Shoulder pain is commonly reported after hepatic surgery; however, the factors affecting post-hepatectomy shoulder pain remain unclear. This study aimed to determine the incidence and risk factors of shoulder pain after hepatectomy.This prospective cohort study recruited 218 patients who underwent hepatic resection at our hospital from June to September 2022. Data were obtained from electronic medical records and follow-up assessments on the second postoperative day. All patients denied chronic pain before surgery. In this cohort study, patients were grouped according to the appearance of shoulder pain. Demographic information and perioperative data were compared between the two groups. The relationship between shoulder pain and independent variables was assessed using univariate binary logistic regression analysis. The potential risk factors were analyzed using multivariable binary logistic regression.P = 0.001). Epidural anesthesia was used more frequently in the case group (P = 0.012). Patients over 60 years of age showed a lower incidence of shoulder pain than younger patients (P = 0.028). According to multivariable binary logistic regression analysis, advanced age and epidural anesthesia were associated with risk of shoulder pain ]: 0.96 , P = 0.002; epidural anesthesia: OR [95% CI]: 2.08 , P = 0.012).Of the 218 patients enrolled in this cohort study, 91 (41.7%) reported shoulder pain. Patients in the case group were significantly younger than those in the control group (The incidence of acute shoulder pain after hepatectomy is 41.7%. The application of epidural anesthesia is an independent risk factor for shoulder pain after hepatectomy, whereas advanced age is a protective factor. Shoulder pain is a common complication after hepatic surgery. The incidence of post-hepatectomy shoulder pain varies between 42 and 75% , 2. In cOverall, there is a paucity of studies on shoulder pain after hepatectomy. The only previous study on post-hepatectomy shoulder pain was a retrospective cohort study. Patients were grouped according to the type of anesthesia. In addition, the sample size in this study was relatively small. Multiple factors are likely associated with shoulder pain after hepatectomy. Identifying the risk factors contributes to the prevention of shoulder pain. To the best of our knowledge, no study with a large sample size has been conducted to determine the possible risk factors for shoulder pain after hepatic surgery.To fill the gap, in the current study, we hypothesized that some risk factors may increase the incidence of shoulder pain. To this end, we conducted a nested case-control study of hospitalized surgical patients.The current study was a case-control study nested in a prospective observational cohort. Because of the observational nature and all data collected from the medical records, the study was approved by the Ethics Committee of the Shanghai Cancer Center , and written informed consent was waived.Patients were recruited consecutively at the Department of Hepatic Surgery at Shanghai Cancer Center, Fudan University, from June 2022 to September 2022. The inclusion criteria were as follows: (1) American Society of Anesthesiologists score of I to III; (2) patients who underwent hepatectomies under anesthesia; and (3) patients denied having chronic pain before surgery .The exclusion criteria were as follows: (1) multivisceral resection, (2) history of shoulder pain, and (3) patients whose surgeries were converted to open surgery after a laparoscopic attempt.Biometrics  and medical data  were collected from the electronic medical record system. Postoperative data were collected within 40–48 h after surgery. When the patient-controlled analgesia devices were taken from the patients, they were asked whether they experienced shoulder pain.All patients underwent standard monitoring. The exclusion criteria for epidural anesthesia were as follows: (1) patients who refused epidural anesthesia, (2) elderly patients who could not maintain an epidural position, and (3) patients who could not cooperate because of language barriers. All epidural anesthesia procedures were performed by the attending anesthesiologists (experience of more than 500 cases). For patients receiving epidural anesthesia, a test dose of 3 mL of 1% Lidocaine was administered after the epidural catheter was inserted. Epidural analgesia was intermittently administered using 0.25% Ropivacaine. The spinal level of epidural anesthesia was tested using wet cotton balls. The spinal level of epidural anesthesia was at T6–T10. None of the patients complained of dyspnea. General anesthesia was induced with Propofol, Rocuronium, and Sufentanil. Desflurane, or Sevoflurane, Propofol, and Remifentanil were used to maintain anesthesia. An intermittent bolus of Sufentanil was used for intraoperative analgesia. Postoperative analgesia was achieved using epidural patient-controlled analgesia in patients receiving epidural anesthesia. According to our institution’s routine protocol, the epidural analgesia pump was set to a volume of 200 mL, containing 300 mg of Ropivacaine and 100 μg of Sufentanil. The patient-controlled device was programmed to deliver a 4 mL bolus with a lockout interval of 20 min and a background infusion of 4 mL/h. For patients receiving general anesthesia alone, intravenous patient-controlled analgesia was administered. The intravenous analgesia pump contained Sufentanil 100μg and Flurbiprofen Axetil 150 mg (or Ketorolac Tromethamine 90–105 mg). Intraoperative and postoperative intravenous analgesia were independently determined by the attending anesthesiologist.The patient was placed in the supine position if the expected surgical site was the left lobe of the liver. When the right liver lobe was expected to be removed, for a good visual field during the surgery, a padded cushion was placed under the patient’s right waist. In laparoscopic surgeries, the pneumoperitoneum pressure was set at 12–15 mmHg.All patients routinely underwent overall pain scale assessments before leaving the post-anesthesia care unit (PACU). Pain intensity was assessed using a numerical rating scale (NRS). Additional intravenous Sufentanil (3–5 μg) or epidural Ropivacaine  was administered if necessary.In this cohort, cases were patients who reported shoulder pain regardless of type (such as dull pain and aching pain) and severity within 48 h after the surgery. Shoulder pain data were recorded as either left, right, or bilateral. Controls included patients who did not report any pain around the shoulder.The sample size was calculated using the PASS . Statistical significance was set at 0.05, with a power of 90%. The ratio of cases to controls was set at 1:1.5 . The odds ratio was set at 2.5, and the proportion in the control group was set at 0.4. The sample size was calculated using the Z-test. Therefore, the calculated minimum total sample size was 205.t-test. Categorical variables  between the two groups were compared using the chi-square test.The Kolmogorov–Smirnov test was used to determine whether the meteorological data followed a normal distribution. Normally distributed continuous data are expressed as mean ± standard deviation. The differences in measurement data  between the case and control groups were calculated using P < 0.2 in the univariate binary logistic regression model were included in the multivariate binary logistic regression model. The odds ratio (OR) for shoulder pain is presented with a 95% confidence interval (CI). The significance level was set at 0.05. All analyses were performed using the Statistical Product and Service Solutions .Univariate binary logistic regression was used to determine the possible risk factors  for shoulder pain. Variables with During the study period, 218 patients underwent hepatectomies. A total of 91 patients reported postoperative shoulder pain. Right shoulder pain occurred in 63 patients, whereas left shoulder pain occurred in 20 patients. Furthermore, eight patients reported bilateral shoulder pain.The overall pain score of all patients in the PACU ranged from 0 to 2 (NRS). Seven patients required additional Sufentanil (3–5 μg). All patients received general anesthesia alone.P = 0.001). Epidural anesthesia was used more frequently in the case group than in the control group (P = 0.012). The mean consumption of Sufentanil was significantly more in the control group (P = 0.005). There were no statistical differences in sex, height, BMI, surgical duration, application of laparoscopes, comorbidities, surgical history, and overall pain scale between the two groups.The patient characteristics are shown in Table n = 122) than in patients receiving general anesthesia alone (n = 96) .In the original cohort, the consumption of Sufentanil (μg) was significantly less in patients receiving epidural anesthesia (P = 0.028). The effects of demographic and perioperative data on shoulder pain were analyzed using univariate binary logistic regression . The application of epidural anesthesia was associated with increased odds of shoulder pain . The effects of the other variables on shoulder pain were not significant.All patients were divided into two groups according to their age. We used a cutoff age of 60 years. The incidence of shoulder pain in the younger age group was significantly higher than that in the older age group .Based on the results of the comparison of the two groups and the univariate binary logistic regression analysis, age and application of epidural anesthesia were included in a multivariate binary logistic regression analysis Fig. . Both vaThis observational study investigated the incidence and risk factors of shoulder pain after hepatectomy. The total incidence of shoulder pain was 41.7%, and epidural anesthesia increased the odds of shoulder pain. By contrast, advanced age decreased the risk of shoulder pain.The total incidence of shoulder pain was consistent with that reported in a previous study . Owing tYounger age has been recognized as a predictive factor for postoperative pain . YoungerShoulder pain occurs more frequently in patients receiving epidural anesthesia than in those receiving general anesthesia alone . In thisSex differences in postoperative pain are well known. However, previous studies focusing on sex differences have yielded inconsistent results. Hans et al. found that females reported a 0.29 point  higher than males . By cont2 is involved in the maintenance of shoulder pain . However, we failed to replicate the findings of this study. This intriguing result could be attributed to the influence of both the surgical procedures and pneumoperitoneum on the diaphragm. Typically, the surgical duration is an important manifestation of surgical difficulty. This result suggests that the extent of resection does not contribute to the risk of shoulder pain.A recent study also emphasized that patients with a lower BMI showed a higher incidence of shoulder pain after laparoscopic surgery for infertility . By contThis study had some limitations. First, the number of possible risk factors was relatively limited mainly because the range of surgical resection was not included in this study. As hepatectomy is a non-standardized surgical procedure because of the size and site of the tumor, a variety of procedures cannot be simply classified. The liver is anatomically close to the diaphragm; therefore, the influence of surgical procedures on shoulder pain should not be ignored. Further studies with larger cohorts are required to investigate the impact of surgical site on shoulder pain. Second, medication administration and use of epidural anesthesia during anesthesia were unstandardized. Third, the surgical approaches were determined by the surgeons and patients. As a result, most patients with intra-abdominal adhesions undergo open surgery. Although the effect of intra-abdominal adhesion on shoulder pain is unknown, it could also increase the risk of bias in this study.The incidence of shoulder pain after hepatectomy is nearly two-fifths. This study demonstrated that epidural anesthesia was an independent risk factor for shoulder pain after hepatectomy, whereas advanced age was a protective factor. Our findings may contribute to the prevention of post-hepatectomy shoulder pain. Despite effective epidural analgesia, systemic analgesia remains necessary to cope with the alternative pathway of shoulder pain. The effect of anesthetic management on shoulder pain requires further prospective studies.


P < .001). No adverse events occurred in either group, and the addition of ultrasound-guided regional anesthesia (RA) for the treatment of dressing pain was determined to be a safe and effective intervention.Burn injuries requiring split-thickness skin grafting procedures often require ongoing wound aggravation in the form of dressing changes. These dressing changes may cause significant pain due to stimulation of damaged nerve endings in the epidermal layer. A randomized control trial, pilot study, was undertaken to evaluate the impact of ultrasound-guided regional nerve block on the outcome of patient reported pain scores by inpatients requiring dressing changes for hand and upper limb burn injuries. Twenty participants aged >18 years, requiring split-skin grafting for burn injuries of <15% total body surface area were enrolled from a tertiary burns unit between August 2018 and September 2020. Participants were randomized to control (10 participants) or intervention group (10 participants). All participants received analgesia as per their treating team, the intervention group received the addition of an ultrasound-guided axillary brachial plexus block prior to their dressing change procedure. The primary outcome was to assess perceived pain at the graft site as measured by the Numeric Pain Rating Scale (0–10) before, during, and after dressing change procedure. There was strong evidence of a difference in the adjusted mean change score between groups, with a mean reduction of 4.3 in the intervention group, indicating reduced pain, and a mean increase of 1.2 in the control group ( Superficial burns are managed with appropriate topical treatments and dressings, while deeper partial, mixed, and full thickness burns may require surgical debridement and skin grafting.1 Neuropathic pain is notoriously difficult to treat and has the potential to result in long-term chronic pain development.2 For patients who undergo split-thickness skin grafting, significant pain is often experienced in the donor site; which is typically located on the anterior thigh.3–6 Burn injuries that require debridement and skin grafting will require ongoing wound aggravation in the form of repeated debridement, dressing changes, and physical therapy. These interventions have the potential to cause pain, significant discomfort and distress to patients.2The experience of burn pain is predominantly caused by damage or disruption to cutaneous nerve endings, resulting in changes to perceived temperature, touch, and pain.6–10 RA is a method of providing analgesia or anesthesia to a targeted area of the body via sensory blockade. Ultrasound-guided RA is a technique that provides safe, effective deposition of local anesthetic (LA) to a targeted nerve, or bundle of nerves under ultrasound guidance.3 The generalized outcome of the published studies looking at nerve blocks and burns patients have demonstrated that RA provides a safe and effective addition to the multimodal management of donor and graft site pain. None of the published studies evaluate RA as an intervention for graft site pain during dressing change.Several studies have looked at the addition of RA for the management of donor site pain in the burn-injured patient.11 RA is an effective primary pain management technique or adjunct to a multimodal regime. However, its application in burns is still underreported and underutilized.5 In particular, an area of burn treatment that has yet to be explored in partnership with RA is that of dressing changes and postoperative procedural pain. Dressing changes typically occur 3 to 5 days post the split-skin grafting procedure and can involve removal of staples, minor debridement, and redressing or splinting. These interventions are well known to cause pain for patients and typically opioids are used alone or in conjunction with other analgesics and sedatives depending on the TBSA of the burn, and the existing pain tolerance of the patient.Early multimodal pain relief is imperative for management of acute pain in the burn-injured patient. Patients are at increased risk of developing long-term chronic pain and psychiatric trauma if acute pain is poorly managed.12 The ABPB block reliably blocks sensation to the forearm hand and wrist. Regional nerve blocks may be administered as a single injection, or the insertion of a catheter to provide continuous or intermittent bolus LA. Single injection nerve blocks typically provide analgesia for between 3 and 12 hours depending on the type of LA used; while catheters remain in situ for several days.This paper reports on a randomized control trial that utilized ultrasound-guided regional nerve blocks for the management of burn-related procedural pain in the upper limbs. The axillary brachial plexus block (ABPB) targets the three terminal branches of the brachial plexus: the median, the ulnar, and the radial nerve.Skin grafting procedures are the most common surgical treatment for burn injuries. In the case of burn injuries that occur to mobile areas of the body, splinting is required for 3 to 5 days to immobilize the grafted area, preserve the skin graft and encourage adhesion. Small grafted areas of the fingers and hands may require a significant number of staples to secure the graft, consequently, removal of staples at the initial dressing change and the immediate range of motion (ROM) exercises may cause significant discomfort.The intention of this study is to evaluate the efficacy of RA as a pain-relieving intervention in patients who require postoperative dressing changes to upper limb burn injuries. These initial dressing changes take place in a ward setting, 3 to 5 days post skin grafting procedure.Recruitment for this two-group parallel randomized control trial occurred between August 2018 and September 2020, at a tertiary hospital acute burn unit. Ethical approval was granted by an independent Human Research Ethics Committee (HREC/17/QRBW/54). Patients who were scheduled for skin grafting procedures for upper limb burn injuries and subsequently required change of dressing as an inpatient postoperatively, were approached. Additional inclusion criteria were <15% TBSA burns, fluency in written and spoken English and ability to provide informed consent, anticipated length of hospital stay of >24 hours postsurgery. Exclusion criteria were intubation, vascular disease or active infection, and contraindication to RA. Twenty participants, aged 18 years or more, were approached and consented to participate in the study. Simple randomization was conducted by a third party, closed opaque enveloped method, with 10 participants randomized, respectively, to the intervention group or the control group.All 20 participants had a standard analgesia regime as per the discretion of the treating team and anesthetist during their initial dressing change and removal of staples post skin grafting procedure. The 10 participants in the intervention group received an ultrasound-guided ABPB of 0.375% ropivacaine 20 to 30 ml prior to their dressing change procedure. Block administration occurred at the patient bedside, or in the anesthetic “Green Room”; a theater induction bay reserved for regional procedures and staffed with an anesthetic consultant and registrar each day. Participants in the intervention group received supplemental oxygen and routine observation monitoring, including noninvasive blood pressure and pulse oximetry during the ABPB administration. Standardized monitoring in conjunction with ultrasound guidance aims to reduce the risks of: nerve injury, inadvertent damage to adjacent structures, and LA toxicity. Participants received 1 to 4 mg intravenous midazolam as sedation as required. The ultrasound-guided ABPB was administered within 1 to 2 hours prior to dressing change by qualified anesthetists, employing standard aseptic technique. The primary outcome of the study was to assess pain at the graft site during dressing change, as measured by the Numeric Pain Rating Scale 0–10 (NPRS). This pain score was then compared to the baseline predressing NPRS scores in both the control and intervention groups.13–17 Pain scores at the donor site during dressing change procedures were collected for comparison and understanding of background pain requirements and site-specific discomfort.Further clinical outcomes of interest included, pain score at the donor site during dressing change, requirement for analgesia and pregabalin dosages, nausea, and vomiting, and achievement of physical therapy ROM goals. Pain management during dressing change was left to the discretion of the Burn team. Morphine equivalent opioid conversion provides a comparison for pharmaceutical opioid dosing; furthermore, it allows for comparison of multiple pharmaceutical opioids that have similar analgesic effects.SD) for normally distributed continuous data. The change in skin graft pain from predressing to dressing change was analyzed using the ANCOVA of NPRS change, adjusted for pre-NPRS scores between the control and intervention groups. Associations between predressing NPRS scores and groups were assessed using Mann–Whitney U-tests. Statistical significance was set at a P value <.05 (two sided). STATA 15 (Stat Corp LLC) was used for all analyses and figure produced in R statistical package version 4.0.2.Data were summarized with frequencies and percentage for categorical data, median (interquartile range [IQR]) for non-normally distributed continuous data and mean  = 47.1, P < .001). There was no significant difference in predressing pain scores between groups (P = .47). The primary outcome was to assess pain at the graft site as measured by the NPRS and compare it to predressing NPRS scores in both the control and intervention group. The median duration of the sensory nerve block in the intervention group was 11.0 hours (IQR 9.2–11.3). There were no adverse reactions or nerve injuries within the intervention group, and 50% received the addition of midazolam as a preprocedural medication. There were no failed block attempts, or any LA top ups required for incomplete block. Pain relief administration during dressing change was left to the discretion of the treating team. Median (IQR) NPRS in donor site during dressing change was 6.0 (3.0–10.0) for the control group and 5.5 (4.0–8.0) for the intervention group. Donor site pain scores were recorded at time of dressing change, and daily for 3 days postdressing change with no statistically significant differences between the groups. During dressing change, 40% of control participants required Nitrous oxide, and neither group reported any nausea, vomiting, or increased sedation during dressing change. Pregabalin administration during dressing change was similar across groups with 70% of the control group, and 80% of the intervention group receiving a median dose of 150 mg.The average length of stay was 8.7 days for the control group and 12.1 days for the intervention group. Sixty percent of participants in each group were discharged with an opioid script, it is unknown if the scripts were dispensed.11 To date there are no published clinical trials focusing on regional nerve blocks during burn dressing changes, this is likely due to a number of reasons including: perceived infection risk; poor access to experienced anesthetic clinicians and procedural equipment; focus on chronic pain interventions; and the paucity of published literature to guide a change in practice.The results of this study demonstrate the effectiveness of regional nerve blocks for the management of procedural pain during upper limb dressing changes in the burn-injured patient. RA is currently underutilized as an analgesic intervention in the burn-injured patient. The contraindications in this cohort are few, and the potential benefits are many.Regional nerve blocks are not appropriate for every burn-injured patient during dressing change, and there are limiting factors including appropriate patient selection, and suitable body region of the burn amenable to an analgesic nerve block procedure. Hand and upper limb burns were chosen for this study due to the large number of staples required to anchor grafts, and due to the early hand mobilization required to ensure optimum rehabilitation. All 10 patients who received the ABPB were unable to perform active ROM for the physiotherapy session immediately postdressing change due to motor block. However, passive ROM was achieved in all 10 patients without difficulty and there were no limitations to this group achieving their targeted active ROM on day 1 post the regional block. Motor block is a known side effect of RA blocks, and participants were made aware of what to expect regarding a lack of sensation and movement. Participants in the intervention group had their hands/arms placed in slings where required, to protect them from accidental injury while mobilizing. The median sensory block length was 11.0 hours and none of the intervention group sustained any nerve injuries.Morphine equivalent pain relief consumption was higher in the intervention group across all time points from predressing change until day 3 postdressing change. This could be due to a number of factors, starting with the slightly larger TBSA% of the intervention group, with 40% having burns ≥5% TBSA and 50% having burns 2% to 4.9% TBSA; compared to only 20% and 30%, respectively, in the control group. This larger area of burn injury could explain the higher requirement for pain relief to treat areas of burn outside the region covered by the ABPB. As per 12 Careful aspiration prior to LA injection decreases intravascular injection. The risk of LA toxicity is low due to weight-based dosing and exclusion of patients with contraindications to LA.18 The median age was 34.5 years with 90% of participants receiving an American Society of Anaesthesiology (ASA) physical status classification score of ≤2, making them a group of participants with mild or no systemic disease. None of the participants reported preexisting chronic pain conditions, or opioid dependence. Ultrasound-guided regional nerve blocks have been growing in popularity throughout the last three decades, and their application to the burn-injured population should not be overlooked.19Ultrasound guidance has introduced an added level of precision and safety to RA through the ability to sight major anatomical structures and nerves; this visual guidance makes nerve or vascular injury less likely.Successful implementation of regional blocks for burn injury procedural pain relies on the availability of trained anesthetists and appropriate monitoring equipment. This study was possible due to the staffing of one consultant anesthetist and one anesthetic registrar every day for the purpose of administering regional anesthetic blocks to surgical patients within the hospital. This resource is invaluable to patients who receive the added anesthesia or analgesia; and the anesthetic registrars who gain education administering a variety of regional nerve blocks under supervision. This resource makes administering regional nerve blocks convenient, safe, and timely. The administration of regional nerve blocks for dressing change may prevent some patients from having an additional general anesthetic. Providing general anesthesia for dressing changes requires significantly more hospital resources and additional risk and recovery time for a patient.There are limitations to the use of regional anesthetic blocks in burns patients, those include: patients with large TBSA burns, or burns in locations that cannot be covered with RA; burn wounds that will require frequent and ongoing wound aggravation; patients with active infection; and patients who are not appropriate for RA due to comorbidities, allergy to LA, or altered anatomy.2The short duration of dressing changes is perhaps one contributing factor to the under-treatment of pain during procedures; there may be a tendency to under-treat procedural pain due to the perception that it should be tolerable for a short period. However, pain associated with dressing changes is acute pain and can be severe. It comes with the same potential adverse consequences as acute pain occurring in the perioperative setting. Poorly managed acute pain can lead to; impaired sleep, delayed recovery, risk of chronic pain development, and reduced quality of life. Another factor is the opioid-based approach to treating burn pain. Opioids do not target the neuropathic pain specific to burns and may often result in side effects like constipation and sedation.This study does present limitations, the study size is small and larger, multicenter randomized control trials would be beneficial. Further studies evaluating different regional blocks for dressing and procedural changes would be of interest. Recruitment for this trial was prolonged due to the emergence of a change in practice. Burns consultants began booking patients for scheduled nerve blocks for dressing changes, making patients ineligible for study recruitment. This was a positive reflection on the perceived benefits of RA for pain relief, however, it did delay recruitment.Participants in the intervention group were asked prior to discharge if they would opt to receive a regional nerve block in the future and 100% of participants said yes.RA should be considered as a pain relief option for the management of procedural pain in the burn-injured patient. Ultrasound-guided regional nerve blocks have the potential to significantly lower pain scores and provide a safe and effective addition to multimodal pain relief in burn-injured patients.


The central nervous system may also be involved in the pathogenesis of classical trigeminal neuralgia (CTN). The present study aimed to explore the characteristics of static degree centrality (sDC) and dynamic degree centrality (dDC) at multiple time points after a single triggering pain in CTN patients.A total of 43 CTN patients underwent resting-state function magnetic resonance imaging (rs-fMRI) before triggering pain (baseline), within 5 s after triggering pain (triggering-5 s), and 30 min after triggering pain (triggering-30 min). Voxel-based degree centrality (DC) was used to assess the alteration of functional connection at different time points.The sDC values of the right caudate nucleus, fusiform gyrus, middle temporal gyrus, middle frontal gyrus, and orbital part were decreased in triggering-5 s and increased in triggering-30 min. The sDC value of the bilateral superior frontal gyrus were increased in triggering-5 s and decreased in triggering-30 min. The dDC value of the right lingual gyrus was gradually increased in triggering-5 s and triggering-30 min.Both the sDC and dDC values were changed after triggering pain, and the brain regions were different between the two parameters, which supplemented each other. The brain regions which the sDC and dDC values were changing reflect the global brain function of CTN patients, and provides a basis for further exploration of the central mechanism of CTN. According to the etiology of TN, it is classified into three subtypes, which are classical trigeminal neuralgia (CTN), secondary trigeminal neuralgia (STN) and idiopathic trigeminal neuralgia (ITN) . CTN is Neurovascular compression (NVC) is the main cause of CTN , and itsIn recent years, many studies have been conducted on the brain function of CTN, among which the resting state functional MRI (rs-fMRI) is a non-invasive technology applicable to several clinical diseases . It showStatic DC (sDC) reflects the strength of connections between the given voxel and the other voxels in the whole brain without a prior definition of the region of interest . TypicalAlthough the rs-fMRI was collected in a quiet state of the subjects, the brain activity fluctuated with time . DynamicIn the study, the pain was triggered by simulating the harmless actions in the daily life of CTN patients, the sDC and dDC values were measured at multiple time points after a single triggering pain. Thus, we hypothesized that: (1) the sDC and dDC values of multiple brain regions in CTN patients were altered after triggering pain; (2) the brain regions where the dDC value changes differed from that of sDC, providing a beneficial supplement to sDC.All the participants provided written informed consent. This prospective study was approved by the local ethics committee of the Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine (IRB# No. 202107002). It was carried out following the Declaration of Helsinki.A total of 85 CTN patients were recruited from the Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, between July 2021 and March 2022. The inclusion criteria for patients with CTN were as follows: (1) patients diagnosed with CTN according to the third edition of the International Classification of Headache Disorders (ICHD-3) and demonstration of NVC (not simply contact) on MRI with morphological changes (atrophy or dislocation) in the trigeminal nerve root; (2) unilateral pain in the distribution of one or more branches of the trigeminal nerve; (3) paroxysmal facial pain precipitated by trigger factors (such as light touching of the face and opening mouth); (4) conventional MRI T1 weighted imaging (T1WI) and T2WI examination showed no abnormal brain signals; (5) no additional neurological or sensory deficits in all patients; (6) no previous surgical or other invasive procedures for CTN; (7) no contraindications to MR scanning; (8) patients underwent microvascular decompression and presented NVC which not only contact; (9) right-handed patients. The exclusion criteria were as follows: (1) patients with CTN who had undergone surgical treatment before; (2) headaches and other paroxysmal or chronic pain conditions; (3) a family history of headache or other pain in first-degree relatives; (4) other somatic or psychiatric conditions; (5) left-handedness; (6) contraindications to MRI .Patients on analgesic medications were asked to discontinue their medications 12 h before the scheduled scanning sessions. Before the MRI scan, a medical history was recorded to determine the zone with substantial pain in daily life. Then, the trigger zone was stimulated within 5 s before the second rs-fMRI scan; the trigger zones were stimulated by the doctors, which was a gentle touch to the patient’s trigger zone with a long cotton swab . The foaIf the patients experienced the stimulation, the pain would be assessed using the visual analog scale (VAS) after scanning. The researchers guided the patients in rating their pain on a scale of 0–10. A higher score indicated a greater pain intensity. A rating of “0” represented no pain, and a rating of “10” meant intolerable pain .Resting-state function magnetic resonance imaging data preprocessing was conducted using the Data Processing and Analysis of Brain Imaging (DPABI6.1) and Statistical Parametric Mapping 12 (SPM12) toolbox based on the MATLAB platform . The preprocessing pipeline included the following steps: (1) removing the first ten time points of each session to ensure that the MRI signal reached a steady state, (2) slice-timing and head motion correction for the remaining images, (3) normalization to the Montreal Neurological Institute (MNI) and re-sampling of the resulting data to obtain 3 mm× 3 mm× 3 mm voxel size, (4) removal of the linear trend of the time course of the blood oxygenation level-dependent (BOLD) signal, and (5) a noise removal process, including the regression of Friston-24 head motion parameters, cerebrospinal fluid signals, and white matter signals. Nine patients were excluded due to large head motion  exceeded 0.2 throughout the scanning), and the remaining 43 patients with CTN were subjected to further analysis.R = Σ(rij), j = 1. N-1 . The correlation coefficient of each voxel was r > 0.32  and were summed to obtain the weighted DC for each voxel. The threshold of 0.32 was used to eliminate the counting voxels with low temporal correlation. The different threshold choices do not alter the results qualitatively  was applied for multiple comparison correction. Comparison between the two groups was performed using SPSS 26.0, the Bonferroni correction procedure (P < 0.05) was used to correct. The pearson correlation analysis was used to assess the association between the average sDC and dDC values of significant clusters and pain characteristics.Data Processing and Analysis of Brain Imaging (DPABI) software was used to compare the sDC and dDC values of regional brain activity, measured three times for CTN patients. Repeated-measures analysis of variance (ANOVA) was used to examine the differences between the groups. The Gaussian random field theory , fusiform gyrus (FFG), middle temporal gyrus (MTG), middle frontal gyrus, and orbital part (ORBmid) were increased in triggering-5 s and decreased in triggering-30 min. The sDC values of bilateral superior frontal gyrus (SFG) were decreased in triggering-5 s and increased in triggering-30 min . The sDCThe dDC value of right lingual (LING) was gradually increased in triggering-5 s and triggering-30 min . The sDCThe sDC value of CAU in baseline was positively correlated with the disease duration. The sDC value of MTG in baseline was positively correlated with VAS. The sDC values of FFG in baseline and triggering-5 s were both positively associated with pain persistence .In the previous study, we explored the local brain function after a single triggering pain in CTN patients, namely, the time-frequency properties of ALFF  . In thisCTN is known as the most severe pain that humans can endure. Currently, most studies on the brain function of CTN patients are based on the cross-sectional rs-fMRI . SeveralIn this study, the sDC values of the right CAU, MTG, FFG, and ORBmid were changed in the same trend, i.e., increased in triggering-5 s and decreased in triggering-30 min, indicating that the connectivity with the whole brain increased significantly for a short period after triggering pain, and then recovered gradually in the four brain regions. However, the recovery levels in triggering-30 min were slightly different, indicating that the four regions participate in the pain process of CTN, but the specific role is diverse.The CAU is a key region of the subcortical network that receives damaging information from the trigeminal nucleus through direct projection from the trigeminal spinal cord nucleus. In addition, the CAU plays a crucial role in assessing the consistency between actions and outcomes . The MTGThe SFG located in the upper part of the prefrontal cortex is involved in socially oriented thoughts and may also be involved in anticipation of impending pain . The SFGThe dDC reflects the time variability of DC, i.e., the fluctuation of DC as time changes. In this study, after triggering pain in CTN patients, we found a brain region with obviously changed dDC value, namely, the right LING, and was different from the brain regions with altered sDC value, indicating that dDC provides additional In this study, we explored the changing trend of static and dynamic functional connections in CTN patients at multiple time points after triggering pain. Compared to the baseline, the sDC or dDC values of each brain region showed a recovery trend at triggering-30 min, but the recovery level was different and did not return to the baseline, which required a prolonged duration to further clarify the changing trend in the brain functional connectivity after triggering pain. Secondly, we did not conduct the classification studies according to the average duration of attack, and in the future, we will study CTN patients depending on the average duration of attack.After a single triggering pain, both the sDC and dDC values of CTN patients were changed in different brain regions, which were complementary to each other. These brain regions which the sDC and dDC values were changing reflected the global brain function of CTN patients and provided a specific basis for further exploration of the central mechanism of CTN.The original contributions presented in this study are included in this article/Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ZD, HY, and QD: study concept or design and revisions to the manuscript. XG: data acquisition and analysis and drafting and writing of the manuscript. LW: data analysis and revisions to the manuscript. MW: make important revisions to the manuscript and edit language. LP, HY, QF, and XZ: data collection. SF: language editing and revisions to the manuscript. All authors contributed to the article and approved the submitted version.


Although pain phenotype affects clinical score in patients with knee osteoarthritis (OA), little information has been available on the relationship between pain phenotype and gait analysis. The purpose was to investigate the relationship between pain phenotype and gait parameters. A total of 34 patients  with end-stage medial compartmental knee OA participated. All the patients were evaluated based on pain detect questionnaire (PD-Q) and pain catastrophizing scale (PCS). They were divided into two categories: Group Low (PD-Q score ≤ 12) and Group High (PD-Q score > 12), PCS + (PCS ≥ 23) and PCS- (PCS < 23). Gait analysis was performed using three-dimensional motion analysis system. Statistical analysis was done to compare gait parameters between groups for each allocation of PD-Q or PCS, separately. P = 0.015). Peak knee adduction moments in Group Low and High were 0.70 ± 0.19 and 0.39 ± 0.14, respectively (P = 0.0022). For PCS allocation, knee extension limitation during mid-stance during gait were significantly larger in PCS- (P = 0.038).Peak vertical ground reaction forces in Group Low and High were 0.99 ± 0.054 and 0.82 ± 0.17, respectively (Patients with high PD-Q score had atypical gait pattern with smaller peak vertical ground reaction force and knee adduction moment, compared to patients with low PD-Q score. Moreover, patient with low PCS had different gait pattern in extension limitation, compared to those with high PCS. PD-Q and PCS would affect gait pattern in patients with knee OA. Level of evidence: III. End-stage knee osteoarthritis (OA) is one of major factors which negatively affect daily activities in the elderly people. Although one of main symptoms in patients with knee OA is subjective pain, radiographic findings do not always match subjective pain level , 2. TherAs knee function is difficult to assess , gait anThe purpose of the present study was to investigate and clarify the relationship between pain phenotype and gait analysis. It was hypothesized that pain phenotype would affect gait characteristics in patients with end-stage knee OA.A total of 34 knees in 34 patients , who were diagnosed as end-stage medial compartmental knee OA of at least grade 3 severities according to the Kellgren–Lawrence scale, participated in the present study. All the patients were scheduled to undergo knee replacement surgery at our university hospital based on two surgeons’ judgement (KH and YN). Surgeries were done from April 2015 to April 2017. None of the subjects had any history of major injuries to the trunk, symptomatic lumbar canal stenosis and hip osteoarthritis. Inclusion criteria was as follows; walk without cane use and read the questionnaire without any assistance. Rheumatoid arthritis, osteonecrosis, and posttraumatic arthritis were excluded from the present study. A written informed consent form approved by Institutional Review Board of our university was obtained in each subject.All the patients were evaluated based on 2011 New Knee Scoring System (KSS), PD-Q and PCS. PD-Q is a validated scale to assess neuropathic pain (NP). Scores range from 0–35, with PD-Q score ≤ 12; no NP (Low score), PD-Q score > 12; possible NP and PD-Q score ≥ 19; likely NP (Intermediate and High score) . PatientAfter a written informed consent was obtained, gait analysis was performed approximately one month before the surgery using three-dimensional motion analysis system which consisted of 8 cameras  and 2 force plates . A total of 46 retroreflective markers (14 mm in diameter) were placed on standardized bony landmarks . A power analysis was performed using G*Power . In terms of allocation based on PD-Q, effect size (d) was calculated using mean value and standard deviation of peak knee adduction moment in both groups. Thereafter, using a large effect size of 1.6 for Mann–Whitney U-test, a sample size of 4 and 10 for each group was estimated .2 for all patients. Twenty-nine patients were allocated to Group L, and five patients were to Group I & H. In addition, fourteen patients were allocated to PCS- and twenty patients were to PCS + . Age, BMI, and gender were not significantly different between groups both for PD-Q and PCS (Table Mean age was 73.2 ± 7.2 years and mean body mass index (BMI) was 24.4 ± 2.5 kg/mCS Table . For PD-P = 0.015, 95% confidence interval [0.00661–0.2509]). Besides, knee adduction moment was also significantly greater in Group L than in Group I & H , while other parameters including gait speed, step length, and stance time were not significantly different between groups , whereas other parameters were not significantly different between groups , whiThe present results supported the hypothesis that pain phenotype would affect gait pattern in patients with symptomatic end-stage knee OA. The most important finding of the present study was that patients with high PD-Q score had atypical gait pattern with smaller peak vGRF and KAM, compared to patients with low PD-Q score.Clinically, several knee scoring systems have been used to evaluate subjective pain in patients with knee OA. For instance, PD-Q has been a useful tool to evaluate a self-reported measure with the purpose of classifying patients as having either unlikely, uncertain or likely neuropathic pain components , 20. In It has been well known that larger KAM is observed in early stance phase of patients with knee OA during gait –14. BaliPCS is a self-reported scale that assesses the level of catastrophizing in the presence of pain. It contains 13 items based on a Likert-type scale from 0 to 4. Higher scores represent higher levels of catastrophizing. It is divided into three domains: rumination, magnification and helplessness. According to a previous study, a score ≥ 23 was classified as “high catastrophizing,” whereas a score < 23 was classified as “low catastrophizing” . In the Several limitations should be described in the present study. First, all subjects in this study had end-stage OA and were candidates for TKA. Therefore, this result could be applied only for the patients with severe knee OA. Second, though the gait characteristics patients with OA were shown, the postoperative outcome of those patients is still unknown. Lastly, the sample size was different between Group L and Group I & H based on PD-Q. The power analysis presented was based on mean and standard deviation obtained from the dataset presented. Post-hoc power analyses might be inappropriate to detect true differences. However, to our knowledge, this is the first study to investigate correlation between gait analysis and patient-reported questionnaire (pain phenotype) in patients with knee OA. Therefore, the results of the current study are considered to contain useful information, when considering the correlation between gait characteristics and pain phenotype in patients with knee OA.Patients with possible and likely neuropathic pain (high PD-Q) had atypical gait pattern with smaller peak vGRF and KAM, compared to patients without NP (low PD-Q). Moreover, patient with low PCS had greater knee extension limitation during mid-stance in gait, compared to those with high PCS. Therefore, PD-Q and PCS would affect gait pattern in patients with end-stage knee OA.


To compare the effect of intermittent tramadol dosing vs tramadol administration via patient-controlled pump on pain after lumbar discectomy.This randomized prospective study enrolled 100 patients who underwent elective LIV-LV lumbar discectomy in the neurosurgery department at Sestre Milosrdnice University Hospital Center from May 2016 to July 2017. Patients were randomized to receive either tramadol (600 mg daily) via a patient-controlled analgesia (PCA) pump or intermittently. Pain was evaluated by the Croatian version of Short-Form McGill Pain Questionnaire.pm on the day of discectomy. However, in the morning and evening on the first postoperative day and in the morning and evening of the second postoperative day, the PCA group had significantly lower pain .Forty percent of patients were women. The median (interquartile range) age of the patients was 51 (40-61) years. The groups did not differ in pain at 7 This is the first study that used the Short Form McGill Pain Questionnaire to compare the effect of tramadol administration via PCA pump and intermittent administration on pain after LIV-LV discectomy in a neurosurgery department. Tramadol showed a good analgesic efficacy in lumbar spine surgery; tramadol via PCA controlled pain more effectively than intermittently administered tramadol.Australian New Zealand Clinical Trials Registry: ANZCTR12618001893291. Lower back pain due to lumbar disc herniation is a common complaint. In more than two-thirds of patients, non-medical pain relief methods did not decrease pain or even increased it . Lumbar Adequate pain management in the postoperative period demands an interdisciplinary approach and is associated with better functional outcomes, early patient mobilization, early hospital discharge, and preventing chronic pain occurrence ,6. UnimoTramadol is an antinociceptive drug with low affinity for opioid receptors that achieves analgesia by combining indirect postsynaptic activation of two adrenergic receptors and opioid activity. It is administered at doses of up to 600 mg daily -13. Tramwww.medcalc.be). Since the trial investigators had no way of knowing which participant would go into which group, they could not influence the randomization. Group assignments were sealed within numbered envelopes given to nurses who administered the analgesia. Thirteen patients were excluded due repetitive side effects after administering metoclopramide (3 × 10 mg/24 hours intravenously) and/or thiethylperazine (2 × 6.5 mg/24 hours intravenously) therapy for nausea and vomiting. We did not collect the data on the number of excluded patients per group. Recruitment was continued until a target of 100 participants was reached (50 in each group)  . Tramadoh group) . During The sample size was calculated assuming an estimated postoperative difference of at least 40% more patients who do not feel pain at the end of the study in the PCA group compared with the INTER group. For the Fisher exact test with 95% of power, an alpha significance of 5%, and an equal number of patients in each group, the study required at least 41 patients per group.Pain was assessed with the Croatian version of SF-MPQ in the evening on the day of the surgery, and in the morning and evening on the first and second postoperative day. The nurses received a one-hour theoretical education on the study topic and the SF-MPQ design with each questionnaire descriptor explained. The lead researcher supervised the daily SF-MPQ use for the first month of data collection to resolve any possible difficulties.The patients signed an informed consent form for study participation. They were explained that they could withdraw their informed consent at any time during the study with no effects on their hospital treatment. The study was approved by the Ethics Committee of Sestre Milosrdnice University Hospital Center (EP-4433/15-9).p values lower than 0.05 were considered significant. The analysis was performed with StatsDirect software, version 3.0.187. .Quantitative data are presented as arithmetic means, standard deviations, and 95% confidence intervals (CI). The Fisher-Freeman-Halton exact test was used for the analysis of differences in categorical variables between the groups. Cronbach α internal consistency coefficient was higher than 0.87, indicating appropriate scale structure of the questionnaire. The test groups scores are presented as scores on each answer ranging from “I don’t feel pain” to “I feel intolerable pain”  and as aThe INTER and PCA group consisted of 50 participants each. The average hospital stay for each group was three days. In the PCA group, tramadol was administered as shown in P = 0.001) (Of the 100 patients 40% were women. Median (interquartile range) age was 51 (40-61) years. The groups did not differ in demographic characteristics. The INTER group was significantly more physically active preoperatively (= 0.001) .At the first postoperative measurement, uncomfortable pain was felt by 28% of patients from the INTER group and by 42% of patients from the PCA group. At the second measurement, uncomfortable pain was reported by 30% and 16% patients, respectively; at the third measurement by 36% and 8%, respectively; at the fourth measurement by 28% and 0% respectively; and at the fifth measurement by 15.2% and 0% patients, respectively . The PCAIn our study, on the day of the surgery, 28% of the INTER group and 42% of the PCA group felt uncomfortable pain. After the second postoperative measurement, the PCA group reported significantly lower pain values. Hadi et al  showed tIn our study, at the first postoperative measurement intermittently administered tramadol showed a superior analgesic efficacy compared with tramadol administered by a patient-controlled pump. However, at later measurements PCA group experienced better analgesic effect. This finding can be explained by the fact that a constant concentration of tramadol in plasma was achieved and the analgesic effect was maintained. The usual intermittent starting dose of tramadol is 100 mg twice a day, which, if the pain intensity does not decrease, has to be increased to 150/200 mg twice a day to a total maximum daily dose of 400 mg, and sometimes up to 600 mg. If administered intramuscularly or intravenously, the recommended dose is 50-100 mg, 4-6 times a day . In thisThis study is limited by a lack of data collection on side effects of tramadol administration. Furthermore, we did not collect the data on the number of patients per group who were excluded due to repetitive side effects after administering metoclopramide and/or thiethylperazine therapy. We observed no erroneous use of PCA by the patients or any complications associated with PCA use.This is the first study that uses the SF-MPQ to compare the effects of tramadol administration via PCA and intermittent tramadol administration on pain after LIV-LV discectomy in a neurosurgery department. Tramadol showed a good analgesic efficacy in lumbar spine surgery; PCA tramadol more effectively controlled pain than intermittent tramadol administration.


Schwannomas are tumors arising from Schwan cells of the neural sheath, which rarely occur in the gastrointestinal tract. The aim of the present study was to analyze the clinicopathological features and treatment outcomes of gastrointestinal schwannomas (GISs).Patients who were diagnosed with GISs in our hospital from January 2010 to December 2021 were selected. Data about demographic characteristics, clinical symptoms, treatment methods and outcomes, pathological results, and follow-up results were retrospectively collected and analyzed.A total of 78 patients with 79 GISs were included, the female-to-male ratio was 55:23, and the average age was 52.12 ± 12.26 years. One-third (26/78) of the patients were asymptomatic. A total of 79 GISs were removed, and the average size was 3.63 ± 2.03 cm . As for tumor location, 54 GISs were located in the stomach, 14 in the esophagus, 2 in the duodenum, 6 in the colorectum (4 in the colon and 2 in the rectum), and the other 3 in the small intestine. A total of 23 and 55 patients underwent endoscopic and surgical resections, respectively. Compared with surgical resection, endoscopic resection is associated with a smaller diameter, lower cost, and shorter hospital stay. Pathological results revealed that S100 was positive in all the GISs. No recurrence was noticed during a median follow-up of 45 months .GISs are rare gastrointestinal tumors with favorable prognoses, which are most commonly seen in the stomach and diagnosed by pathological findings with immunohistochemical staining. Surgical resection remains the standard method for removing GISs, while endoscopic resection may serve as an alternative method for selected patients with GISs and may be attempted in GISs with a diameter of <3 cm and no signs of malignancy. With the wide application of esophagogastroduodenoscopy, colonoscopy, and endoscopic ultrasonography (EUS), the detection rate of gastrointestinal submucosal tumors (SMTs) has increased obviously . GastroiRemoval of the tumor is recommended for symptomatic and large gastrointestinal SMTs (≥2 cm), and periodic surveillance is suggested for asymptomatic and small ones (<2 cm) . HoweverCurrently, most of the studies focused on gastric schwannomas, and few studies reported the GISs in the whole gastrointestinal tract , 19, andThis is a retrospective study conducted in a tertiary hospital in China and was approved by the ethics committee of the Second Xiangya Hospital of Central South University. All the patients or legal guardians provided signed informed consent before the procedure was performed. The inclusion criteria of the study were as follows: 1) GIS confirmed by postoperative histological and IHC results, 2) patients who underwent endoscopic or surgical resection at our hospital, and 3) complete medical records. Exclusion criteria were as follows: 1) patients who were diagnosed with GIS preoperatively but did not receive endoscopic or surgical resection; 2) patients who underwent endoscopic or surgical resection at other hospitals but sent the specimen to our hospital for a confirmed diagnosis. Their demographics (age and gender), tumor-related parameters , treatment methods, complications, hospital stay, and follow-up data were retrospectively collected and recorded.Telephone calls and outpatient interviews were used for follow-up. CT or endoscopy was performed every 6 months during the first year and annually thereafter.SPSS 25.0 software  was applied for data analysis. Continuous variables were presented as mean ± standard deviation and analyzed using Student’s t-test. Qualitative data were presented as frequencies and calculated using the chi-square test or Fisher’s exact test. A two-tailed p-value of <00.05 was considered statistically significant in all cases.From January 2010 to December 2021, a total of 88 patients were diagnosed with GIS in the pathological database of our hospital, among whom four patients confirmed the diagnosis of GIS by biopsy but refused to have the lesions removed, and six patients underwent surgical resection at other hospitals and sent the specimen to our hospital for a confirmed diagnosis. Therefore, a total of 78 patients were included. Within the same period, a total of 2,104 patients with gastrointestinal SMTs  were treated in our hospital; therefore, GISs account for 3.71% of all the gastrointestinal SMTs.Among the 78 patients, 55 were female and 23 were male. The average age was 52.12 ± 12.26 years . A total of 79 GISs were removed, and the average size was 3.63 ± 2.03 cm . As for tumor location, 14 were in the esophagus Figure 1A total of 48 patients had comorbidities, 5 of them had coexisting tumors , and 10 had coexisting gastrointestinal polyps. A total of 52 patients had symptoms, and the most common symptoms were abdominal pain (29/78). A total of 26 patients were asymptomatic, and their GISs were found accidentally by endoscopy or CT examination. A total of 70 and 5 patients underwent esophagogastroduodenoscopy and colonoscopy preoperatively, respectively, and only 2 patients with gastric schwannomas showed ulceration in the covering mucosa, while the others showed intact mucosa. A total of 38 patients underwent EUS examination preoperatively, and echo analysis revealed that 36 of them were low echoes (14 were homogeneous and 22 were heterogeneous), and 2 were medium-high echoes. A total of 62 patients received CT examination preoperatively, among whom 28 showed homogeneous tumors; 16 patients showed heterogeneous, slow, and progressive enhancement; and 3 patients showed strong enhancement. However, others did not describe such information or received a non-contrast CT examination. Only one patient showed necrosis on CT scans. As for the growth pattern, 49 of the 79 GISs were intraluminal growth, 18 were extraluminal, and the remaining 12 were mixed.via pathological and IHC staining. A total of 77 GISs from 76 patients were diagnosed with benign GISs, and only 2 patients were considered malignant. S100 staining was positive in all the patients, while SOX-10, Vimentin, Dog-1, CD34, SMA, and CD117 were positive in 97.2% (35/36), 100% (32/32), 0% (0/68), 24.2% (18/74), 17.9% (14/78), and 6.4% (5/78), respectively. Ki-67 was performed in 70 patients and was positive in 63 patients, the index was 1%–10% in most of the patients (61/63), and only the 2 patients diagnosed with malignant GIS had a Ki-67 index of >10%.All the patients confirmed the diagnosis of GISs postoperatively esophagomediastinal fistula; no patient died of these complications. During a median follow-up of 45 months , no recurrence was noticed. Two patients died during follow-up, and GIS was not the cause of death (one died from pancreatic cancer and the other from coronary heart disease).A total of 23 and 55 patients underwent endoscopic resection and surgical resection, respectively. A total of 79 GISs were removed, and 74 were in the muscularis propria layer and 5 in the submucosal layer. Among the 23 patients who received endoscopic resection, 4 underwent endoscopic mucosal resection, 6 endoscopic submucosal dissections, 4 endoscopic submucosal excavation, 4 endoscopic full-thickness resections, and 5 submucosal tunneling endoscopic resection. Of the 55 patients who received surgical resection, 20, 24, 7, 2, 1, and 1 received laparoscopic, open, robot-assisted, thoracoscopic, laparoscopic, and endoscopic cooperative surgery and transanal endoscopic microsurgery, respectively. Compared with patients who underwent surgical resection, patients who underwent endoscopic resection had a small tumor size (1.87 ± 1.36 vs. 4.38 ± 1.82 cm) but a lower cost  and shorter postoperative stay (7.48 ± 5.29 vs. 10.25 ± 4.46 days) Table 2.In the present study, we summarized the clinical data of 78 cases of GISs and demonstrated that GISs are rare gastrointestinal tumors and most commonly seen in the stomach. Both endoscopic and surgical resections are acceptable for selected patients with favorable prognoses. As far as we know, this is the largest single-center report about GISs until now.GISs are rare gastrointestinal mesenchymal tumors and account for about 2%–6% of all gastrointestinal mesenchymal tumors . GISs arGastrointestinal endoscopy, EUS, and CT were useful for the detection of GISs and differentiating GISs from other gastrointestinal SMTs. Usually, the covering mucosa of GISs are smooth and intact; erosion or even ulceration was reported in few patients 0%–26.92%) , 22, 27..92% , 22Confirmed diagnosis of GISs depends on pathological findings with IHC results. S100 is a specific marker for GISs with a positive expression rate of 97.6%–100%. Other occasionally positive markers reported included Vimentin, CD34, and SOX10 , 22. No via endoscopic resection (The treatment strategy of GISs is based on the size, location, and association with surrounding tissues; available treatment modalities include endoscopic resection and surgical resection . Currentesection , 33. Sevesection , 34–37. esection  retrospeThe present study has several limitations. First, this is a single-center, retrospective study. Second, only a portion of the patients received preoperative CT and/or EUS examination. Third, the IHC staining parameters were not exactly the same among patients; therefore, it is difficult to provide an exact positive proportion for some indicators. In conclusion, we found that GISs are rare gastrointestinal tumors with favorable prognoses and are most commonly seen in the stomach. Surgical resection is the standard method for removing GISs, while endoscopic resection may serve as an alternative method for selected patients with small GISs ≤3 cm.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the ethics committee of the Second Xiangya Hospital of Central South University. The patients/participants provided their written informed consent to participate in this study.Research design: HP, LH, HZ. Administrative support and organization: DL. Data collection and analysis: HP, LH, YT, YC and LL. Manuscript drafting: HP, YT and HZ. Modification and final approval: All authors. All authors contributed to the article and approved the submitted version.


Reducing injection-site pain (ISP) in patients with chronic conditions such as growth hormone deficiency is a valuable strategy to improve patient compliance and therapeutic efficiency. Thus understanding different aspects of pain induction following subcutaneous injection of biotherapeutics and identifying the responsible factors are vital. Here we have discussed the effects of formulation’s viscosity, concentration, osmolality, buffering agents, pH, and temperature as well as injection volume, dosing frequency, and different excipients on ISP following subcutaneous injection of commercially available recombinant human growth hormone products. Our literature review found limited available data on the effects of different components of parenteral rhGH products on ISP. This may be due to high cost associated with conducting various clinical trials to assess each excipient in the formulation or to determine the complex interactions of different components and its impact on ISP. Recently, conducting molecular dynamics simulation studies before formulation design has been recommended as an alternative and less-expensive approach. On the other hand, the observed inconsistencies in the available data is mainly due to different pain measurement approaches used in each study. Moreover, it is difficult to translate data obtained from animal studies to human subjects. Despite all these limitations, our investigation showed that components of parenteral rhGH products can significantly contribute to ISP. We suggest further investigation is required for development of long acting, buffer-free, preservative-free formulations. Besides, various excipients are currently being investigated for reducing ISP which can be used as alternatives for common buffers, surfactants or preservatives in designing future rhGH formulations. BioRender.com”.“Created with  Since then, rhGH has been the focus of interest for biotech and pharmaceutical companies, and several rhGH-based biopharmaceuticals have been introduced for the management of different disorders (Between 1963 and 1985 nearly 35000 children with growth hormone deficiency (GHD) received hGH extracted from the cadaver’s pituitary gland , and larisorders Table 1.Growth hormone deficiency involves children and adults and can be congenital  or acquired . Recombinant growth hormone replacement therapy is a routine treatment for children and adults with GHD. Due to the short plasma half-life of hGH (0.36 and 3-4 hours after subcutaneous (SC) and intravenous (IV) injections), frequent injections are necessary . Once GHvia improving patient adherence. The ideal parenteral rhGH preparation should remain stable and effective during product manufacturing and storage, induce no adverse effects or immune responses, and induce minimum pain and discomfort upon injection while being easy to use. To meet this need, different injectable formulations, delivery systems, injection devices, and routes of administration have been introduced in the last few years.Although the duration of treatment is still under debate, the treatment usually lasts for several years. Due to the chronic nature of the condition, there is a strong demand for novel formulations with higher stability, more straightforward application, and enhanced patient convenience to improve therapeutic effectiveness The current review discusses the effect of parenteral rhGH formulations’ characteristics on their therapeutic efficacy regarding patient adherence . Here we have discussed the effects of formulation’s viscosity, concentration, osmolality, buffering agents, pH, and temperature as well as injection volume, dosing frequency, and different excipients on ISP following subcutaneous injection of commercially available rhGH products.According to the International Association for the Study of Pain (IASP) definition, pain is an unpleasant experience with physiological or psychological routes, accompanying or resembling tissue damage . Due to ISP can be affected by the characteristics of the formulation or the injection device. Needle size, length, and the angle of injection are the mechanical features of injection devices determining the degree of ISP in SC injection. Different self-injecting needle pens and needle-free devices have been developed for more straightforward injection, accurate dosing, electronic monitoring, and injection pain reduction –48.Parenteral rhGH formulations are carefully designed preparations containing different excipients such as buffering agents , tonicity adjusting excipients (mannitol and sodium chloride), bulking agents , surfactants (polysorbate 20 and poloxamer 188) and preservatives . These excipients are necessary to provide stability and maintain hGH functionality during manufacturing and storage and prevent microbial contamination. ISP can be affected by various formulation features, including concentration, osmolality, viscosity, pH, injection volume, preservatives, and buffers . In the via injection. As for hGH therapy, it has been shown that patient non-adherence varies from 5 to 82%  reaches its peak plasma concentration (Tmax) at 2 and 4 hours and returns to its baseline after 9 and 18 hours following IM and SC injections, respectively (The SC route is preferred to intramuscular (IM) injection for biopharmaceuticals by both patients and physicians due to lower pain, the possibility of at home-administration, and lower cost burden for patients who need to meet their physicians regularly and receive their hGH injections in medical facilities, all of which favor patient convenience . No diffectively , 58. Accectively .max), Tmax, and antibody responses were similar for SC and IM injections of hGH (0.03 mg/kg/day) in children with GHD. In contrast, SC injection yielded a larger integrated hGH concentration. Patient acceptance and compliance were also significantly higher for SC injection since it was less painful. Their results concluded that the SC route is safe, efficient, and well accepted by the patients for hGH administration  before injection implies a significant negative impact on patient compliance. In their research, the solution form (Norditropin® SimpleXx®) was preferred to the powder form due to its easier application. Their results suggest that the level of necessary reconstitution before use should be considered in the development of the formulations for improving compliance (The frequency of injections and necessary preparation steps before injection can significantly influence patients’ compliance . For exampliance .® SimpleXx®) was preferred by 85% of the patients to the freeze-dried powder form due to improved handling. Assessment of pain perception at the injection site showed that 35% of patients found the liquid form less painful, and 59% reported similar pain intensity as the powder form. For 6% of patients, the liquid form was more painful  was evaluated in 109 pediatric patients with GHD in an open-label, randomized, multicenter, cross-over study for one month . AccordiProtein solution viscosity is an important consideration in developing liquid biopharmaceutical formulations. Injectable formulations with high viscosity often face issues of low protein stability and poor flow features. Various features of the protein including shape, size, charge distribution, concentration, and association kinetics are involved in determining the viscosity of the solution. On the other hand, these molecular features are affected by solution conditions such as temperature, ionic strength, additives, and pH . FurtherThe role of viscosity in ISP and its possible underlying mechanism have not been thoroughly investigated. However, Schwarzenbach et al. showed that the solution’s viscosity had a significant effect on ISP. Subcutaneous injection of solutions with low (1 cP) and medium viscosity (8-10 cP) were found to be more painful compared to highly viscose (15-20 cP) solutions . Their rViscosity-reducing gents such as NaCl and amino acids are commonly added to formulations as tonicity adjusting agents to reduce ISP since injection of hyper- or hypotonic parenteral formulations can induce cell shrinkage or swelling leading to increased pain . HoweverHigher injection volumes are associated with higher ISP and the maximum volume of 2 mL per dose is recommended (1.5 mL is common). In this regard, it has been shown that SC injection of smaller volumes of rhGH preparations is less painful and improves patient convenience –91. In aOne approach to reducing the injection volume is to increase hGH concentration. However, as mentioned previously, highly concentrated hGH formulations have higher viscosity and thus a higher risk of aggregate or insoluble particulate formation, compromising product stability and safety. This finding suggests the confounding effect of protein concentration and formulation’s viscosity on ISP. Hansen and colleagues studied the effect of hGH concentration and injection volume on ISP and concluded that hGH concentration was directly associated with pain perception following SC injection. They observed that injection of 3 mg/300 µL of hGH solution was more painful compared to 1 mg/300 µL solution. Consistent with previous studies, they observed that increasing the injection volume from 300 to 600 µL while maintaining hGH concentration (2 mg) caused more pain .The injection volume is determined based on product concentration and dosing regimen. Daily hGH dosing is highly patient-specific  and can be determined according to weight-based or non-weight-based strategies. For example, The recommended daily dose for treatment of GHD, according to patient’s age and non-weigh-based approach, is as follows; 0.4-0.5 mg/day for patients ≤ 30 years old, 0.25 mg/day for patients between 30 and 60 years old and 0.15 mg/day for patients≥60 . Hence tLow stability and relatively short plasma half-life of rhGH demand frequent injections . In addim-Cresol, and benzyl alcohol are the most commonly used preservatives in multi-dose rhGH products.Parenteral rhGH products are available as single- or multi-dose preparations. The single-dose formulations are used for a single injection in a single patient. Due to the disposable nature of these preparations, they usually do not contain antimicrobial preservatives. On the other hand, multi-dose vials or cartridges can be used more than once and require additional preservatives to prevent microbial contamination after the first use. Antimicrobial preservatives have been associated with ISP in parenteral biopharmaceuticals, including rhGH products. Phenol, m-Cresol was associated with higher local pain compared to 0.9% benzyl alcohol (m-Cresol (0.25%), or benzyl alcohol (0.9%)+glycerol (0.1%). Based on their results, the m-Cresol injection was more painful compared to benzyl alcohol, while no significant difference was observed between injection of 0.9% and 1.5% benzyl alcohol preparations   . Similar as well . Anotherectively . Based o®. According to their results, SC injection of benzyl alcohol-containing multi-dose formulation was less painful compared to the benzyl alcohol-free single-dose form  . InjectiThe ideal rhGH formulation should be prepared with near physiological pH . However2+ can prevent pain induction in citrate-buffered preparations  1.36 mg L-histidine, 6 mg Phenol with pH=6.15, B), 10 mM Na-Citrate, 5 mg Phenol with pH=6 and C) 0.9% normal saline, 9.0 mg benzyl alcohol with pH=8.3. They observed that the citrate-buffered formulation induced higher ISP, while the histidine-buffered formulation did not imply more pain compared to normal saline. They suggested that histidine is superior to citrate in reducing the ISP of rhGH injection  to the formulation will increase pain due to radical pH changes within the SC tissue following injection . Accordinjection . Meanwhinjection . It shouIn addition, citrate concentration has been directly associated with the severity of injection pain. Shi and colleagues showed that SC injection of 20 mM citrate solution was more painful compared to 5 and 10 mM solutions . They alAs presented in + concentration at the injection site. These sustained protons can induce pain via activating ASICs and transient receptor potential ion channels, which is in line with the results reported by Yang et al.  and Aquafol™ . They also observed that the injection of P188-containing micro-emulsified formulation was more painful  and poloxamer 188 (P188 or pluronic F68) are commonly used non-ionic surfactants in parenteral hGH products. Despite their protective role, both PS20 and P188 are susceptible to auto-oxidation producing reactive species that can induce protein degradation or injection-site reactions (ISR), including injection-site pain. Singh and colleagues suggested that PSs’ degradation in biopharmaceutical preparations can be responsible for ISRs following the administration of biologics. They suggested that using high-quality raw materials and optimizing shipping and storage conditions can minimize PSs-induced ISR . Jewell  painful . It has  painful .via activating stretch receptors  solutions is attributed to its antioxidant activity –135. In Warming parenteral solutions before infusion is a well-known strategy for reducing injection pain as the infusion of preparations with room temperature (20-25°C) have been less painful . The ratDespite recent advances in the field of formulation development, limited or conflicting data are available in the literature on the effect of formulation components on ISP. In addition, the mechanisms by which each of the formulation components may contribute to injection pain remains elusive. Another issue arises from the fact that a large number of reports regarding injection pain are conducted on animals which makes it difficult to translate these findings to human subjects. Another problem with the existing studies that may in part explain their inconsistent results is using different approaches for quantifying and assessment of pain in tested subjects. The lack of comprehensive studies regarding the impact of different formulation variables on ISP may be due to the high cost associated with conducting various clinical trials for pharmaceutical companies and the difficulty in studying the complicated interdependent interactions of these formulation parameters on ISP and identifying the exact mechanism by which they affect injection pain.This review aimed to explore the effect of different formulation variables on ISP in GHD patients. Our investigation suggests that complex interactions between the formulation variables should be considered in addition to the individual contribution of each variable in ISP. In some cases, such as protein concentration, formulation’s viscosity, and injection volume confounding effects were observed which require further investigation. In addition, we found no report in the literature on the effect of growth hormone concentration and formulation’s osmolality on ISP in parenteral rhGH products.Formulation components in injectable preparations should be selected cautiously. For example, incompatibility between surfactants and other excipients in the formulation might promote surfactants’ degradation leading to increased ISP. In addition, using high-quality excipients with no residual contamination can inhibit protein and excipients degradation as well as subsequent ISR including injection pain. Using molecular dynamics simulation before formulation design has been suggested in a recent study for easier assessment of the interactions between different formulation components . More reBased on the literature data presented in this review, we suggest the following considerations in designing future hGH parenteral formulations with decreased ISP; First of all, The confounding effect of protein concentration and viscosity needs further investigation. Regarding the formulation’s tonicity, isotonic rhGH preparations with 300 mOsm/Kg are preferred . FormulaLiquid preparations are preferred to lyophilized powder forms due to lower ISP and easier preparation steps before injection , 77–81. 2+ ions or ASIC1 inhibitors in the formulation may negate the impact of citrate on ISP (The product’s pH should be set close to 7.4 to decrease ISP , 119–121e on ISP .m-cresol in multi-dose preparations is advised (Regarding antimicrobial preservatives, avoiding the use of  advised , 104–106 advised –110.High-quality and highly pure surfactants can reduce injection pain . Using aBT: conceptualization, writing-original draft, investigation. MJ: conceptualization, supervision. NZ: writing-review and editing, supervision. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The aims of this study were to investigate otolith dysfunction, especially isolated otolith dysfunction  in persistent postural-perceptual dizziness (PPPD) patients. Twenty-one patients who had been diagnosed with PPPD were enrolled in this study. The subjects filled out questionnaires [the Dizziness Handicap Inventory (DHI) and the Niigata PPPD Questionnaire (NPQ)] and underwent vestibular evoked myogenic potential (VEMP) tests, video head-impulse tests (vHIT), and stabilometry. Among the 21 subjects with PPPD, 9 showed isolated otolith dysfunction, 4 exhibited both otolith dysfunction and semicircular canal dysfunction, and 2 demonstrated isolated semicircular canal dysfunction. Six subjects exhibited normal VEMP and vHIT results. Concerning the subjects' questionnaire scores and stabilometric parameters, there were no significant differences among subgroups when the subjects were classified according to their VEMP and vHIT results while stabilometric parameters obtained in PPPD subjects were significantly increased than published data of healthy subjects. As precipitating conditions for PPPD, vestibular neuritis was the most frequent and the second most was idiopathic otolithic vertigo. In conclusion, the majority of PPPD patients had otolith dysfunction, and most of them showed isolated otolith dysfunction. Idiopathic otolithic vertigo can be a precipitating factor of PPPD. While otolith dysfunction may be associated with initiation of PPPD symptoms, PPPD symptoms are also considered to be associated with other dysfunctions of the sensory processing system. Persistent postural-perceptual dizziness (PPPD) is characterized by chronic dizziness and/or non-spinning vertigo, mainly in the upright position during standing or walking . PPPD isHerein, we studied peripheral vestibular dysfunction in patients that had been diagnosed with PPPD using VEMP testing and the video head impulse test (vHIT), which is a clinical test of the semicircular canal, which senses angular acceleration , 10.Twenty-one patients  that had been diagnosed with PPPD according to the diagnostic criteria outlined by the Barany Society  testing, vHIT testing, and stabilometry , 12, 13.Electromyographic (EMG) signals were recorded using surface electrodes placed on the upper half of each sternocleidomastoid muscle (SCM) (active), with a reference electrode placed on the lateral end of the upper sternum. While in the supine position, the subjects were asked to raise their heads to contract the SCM. The EMG signals were amplified and bandpass-filtered  using the Neuropack system . Short tone bursts  were used for stimulation at a repetition rate of 5 Hz. The analyzed period was 100 ms long (20 ms before and 80 ms after the stimulus). The rectified EMG signals obtained during the pre-stimulation period were used to assess background muscle activity , 17.The amplitude of p13-n23 (the first positive-negative deflection) and the latency of p13 were analyzed. The normalized amplitude (NA) was calculated as the p13-n23 amplitude divided by background muscle activity. Background muscle activity was calculated using rectified EMG signals obtained during the pre-stimulation period (−20 to 0 ms). Asymmetry ratios (AR) for the cVEMP were calculated as follows: AR = 100 × (NAl – NAs)/(NAl + NAs), where NAl represents the NA on the larger response side, and NAs represents the NA on the smaller response side. The upper limit of normal for the AR was set at 41.6 . The uppEMG signals were recorded using surface electrodes placed 1 cm below the center of each lower eyelid (active) and 2 cm below the active electrode (reference). During recordings, the subjects were instructed to maintain an upward gaze. Bone-conducted stimulation  was presented using a 4810 mini-shaker  placed on the Fz position at a repetition rate of 5 Hz. The peak driving voltage was adjusted to 8.0 V, which produced a peak force level of 128 dB (re: 1 μN). The signals were amplified and bandpass-filtered  using the Neuropack system. The raw amplitude of N1-P1 (the first negative–positive deflection) was analyzed. The upper limits of normal for the AR and N1 latency were set at 27.3 (AR) and 11.7 ms (N1 latency) .The Eye-See-Cam system  was used for the vHIT. The patients were subjected to passive high-acceleration, low-amplitude head rotations in the planes of the lateral, right anterior-left posterior, and left anterior-right posterior semicircular canals , 10, 18.We used the Gravicorder GW-31  for the stabilometric recordings. It contains vertical force transducers, which can be used to measure instantaneous fluctuations in the center of pressure (COP). The stabilometric measurements were performed in both eyes-open and eyes-closed conditions for 60 s each. The positions of the subjects' feet and arms during the recordings were based on the standard Japanese methods . The subThe outcome measures were the total length of sway of the COP over 60 s while the subjects had their eyes open or closed  and the enveloped area traced by the sway of the COP over 60 s while the subjects had their eyes open or closed .We used the DHI and NPQ for assessing subjective symptoms. The original DHI was developed by Jacobson and Newman  to assest-test was used. P-values of <0.05 were regarded as statistically significant.For comparisons among the patients, the Kruskal-Wallis test was used. For comparisons between the patients in this study and the published data for healthy subjects, the We obtained informed consent from each participant. This study was approved by the ethics committee of Teikyo University (TR20-078).Among the 21 subjects, 9 (42.8%) showed isolated otolith dysfunction . Four suAmong the 9 subjects with isolated otolith dysfunction, 2 exhibited bilateral abnormal responses, while 7 exhibited unilateral abnormal responses. Three of the 9 subjects with isolated otolith dysfunction showed both abnormal cVEMP and oVEMP responses. In 4 subjects, normal cVEMP were seen, but oVEMP were absent. On the other hand, in 2 subjects cVEMP were abnormal, but normal oVEMP were observed.N = 7, 33.3%). The second most was idiopathic otolithic vertigo (OV) . The diagnosis of OV was done according to symptoms in diagnostic criteria proposed by Sue et al. (Precipitating conditions for PPPD are summarized in ) N = 4, .0%. The p > 0.05 Kruskal-Wallis test). The PPPD patient group (N = 21) showed significantly larger values of the examined stabilometric parameters than the 55–59-year-old healthy group (t-test p < 0.01) (Comparisons of the outcome measures are shown in  < 0.01) .PPPD is characterized by chronic dizziness and/or non-spinning vertigo, mainly in the upright position during standing or walking . PPPD isMurofushi et al. reported episodic non-spinning vertigo with dysfunction of the otolith organ , 3. MuroThe present study showed that 13 of the 21 PPPD patients (61.9%) had otolith dysfunction. Among these 13 patients, 9 had isolated otolith dysfunction. Otolith dysfunction seems to be one of the causes of PPPD. In this study, OV was the second most condition precipitating for PPPD while the most was VN. Because both VN and OV should include acute otolith dysfunction, otolith dysfunction seems to contribute to the initiation of PPPD symptoms. However, there were no significant differences in stabilometric findings or questionnaire scores between isolated otolith dysfunction type and other subtypes of PPPD based on which vestibular end-organ was damaged at the time of PPPD. These findings suggest that the continuation of PPPD symptoms, such as floating dizziness during walking, might also require dysfunction of other areas of the sensory processing system than the peripheral vestibular system.Yagi et al. reported that three clusters of PPPD patients were revealed: the visual dominant subtype, active-motion dominant subtype, and mixed subtype . The visThe main limitation of this study is that the size is small. Large-sized study should be performed in the future. Furthermore, while this study showed that OV could be a precipitating factor of PPPD, there is still remained to be clarified how often OV will proceed to PPPD. In this cross-sectional study, symptoms and sway measured with stabilometry do not differ between subjects with isolated otolithic abnormalities and others. In order to determine if otolithic abnormalities affect the prognosis of patients with PPPD a follow up study is required. Thirdly, precipitating factors of PPPD might be biased by the department or institute where patients were seen. While Waterston reported that anxiety was the most as a precipitating factor and the second most was vestibular migraine , in the In conclusion, the majority of our PPPD patients had otolith dysfunction, and many of them showed isolated otolith dysfunction with preserved semicircular canal function. While otolith dysfunction may be associated with initiation of PPPD symptoms, persistence of symptoms might also require dysfunction of other areas of the sensory processing system than the peripheral vestibular system.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by Teikyo University Ethics Committee. The patients/participants provided their written informed consent to participate in this study.TM wrote the manuscript. KN and MT reviewed and edited the manuscript. All authors contributed extensively to the work presented in this article and collected data.This study was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (19K09856).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.