagnosis of arthritis and arthrosis in other joints, tooth pain, oral pathologies, and patients who used cyclobenzaprine in the week of the evaluation.Demographic data were collected from all survey participants, such as sex, age, and self-reported race; they were divided into whites and nonwhites due to the n and low number of other races. In addition, the data were collected on drug use and the presence of comorbidities , and data were collected on patients’ habits such as smoking (smoker and nonsmoker) and the amount of coffee intake (less than 3 cups and more than 3 cups per day).For the analysis of DFD types, an experienced surgeon evaluated the participant’s profile and occlusion, as well as classified the face profiles into three categories: I, II, or III. Profile I is a straight profile, and profile II presents a negative step between the maxilla and mandible corresponding to patients with mandibular retrognathism. Profile III presents a positive step between the maxilla and mandible, thereby indicating anteroposterior maxillary deficiency, mandibular prognathism, or both . They weAll participants were diagnosed with TMDs through the DC/TMDs. The tool was used by trained and calibrated examiners. This tool consists of two axes: Axis I, which includes the information collected on the physical examination, and Axis II, which features emotional aspects. Both axes were used in this research .Axis I consists of three questionnaires: TMD pain screening, DC/TMD symptom questionnaire, and TMD physical examination. To diagnose TMDs in patients, the DC/TMD procedures involved gathering the patient’s medical history, performing a physical exam that included muscle palpation (applying 1.0 kg pressure) and joint palpation (applying 0.5 kg pressure), assessing the presence of symptoms during mandibular function, and measuring the maximum opening of the jaw both with and without pain. Based on the collected findings, the tool identified two main categories of physical diagnoses (muscular and joint). It generated a decision flowchart and a table of diagnostic criteria to assist in the diagnostic process; painful TMD conditions in the muscles were classified as myalgia, local myalgia, myofascial pain, myofascial pain with spreading, and myofascial pain with referred pain; Axis I also classified headaches attributed to TMDs as present or absent . RegardiAxis II incorporates behavioral instruments regarding pain, the psychological state, and psychosocial and behavioral functioning. For Axis II, the tools used were the Patient Health Questionnaire (PHQ-15), the Generalized Anxiety Disorder (GAD-7), the human body pain drawing to identify pain points in and beyond the face, and the Oral Behaviors Checklist (OBC), which was used to diagnose awake and sleep bruxism. The OBC is a self-evaluation tool with 21 questions in which the patient answers the weekly and monthly frequency of oral and parafunctional behaviors. According to the sum of the scores, the result is classified as no oral behaviors for scores up to four points, mild from four to twelve points, moderate from thirteen to nineteen points, and severe with more than twenty points. Based on the OBC data, combined with the clinical evaluation, the awake bruxism was classified as absent, infrequent, frequent, or very frequent according to the answers to the OBC questionnaire of the DC/TMDs. Sleep bruxism was classified as absent, possible, or probable. It was considered possible when it had a positive response in the OBC questionnaire and probable when, in addition to a positive response in the OBC, it presented at least one of the clinical signs: dental wear; marks on the soft tissue such as jugal mucus and tongue and/or muscle fatigue upon awakening; pain in the masseter and temporal muscle palpation; and/or masseter hypertrophy.  The PHQ-The individuals were diagnosed according to the present or absence of the types of TMDs. Similarly, structural TMJ disorders were grouped as absent or present, thereby considering the sides of the TMJ (right and left) individually. Our study considered the presence of arthralgia, regardless of the affected side. As for the Axis II, the participants were classified as 1—without anxiety and mild anxiety—or 2—moderate and severe anxiety (GAD-7). Regarding the PHQ-15, the participants were classified as 1—without symptoms and mild symptoms—or 2—moderate and severe symptoms.Regarding the OBC, parafunctional habits were dichotomized according to 1—absent and minor—or 2—present and very present. Wake bruxism was also dichotomized into 1—frequent and infrequent—or 2—frequent and very frequent.The results obtained were submitted to descriptive and inferential statistical analysis. The categorical variables of the DC/TMDs between the groups were compared using the chi-square test or the Fisher exact test. For the numerical variables, the normality condition was evaluated by the Kolmogorov–Smirnov test. The comparison of numerical variables with non-normal distribution between groups was performed using the Mann–Whitney test. The variables of awake bruxism and sleep bruxism were compared with smoking and coffee habits in the general sample using the chi-square test or the Fisher exact test.SPSS Statistics v. 24 .The level of significance adopted was 5%. The data were analyzed using the software p = 1.0), age (p = 0.823), and self-reported race (p = 1.0). The sample was primarily composed of women, with 52 of them (65%) and 28 men (35%) being equally distributed between groups. The median age was 30 (19–61). Regarding the ethnicity, 65 participants (81.25%) were white, and 15 were nonwhite (18.75%). The groups were matched for sex (p > 0.05).There was no association between the variables awake bruxism and sleep bruxism with the variables smoking and drinking more than three cups of coffee in the general sample .In analyzing the 18 participants who experienced joint pain  in the DFDs group, it was verified that 13 (72%) presented bilateral arthralgia, while 5 (28%) presented unilateral arthralgia. Also, 12 individuals (67%) presented disc displacement with reduction associated, with 4 of them presenting unilaterally, and in 8 (44.4%) of them it was present on both sides of the TMJ. In the group no DFDs, the four participants with arthralgia had no other joint disorders associated.In terms of diagnosing disc displacement, our analysis found that, despite presenting similar results between the groups, 12 of them had painful symptoms related to their disc displacement, while 10 did not experience pain. Degenerative diseases in the TMJ were identified in one patient from the group with DFDs and in two from the group without DFDs. No patient had a disc displacement without reduction.p = 1.0). The median mouth opening with pain was 48 mm (33–65 mm) in the DFDs group and 45 mm (30–78 mm) in the no DFDs group (p = 0.117).There was no difference in the maximum mouth opening between groups with and without DFDs. The median pain-free mouth opening value in the DFDs group was 43 mm (22–63 mm), and, in the group without DFDs, it was 45 mm (20–77 mm) (p > 0.05) in anxiety levels (GAD-7), in physical symptoms (PHQ-15), and in pain in and beyond the face (p = 0.262).Regarding the variables of Axis II of the DC/TMDs, there were no differences between the groups (the face . When cop > 0.05). Regarding sex, women had a higher prevalence of joint pain (p > 0.001). The variables of the subjects’ self-reported race, age, facial profile, and asymmetry variables were unrelated to arthralgia within the DFDs group (p = 0.046). The diagnosis of TMDs is complex, mainly due to their different diagnostic methods and their multifactorial etiologies. Regarding the occlusal factor, after years of debate about the role of occlusal characteristics as causal or risk factors for TMDs, a low relevance for dental occlusion and the interarcaded relationship is currently attributed . HoweverThis study focused on patients seeking OS, because it is necessarily understandable that temporomandibular dysfunctions are experienced in this population for the proper management and care of the patients before surgery. If patients undergo surgery with a previous pain, they will have more challenges in dealing with the postoperative period in functional and psychological terms. Also, long-lasting pain leads to changes in the central nervous system, thus causing central sensitization and increased postoperative pain sensitivity .A recent systematic review showed that patients undergoing orthodontic surgical treatment have a higher incidence of TMDs when compared to a control population . HoweverThe main finding in this study was that surgical patients with DFDs present a higher prevalence of arthralgia compared to a control population, thus corroborating another study . ArthralThe relationship between bruxism and the symptoms of temporomandibular disorders is deeply discussed in the literature, due to the complexity of the etiology and diagnosis of both conditions ,26. In tIn our study, we did not found any association between awake or sleep bruxism and smoking or drink coffee habits. However, is important observe that we had just seven smokers and three individuals that drank more than three cups of coffee in the general sample. So, it is possible that we did not find an association with these variables due to few individuals presenting these habits. According Bertazzo et al., more than eight small cups could be considered a risk factor for bruxism. Thus, we should not put away these habits as possible risk factors of bruxism .Although there was no difference in the incidence of muscle TMDs between the groups, this study’s findings revealed that both groups had a high prevalence of the condition (55–60%). This could be associated with the period of high stress and poor sleep quality in the population over the data collection period, which was during the pandemic (2020–2021), when there was a significant increase in these symptoms reported by the population. The result of a higher prevalence may be due to the increased incidence of muscle TMDs occurring in the pandemic period compared to previous years , thus reIt is also important to highlight that other studies analyzing specific subtypes of deformities found some different findings. For example, a systematic review suggested that class II skeletal profiles and hyper-divergent growth patterns were likely associated with an increased frequency of TMJ disc displacement and degenerative disorders. Another study that used cone beam tomography and the RDC/TMDs to diagnose TMDs found more prevalent bone changes in patients with the class II skeletal malocclusion . Also, aThis study also investigated psychosocial variables between groups and their relationships with arthralgia. Although we found no associations in this study, this could also be due to having a small and restricted sample. Temporomandibular disorders are complex conditions, and their interrelationships should be seen through pain models, thereby inserting the biopsychosocial perspective in the evaluations. Thus, these variables should continue to be investigated in other studies.Thus, we believe that the most important limitation of this study is the sample size (DFDs = 40 and no DFDs = 40), given that important associations could be found with a larger n. It was also impossible to segment the sample according to the type of deformity. Another constraint was that bruxism was identified without polysomnography, which made it impossible to deliver a definite diagnosis according to the international consensus on bruxism . Also, wTherefore, we suggest further prospective cohort studies with larger samples to better investigate our findings, thereby focusing on treatment options for these patients. We also recommend future studies to investigate additional factors that may contribute to TMDs in this population.Finally, it is important to point out that understanding the profiles of these patients and their functional problems before OS can positively influence the outcome of ortho-surgical treatment, which is still a wildly neglected factor by surgeons. The prior identification of patients with TMDs, parafunction, or both, should imply a treatment plan mainly incorporating cognitive–behavioral approaches to help patients understand their need to maintain relaxed the masticatory muscles.The prevalence of arthralgia was higher in orthosurgical patients with dentofacial deformity when compared to individuals without dentofacial deformity. Sleep bruxism was associated with the occurrence of joint TMDs in these patients. Detecting these conditions and carrying out adequate management before surgery can ensure a better prognosis. Thus, further studies should investigate the additional factors that may contribute to TMDs in this population and determine new protocols of preoperative management.


Opioids are the most frequently used pain medications by US burn centers to control severe procedural pain during wound care. Concerns for long-term opioid use have prompted the exploration of non-pharmaceutical interventions, such as virtual reality (VR), for procedural pain management. The primary objective of this pilot study was to evaluate the feasibility and efficacy of VR pain alleviation treatment in reducing adult burn patients’ perceived pain during burn dressing changes. Adult patients aged 18–70 years were recruited from the inpatient unit of a single American Burn Association–verified burn center between May 2019 and February 2020 and randomly assigned to one of three arms. Active VR participants played four VR games; passive VR participants were immersed in the same VR environment without the interaction elements; and a standard of care control group. 71 patients were screened for eligibility and 33 were deemed eligible to approach for informed consent, with 14 agreeing to participate in this study. Of these 14 patients, 4 were randomly assigned to the active VR, 4 to the passive VR, and 6 to the control group. Self-reported overall pain was lowest among participants in the active VR  and highest among participants in the passive VR  across all three dressing changes. Self-reported worst pain was lowest among the active VR at the first and last dressing , but the control group has the lowest self-reported worst pain at the second dressing (71.3). VR is a useful non-pharmacological tool for pain distraction but designing and implementing clinical research studies face many challenges in real-world medical settings. Lessons from this study have important implications for future VR studies by other researchers.Trial Registration: ClinicalTrials.gov Identifier: NCT04545229. In this paper we describe our experience conducting a randomized clinical trial using virtual reality as a pain distraction during inpatient burn care. This pilot study was designed to evaluate feasibility and efficacy of virtual reality as a pain distraction treatment. Three intervention groups were compared across multiple burn care procedures. We enrolled 14 patients across 10 months of recruitment. While our sample size was too small to consider significance testing, we did find that the group with active virtual reality participation reported less pain than those in the other two groups. We documented many challenges with using virtual reality during burn dressing changes, including the severity of injuries and the need for high-dose opioids, lack for interest in virtual reality, the unique nature of inpatient wound care, and methods of interacting with a game. COVID-19 also created recruitment restriction for our study. We proposed methods for circumventing these challenges for future researchers when designing virtual reality studies among adult patients. Burn injuries affect millions of individuals around the world . There wResearchers have shown that high dose opioid medications for acute pain management are more likely to increase the risk of long-term opioid use and opioid addictions, for both pediatric and adult populations ,6. BalanIncreasingly, non-pharmaceutical interventions have been explored for procedural pain management, with virtual reality (VR) being one of these promising interventions . NumerouThe primary objective of this pilot study was to investigate feasibility and efficacy of VR pain alleviation treatment (VR-PAT) on reducing adult burn patients’ perceived pain during burn dressing changes. We hypothesized that VR-PAT would decrease self-reported pain intensity among inpatient adult burn dressing changes. Findings and lessons from this study have important implications for this strategically chosen research pathway and for future VR studies by other researchers.This three-group pilot randomized clinical trial (RCT) was designed to test feasibility and efficacy of a smartphone VR-PAT in reducing self-reported and observed pain of adult burn injury patients during repeated inpatient dressing changes. Adult patients with burn injuries were recruited between May 2019 and February 2020 from an American Burn Association-verified Burn Center and randomly allocated to one of three treatment arms: active VR, passive VR, or a standard of care. Eligible subjects were 1) 18–70 years of age (inclusive), 2) their first admission for this acute burn injury, 3) require dressing changes, 4) using opioids for dressing changes, and 5) whose burn is ≤4 days from their burn injury. Patients were excluded if they had 1) severe burn(s) on the face/head preventing utilization of VR, 2) cognitive/motor impairment preventing valid administration of study measures, 3) unable to communicate in English, 4) prisoners and patients who were pregnant, and 5) patients admitted to the intensive care unit. The institutional review board of The Ohio State University reviewed and approved this study. Written informed consent was collected from each patient prior to participation in the study. The initial funding of this pilot study met the nonapplicable study definition of the Food and Drug Administration Amendments Act §801 for registration at ClinicalTrials.gov. However, a late voluntary registration was made .. Of these 14 patients, 4 were randomly assigned to active VR, 4 to passive VR, and 6 to the control group. Patient recruitment was stopped in March of 2020 because of the hospital restrictions in response to COVID-19 and the future uncertainty promoted the funding agency to withdraw the funding soon after.This pilot study intended to assess the feasibility of VR-PAT among hospitalized adult burn patients, so formal power and sample size calculations were not conducted. Instead, the intention was to generate preliminary data to estimate the effect size of VR and variances of the outcome measures that could be used to calculate the sample size and power of a future larger-scale randomized trial. Based on our previous VR study among pediatric patients and the availability of adult burn patients at the adult burn center, the planned enrollment was 60 patients equally randomized into three groups . A total of 71 patients were screened for eligibility and 33 were deemed eligible to approach for informed consent, with 14 agreeing to participate in this study  ,17 site.Using the electronic medical record, clinicians documented demographics , injury information , burn severity , burn location and any illicit drug use prior to injury.Participants self-reported their expectations for the dressing change (How much would you like something fun to do during the dressing change? and How much do you think having something to do during the dressing change would be helpful?) on a visual analog scale . Subjects assessed their state anxiety using the 20-question Spielberger State-Trait Anxiety Inventory (STAI) ,19, rateResearchers observed the dressing change and documented the total time of the dressing change and VR use, number of times the participant voluntarily interrupted the VR, whether the participant was fully engaged with the VR, and whether they appeared distracted.Participants self-rated overall pain, worst pain, time spent thinking about pain, and how much the wound bothered them on a VAS (higher score indicate more pain) and perceived length of dressing (in minutes). Those using the VR were also asked to report any symptoms using the Simulator Sickness Questionnaire  .Participants were asked if they were happy with the VR, whether it could be made better, and if they would want to use it again in the future. They were also asked to report how much fun they had and how engaging they thought it was on a VAS .For patients using the VR, the nurse performing the dressing change reported whether the VR-PAT was helpful and easy to use on a VAS .Clinicians documented the MMEs consumed by the participant on each day of participation.A clinician called participants 2–6 weeks following discharge as part of clinical care and asked whether they were still using opioid medications to control pain and calculated the 24-hour MMEs.S1 Fig). VR-PAT is a stand-alone game that was developed by Nationwide Children’s Hospital, an affiliated hospital of The Ohio State University. Each subject had their own VR headset that was used by only them for the entirety of the study and was theirs to keep at the end of their study participation. The headset was wiped down between uses with a hospital-grade alcohol wipe as per infection control policies.VR-PAT was administered using a lightweight, low-cost VR headset paired with an Apple iPhone XS and Bluetooth gaming controller . The games played in the order of City, Cave, Forest, and Town for all participants. Participants interacted with the game by tilting their head and pressing a button on the gaming controller.Active VR participants played a series of four VR games specifically designed for this study. These games were broken down into two categories: projectile games (Town and Cave) and rhythm games (City and Forest)  provided in the clinical setting.Demographic and burn characteristics were described using frequencies and percentages for the categorical variables and median and range for continuous variables. Mean was calculated for the primary outcome of reported pain  across dressing changes and intervention type. VR usage was evaluated by the median length of the dressing time (in minutes) and time using the VR (in minutes). Opioid medication was converted to MME for each medication per 24-hours of admission and added together to get a total amount of opioids.Table 1). Burn injuries varied from 1.0 to 17.8% TBSA (median 8.4%) and the largest proportion of the burns were partial thickness (median TBSA = 8.4%). The largest full thickness burn was 3.0% TBSA.Of the 14 participants in this study, they were a median 38.4 years of age, mostly male (71.4%), and White (85.7%) , but the control group had the lowest self-reported worst pain at the second dressing (71.3). Again, the passive group reported the highest worst pain across the first two dressings  and tied for the highest worst pain with the control group at the last dressing (100.0).Average self-reported overall pain was lowest among participant in the active VR group  and highest among participants in the passive VR group  across all three dressing changes (Table 2). Conversely, the control group used the least opioids for the first two dressings  and the passive group used the most opioids for the first two dressings . In comparison, the control group had the shortest dressing time for dressing 3 (median 49 minutes) compared to the active and control groups .Dressing 1 and 2 was longer for the control group  than the active and passive groups   or video (passive) and did not want to participate for the full dressing. Additionally, some patients began the dressing change with a shower to loosen the dressing, which we found not to be conducive with the VR-PAT process.First, adults were less interested in participating in VR research than pediatric patients. Some adult patients felt distraction was not necessary or that they did not want to bother with learning how to play the game. Several adults also did not want to be in the virtual VR environment because of motion sickness. Over 53% of the patients screened for eligibility were not eligible to participate, with most of these patients being over the age limit, having facial burns, presented too many days out from the initial injury, and being admitted to the intensive care unit. While some adults were not interested in participating in a VR intervention, there was not a difference among participants in acceptance of the VR. After each dressing, participants in the VR groups were asked, “Were you happy with the VR?” and “Would you want to use it again in the future?” Only 1 participant reported they were not satisfied with the VR and would not want to use it again (after their second dressing). Our data are not robust enough to determine the relationship between age and acceptance by group more fully because almost all of them said they were happy with the VR and would like to use it again. Previous studies found that it may be harder to recruit older patients into the VR trial, but once they agree to participate, the adherence to the VR interventions is about the same or higher in comparison with younger patients. –22. FutuThe second lesson was that the inpatient adult burn injuries were more severe than those encountered in our pediatric outpatient study. These inpatient dressings were also longer than those in our pediatric pilot study, resulting in some participants feeling that the games were repetitive and choosing not to wear the VR for the entirety of the dressing or requesting to not participate in the VR groups in the next dressing. Suggestions were for more levels or increased gamification to be entertaining for a longer period. Additionally, because of the increased burn severity, the dressing change was more painful, requiring more pre-procedural pain medications and rescue opioid medications. This increased pain broke through the distraction, leading us to hypothesize there is a pain threshold for where VR distraction can be beneficial. This is an important consideration for future VR studies. Future research needs to determine where this pain threshold is and whether a more difficult game can circumvent this issue. Our game was designed to be easy for participants of all ages and skill levels to avoid any feelings of frustration or discouragement. On the other hand, the feedback of increasing the difficulty or adding more levels is good advice for future research. Additionally, this pilot study only measured pain using self-reported pain scales, which can be very subjective. Future research should consider incorporating objective pain measures, including wearable devices that monitor heart rate and blood pressure, to evaluate pain in conjunction with self-reported measures.The third lesson was the unique circumstance that many inpatient dressing changes began with a shower to loosen the previous dressing. We did ask the first few participants to use the VR-PAT during this part of the procedure as the phone and headset were water resistant. However, participants began experiencing nausea and headaches during this part of the procedure, which medical professionals felt could have been exacerbated by the pain of removing the dressing and the heat/steam of the shower. Upon this realization, the study procedures were changed to only using the VR after the shower portion of the procedure, which did help to reduce these feelings. Additionally, a portion of the participants required additional rescue medications during the procedure, which had their own host of side effects that were similar to simulator sickness symptoms. It was difficult to parse out who was reporting simulator sickness symptoms due to the medication or the VR-PAT, as even participants not in the VR groups reported symptoms. There was less reliability in reporting of all questionnaires among those who required additional medication, with some questionnaires being left blank. This pilot study did not collect individual medications or the timing of these, so the 24-hour MME variable cannot be broken down into pre-medication, rescue medications, or medications for background pain. Timing of medication use and type of medication are important confounding variables for analyses among this patient population. Future studies should collect medications at a more granular level, including those for anxiety to further understand the effectiveness of a VR intervention for procedural pain.The fourth challenge was the difficulty of using a controller for the game play. As the game play only required the pressing of one button and no movement , we did not expect it to disturb the dressing change. However, due to the location of some injuries, participants needed to roll to one side or switch hands when both were burned, and this caused game interruptions. Future studies should consider a hands-free VR system to minimize hand involvement and interference with the dressing procedure.The final challenge was the COVID-19 pandemic. Study recruitment was paused in March 2020 in compliance with hospital policies. Our funding period ended before recruitment could recommence, thus further limiting our study participants.VR is a useful non-pharmacological tool for pain distraction but designing and implementing clinical research studies can face many challenges in the real-world medical settings. Future studies should consider these challenges when working with adult burn patients and work closely with clinic staff and patients to pilot test study protocols before launching a full-scale VR intervention study.S1 CONSORT Checklist(DOCX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.


The Lysholm scores of group A (62.94 ± 8.68) was higher than that of group B (46.68 ± 9.82) measured 4 weeks following surgery, but there was no difference at 8 weeks (P=.237), and both groups had similar time to return to normal activities (P=.363). For discoid lateral meniscus patients who underwent isolated saucerization, short-term splint immobilization did not significantly help relieve postoperative pain. There was a comparable time-course for return to normal activities in both study groups.There are no universal guidelines for rehabilitation after saucerization for children with discoid lateral meniscus. This study determined if short-term knee splint immobilization and delayed rehabilitation produces the same benefit as early rehabilitation after saucerization in children, in terms of knee function and pain intensity. A retrospective review was performed by categorizing patients into 2 groups depending on whether a splint immobilization was adopted postoperatively: for group A, rehabilitation began early without splint immobilization after surgery, and for group B, a knee splint was immobilized for 2 weeks. Numerical rating scale scores were collected in patients 1, 3, and 7 days, Lysholm scores were measured at 4 and 8 weeks postoperatively, and the gradual return to normal activities was documented. Forty-eight patients and 53 knees were included: group A had 30 patients with 31 knees, and group B had 18 patients with 22 knees. There was no improvement in numerical rating scale scores on the 1 For patients undergoing saucerization treatment of the lateral meniscus without splint immobilization, physical therapies starting 2 weeks after surgery is generally advised, but others recommend an early rehabilitation as soon as postoperative pain is tolerable. While much has been written about discoid menisci in adults, less is known about postoperative therapies in the pediatric population.Meniscal rim preservation through partial meniscectomy is currently recommended for a symptomatic discoid lateral meniscus (DLM) in children.  Meanwhile, most pediatric patients have weak self-control and tend to be hyperactive. Early aggressive activity after surgery can result in inflammation and chronic pain. Splints are widely used in pediatric patients. Basic indications of splinting include protecting operative sites, controlling pain, and decreasing bleeding or swelling. A previous study showed 2-week period immobilization had no statistical differences in range of motion (ROM) and thigh muscle strength after anterior cruciate ligament reconstruction when compared to 3-day period immobilization. However, excessive use of splint or brace after surgery can lead to joint stiffness and muscle weakness.,10 Consequently, a short-term splint immobilization is applied in our institution for children with DLM after surgery.Surgery can be painful, and this may negatively impact the well-being of children after the procedure. Pain may adversely affect postoperative recovery including limiting postoperative joint movement and reducing muscle strength. Postoperative pain is most commonly treated with analgesics, but often there is insufficient relief.The purpose of this retrospective study was to determine whether short-term splint immobilization would be of benefit to the patient by relieving postoperative pain, and to determine if the splint fixation would affect the time-course for postoperative recovery.Ethical approval for this retrospective study was obtained from the ethics committee of Children’s Hospital of Soochow university (2022CS170). All patients and their parents gave informed consent prior to participating in the study. This is a single-institution, retrospective review of archived data between 2015 to 2020 for patients undergoing treatment for DLM.Initially, patients enrolled between 2015 to 2017, who received saucerization without repair of the meniscus were treated with early-stage rehabilitation. Immediate weight bearing without external immobilization was advised to begin on the first postoperative day, and continuous passive motion was initiated after pain relief. However, some patients had difficulty to adhere to medical advice to initiate early rehabilitation because of postoperative pain. After 2018, we chose another line of treatment, a short-term knee immobilizing splint fixation for 2 weeks, and then rehabilitation therapy was initiated. To correlate the short-term brace immobilization with the postoperative degree of pain and functional outcomes, patients were divided into 2 groups: group A was treated between 2015 and 2017, and group B was treated between 2018 and 2020.Patient Inclusion criteria were the following: <18 years of age; Diagnosed with symptomatic discoid lateral meniscus; Underwent saucerization surgery in the absence of other treatment; Had adequate clinical documentation; Were able to be followed for more than 6 months. The exclusion criteria were as follows: Patients received saucerization with repair of the meniscus; Inadequate documentation; Patients received femoral nerve blockade during perioperative period; Insufficient follow-up. The Lysholm Knee Scoring Scale refers to instability and postoperative outcomes, which were used to evaluate clinical outcomes. After data collection age, gender, duration of symptoms, type of DLM according to Watanabe classification, body mass index (BMI), operation time, NRS at 1, 3, and 7 days postoperatively, Lysholm scores at 4 and 8 weeks, and time to return to normal activities were evaluated. Information was mined from inpatient and outpatient medical records, and telephone follow-up as required.The numerical rating scale (NRS) scores was used to assess postoperative pain in which 0 indicates no pain, and 10 severe pain.,3All patients with DLM received general anesthesia. Two specialists performed surgical interventions, routine diagnostic arthroscopic inspection of the knee joint was performed, and the presence of a discoid meniscus and the type of DLM was confirmed. Meniscus saucerization was executed by using meniscal baskets, meniscectomy and shavers, starting at the free edge to respect the central portion piece-by-piece. Saucerization was performed cautiously, proceeding until a 6 to 8 mm residual peripheral rim was achieved. The surgeon also searched for meniscus tears and assessed meniscal stability. When meniscus margin hypertrophy and internal horizontal tears were observed, the inferior or superior leaf was resected. Additional interventions such as all inside, inside-out or outside-in repairs were considered based on the types of meniscus tears or meniscus stability.Since postoperative hospitalization was 1 to 2 days, patients received home exercise program and information from physical therapist without supervision. In group A, starting on the day after surgery, partial weight bearing on the leg was advised with the use of crutches. Ice and compression therapy was used to reduce inflammation and swelling within 2 weeks. The patient underwent isometric contraction training of the quadriceps and hamstring muscles at an early-stage depending on pain tolerance levels. Passive ROM started at the same time, progressing to dynamic proprioceptive training. For those in group B, the knee immobilizing splint was placed after surgery. Then, protected weight bearing was initiated, and quadriceps active contraction and ankle pump training were used. Gradual progressive ROM was started after removing the splint at 2 weeks postoperatively.t test. The Mann–Whitney U test was used to compare differences in BMI, duration of symptom, surgical time, NRS scores at 1, 3, and 7 days postoperatively, Lysholm scores at 4 and 8 weeks, and time to return to sport. The Chi-squared test was used for between-group comparisons of gender distribution and affected side. P values < .05 were considered statistically significant.IBM SPSS Statistics for Windows, version 25.0  was used for statistical analysis. Parametric and nonparametric tests assessed statistically significant differences between groups. Between-group differences in patients ages were compared using the student For group A, 53 patients who suffered from DLM were treated between 2015 and 2017. In total, 18 patients were excluded because they underwent saucerization with repair of meniscus and 5 patients were excluded because of incomplete clinical data. There were 30 patients, 16 male and 14 female with 31 knees eligible for inclusion in the study. The average age at hospitalization was 10.8 years . About 21 knees of discoid menisci were classified as Watanabe I and 10 knees were Watanabe Ⅱ. The mean preoperative duration of symptoms was 7.2 months .For group B, 60 patients with symptomatic DLM were treated at the hospital between 2018 and 2020. Overall, 34 patients who received saucerization plus meniscus fixation and 4 patients received femoral nerve blockade were excluded, while there was inadequate follow-up in 4 patients. Thus, 18 patients, 7 males, and 11 females with 22 knees were included. The average age was 10.1 years . There were 14 cases with Watanabe type I discoid menisci and 8 cases with Watanabe type II. The mean preoperative duration of symptoms was 8.9 months .P=.409).There were no significant differences in patient characteristics including age, sex distribution, BMI, type of DLM and duration of symptoms (see Table P=.519), 3rd (P=.421), and 7th (P=.295) postoperative days in group B compared to group A (Table P<.01). However, at 8 weeks postoperatively, there was no statistically significant difference (P=.237), and both groups returned to normal activities (P=.363) (Table There was no improvement in NRS pain scores on the 1st ( 3rd P=.41, and 7t,14 Patients with DLM are prone to injury due to the unusual shape and size of the meniscus. Conservative approaches are adopted for the treatment of asymptomatic or minimal symptomatic DLM. Operation should be considered when the patient presents with persistent symptoms, including pain, blockage, edema, or limitation of normal activities.  The current study advocates restoring a stable and as near to normal meniscus, especially in younger patients.The DLM is a congenital abnormal meniscus variant with an incidence of 10% to 13% in Asia, 3% to 5% in the West. ,16 Despite increasing emphasis on meniscus repair, arthroscopic saucerization without repair of menisci still accounts for the largest proportion in the treatment methods of pediatric symptomatic DLM. However, there is no universal agreement regarding rehabilitation protocols that will be beneficial to patients, especially in children. For adults who have undergone isolated meniscus plasty, early postoperative rehabilitation has been advocated. However, children have poor compliance with functional exercises, and postoperative pain hinders rehabilitation despite the use of analgesics. Knee immobilizers are commonly used for postoperative pain management. Splints can decrease bleeding and protect operative sites. There is a dearth of information regarding the risk/benefit ratio of short-term knee immobilization with a splint following DLM after arthroscopic saucerization in children.Arthroscopic saucerization is a type of partial meniscectomy, consisting of removal of the central portion of the meniscus, and restoring its “C” shape in order to preserve its function of absorbing and distributing weight loads. A previous study noted that obesity is associated with worsening knee function after arthroscopic partial meniscectomy, and Kose et al, showed that the age at the time of surgery was the only predictor that correlated with the Lysholm score at the final follow-up. In our work, there was no statistically significant difference between age, gender, BMI and symptom durations, thus potentially reducing outcome bias.There are several prognostic factors for DLM reported in the literature. A retrospective study with 502 patients showed that 4 variables, including male sex, BMI < 18.5 kg/m2, age of onset < 14 years, and symptoms duration < 24 months are related to good postoperative outcomes.,23Because of enhanced focus on meniscus stability and meniscus repair, after 2018, a smaller percentage of DLM patients received saucerization alone in group B. We acknowledge that some patients who should have received saucerization plus meniscus repair prior to 2018 only received saucerization for DLM, which may have affected the course and choice of postoperative rehabilitation. However, studies comparing saucerization alone and meniscus plasty with fixation noted only small differences in the degree of long-term knee degeneration and showed no significant clinical differences in short-term follow-up. Considering the small number of cases using peripheral nerve block during the study period, they were not recorded and evaluated. Postoperative pain may cause adverse effects on surgical outcome, including limited ROM and resistance to rehabilitation. There have been increasing efforts to improve the perioperative pain management in children, but it is still suboptimal. Rest, ice, compression, elevation, bracing, and oral analgesics including acetaminophen, nonsteroidal anti-inflammatory drugs are common treatments for postoperative pain. Knee immobilizers and braces are commonly used both in children and adults after surgery. However, our study showed 2 weeks brace immobilization did not significantly improve postoperative pain control. A similar conclusion was documented by Hiemstra et al, where 88 patients underwent hamstring tendon anterior cruciate ligament reconstruction. Postoperatively, patients were randomly assigned to either the immobilized group or the no immobilizer group, data showed that there was no difference in pain scale scores nor medication consumed at 2 to 3 weeks.Due to the short length of hospital stay after DLM operation, patients with DLM might not receive adequate pain control. Peripheral nerve blockade has been shown to improve postoperative analgesia while decreasing the requirement for opioids in the pediatric population. Another study compared early versus delayed physical therapy, and showed that there was no significant difference in patients who received weight bearing at 3 or 10 days postoperatively.In terms of recovery time, our study indicated the Lysholm score of group A was significantly better than that of group B 4 weeks after surgery. However, there was no significant difference between the 2 groups in measurable knee function at 8 weeks postoperatively. Time to return to normal exercise after surgery did not differ significantly between the 2 groups. Short-term splint immobilization may delay the recovery of knee function in early-stage but has no significant effect on the final outcome. Goodwin and Morrissey reported that physical therapy had little or no effect on return to daily activities in adult patients with arthroscopic partial meniscectomy. indicated no differences in subjective evaluation of knee function and the ability to resume work between outpatient physical therapy compared to home exercise following arthroscopic knee surgery. Additionally, a meta-analysis comparing outpatient physical therapy plus home exercise versus home exercise alone after arthroscopic partial meniscectomy, demonstrated a 9° increase in knee flexion ROM, but there were no significant clinical changes between groups.Our study does have limitations that need to be documented. Due to the retrospective nature of this study, the data on ROM or muscle strength were not complete. It was a retrospective study with low patient enrollment. Randomized clinical trials are needed to provide additional evidence-based findings. All the surgeries were performed by 2 attendings, the result of the study may not be generalized. The form of rehabilitation training in our study was home exercise, where patients were provided with an exercise program and information, but patients did not receive supervision from a rehabilitation therapist. Because of this, it is likely that the duration, frequency, and intensity of rehabilitation training was inadequate. However, a prospective randomized study by Jokl et alThis study found that male and female pediatric DLM patients with arthroscopic saucerization alone, and short-term knee splint immobilization did not have reduced postoperative pain, and there was no effect on the time to return to normal activities.Conceptualization: Yao Liu.Data curation: Yao Liu, Ya Liu, Lun-Qing Zhu, Yun-Fang Zhen.Formal analysis: Yao Liu, Ya Liu, Lun-Qing Zhu, Xiao-Dong Wang.Investigation: Ya Liu, Lun-Qing Zhu.Project administration: Fu-Yong Zhang.Resources: Yao Liu, Ya Liu.Supervision: Ya Liu, Lun-Qing Zhu, Yun-Fang Zhen, Fu-Yong Zhang, Xiao-Dong Wang.Writing – original draft: Yao Liu.Writing – review & editing: Yao Liu, Ya Liu, Lun-Qing Zhu, Yun-Fang Zhen, Fu-Yong Zhang, Xiao-Dong Wang.


Episil® is a bio adhesive barrier-forming oral liquid gel that has been used in recent years to relieve pain of oral mucositis (OM) with radiotherapy (RT) or chemoradiotherapy (CRT) in head and neck cancer (HNC) patients. We conducted a retrospective analysis of the clinical effects of Episil® on OM in these patients.Between June 2018 and May 2020, 65 patients with HNC were treated with RT or CRT at our hospital.P < 0.001). Episil® was used in 26 patients. Among them, 10 discontinued its use due to ineffective pain relief, usage difficulties, and taste intolerance. The median duration of use was 30 days and was significantly longer (34.5 days) (P < 0.001) when patients experienced pain relief at treatment initiation.The median total RT dose was 50 Gy  and the completion rate was 63/65 (97%). The median time to OM resolution was 47 (6–90) days and was significantly longer (53 [27–90] days) when the total RT dose was ≥51 Gy (Although Episil® has been shown to be effective in improving the pain of OM caused by RT for HNC patients, and medical professionals are required to give careful attention to each patient. AdditioEpisil® should be swirled around the mouth approximately 1 h before eating to form a protective layer over the painful areas. Additionally, topical analgesics may be co-administered to intensify the therapeutic effect. It should be noted that Episil® and the topical analgesics should not be swallowed. Episil® adheres to ulcerative areas and within 5 min forms a protective membrane that acts as a mechanical barrier, relieving pain. Additional effects of the bio adhesive lipid formation include lubrication, moisturization, and mechanical protection of the sore mucosa.Although some bio adhesive barrier-forming oral liquids do provide comfort for patients, due to the insufficient evidence with regard to their ability to reduce the severity of mucositis, the current MASCC/ISOO guidelines do not mention the effectiveness of these agents . The EurWhile previous studies have reported that Episil® is an effective and safe product when used for the relief of pain caused by OM in patients with cancer ,11, thes2This was a retrospective study that examined the clinical data of 65 patients with HNC who underwent RT or CRT at our hospital between June 2018 and May 2020. Among the 65 tumors, 64 were histologically confirmed as squamous cell carcinomas, and one as malignant lymphoma .Table 1B2/w), tegafur-gimeracil-oteracil-potassium (TS-1®) (80 mg/m2), or cetuximab (400 mg/m2/w and 250 mg/m2/w)  (46 patients) or intensity-modulated RT (IMRT) (19 patients). The overall therapeutic irradiation dose was 30–70 Gy . The purpose of RT was post-operative irradiation. Two patients had their planned RT doses reduced and interrupted (30 Gy and 54 Gy) due to a deterioration of their nutritional status. The original dose for a 30 Gy patient was 50 Gy, and the original dose for a 54 Gy patient was 60 Gy. RT was performed once a day (2 Gy) five times a week. In addition, 63 patients received concurrent chemotherapy; the regimens included either cisplatin  .Table 2RPrior to the start of RT, an oral care team comprising an oral surgeon and a dental hygienist examined the oral cavity and administered oral hygiene care to patients with HNC. Simultaneously, the patients were oriented regarding OM management, including instructions with regard to tooth brushing, mouth washing, oral moisturizing, nutrition, and the use of Episil® during treatment.During the treatment, daily assessment of OM severity was conducted regarding functional disorders, symptomatic aspects, and clinical examination according to the common terminology criteria for adverse events (CTCAE) version 4.0. OM severity was graded as follows: grade 1, asymptomatic or mild symptoms, intervention not indicated; grade 2, moderate pain, not interfering with oral intake, diet modification indicated; grade 3, severe pain, interfering with oral intake; grade 4, life-threatening consequences, urgent intervention indicated; and grade 5, death.When OM was first observed and the patients started to experience pain, we prescribed our original mouthwash containing sodium gualenate hydrate, sodium bicarbonate, and 0.2% lidocaine (Xylocaine), which was gargled 6–8 times a day. We discussed regarding Episil® use with the patients and left the decision of receiving it to the patients. Episil® was administered by one dentist (Y.K.), and the patients were instructed to use it three times per day, for at least 5–10 min before a meal. The dental hygienist explained methods of easier administration, as described earlier in the manuscript, for those patients who experienced difficulties using Episil® in this manner.We assessed the pain relief after RT according to the WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain (1). To minimize the impact of confounding factors, we confirmed the timing of all pain medications, including opioids, and ensured that there was at least a 2-h interval before commencing with Episil®. The pain-relieving effect of Episil® was confirmed by one dentist (Y.K.) after 6 h of its use through an interview with each patient and recording the patients' impressions of its use. The details of the questions are summarized in U test or Pearson’s Chi-square test. Fisher’s exact test was performed when more than 20% of the cases contained an expected value of 5 or less, and the chi-square test was used to calculate the other cases. The description has been corrected. The p-values calculated by Fisher’s exact test are marked with *. The statistical significance was set at P < 0.05.All the statistical analyses were performed using the IBM SPSS version 22.0 . The measurement data are expressed as the median, maximum (max), and minimum (min) values and were analyzed using the Mann–Whitney 33.13.2The overall number of median days to the resolution of OM was 47 days . The number of days to resolution of OM was not related significantly to the use of Episil® or the highest previous grade of OM during RT ; however3.3The median duration of Episil® use was 30 days . Patients who experienced pain relief at the start of Episil® use had a significantly longer duration of Episil® use (>29 days) . In cont4The use of Episil® has been shown to relieve pain and improve malnutrition in patients with HNC . The resThe results of this study showed that the use of Episil® had no effect on the healing time of OM caused by RT, which is consistent with a previous report . The dosThe method and site of RT and concomitant chemotherapy may affect the patients' QOL. In particular, the impact of IMRT on the patients' QOL is controversial. The results of the meta-analysis conducted by de Felis et al. indicated that IMRT was superior to 3D-CRT, in terms of xerostomia rates . HoweverThis study had some limitations. It was not a randomized controlled trial and the nutritional improvement with the use of Episil® was not evaluated, as was reported in previous studies . AlthougAlthough Episil® has been shown to be effective in improving the pain of OM caused by RT for patients with HNC, Episil® needs to be improved, and medical professionals are required to give careful attention to each individual patient.The study was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the Faculty of Dentistry of Tokyo Medical and Dental University. The requirement for written informed consent from each patient was waived because of the retrospective nature of the study . The requirement for patient consent was waived due to the retrospective study design.Kanade Ito and Yuji Kabasawa: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, patients, analysis tools or data; Wrote the paper.Shiori Tokura, Itsuki Takazaawa, Hitomi Nojima., Msahiko Miura, Hiroyuki Harada and Ryoichi Yoshimura: Contributed reagents, patients, analysis tools or data.Naomi Yoshida, Tohko Nakanishi, Kikue Akiyama, Yuki Onuma and Toshiko Adachi; Contributed reagents and patients. of the manuscript.Data will be made available on request.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper