Ten healthy control volunteers and fourteen patients with neuropathic CLBP due to lumbar disc herniation underwent cerebral SPECT scans. A quantitative comparison of rCBF findings between patients and controls was made using the Statistical Parametric Mapping (SPM), revealing clusters of voxels with a significant increase or decrease in rCBF. The intensity of CLBP was assessed by NRS and by DN4. RESULTS: The results demonstrated an rCBF increase in clusters A  and B  and a decrease in cluster C . NRS scores were inversely and moderately correlated with the intensity of rCBF increase in cluster B, but not to rCBF changes in clusters A and C. DN4 scores did not correlate with rCBF changes in all three clusters. CONCLUSIONS: This study will be important for future therapeutic studies that aim to validate the association of rCBF findings with the pharmacokinetic and pharmacodynamic profiles of therapeutic challenges in pain.Recent neuroimaging studies have demonstrated pathological mechanisms related to cerebral neuroplasticity in chronic low back pain (CLBP). Few studies have compared cerebral changes between patients with and without pain in the absence of an experimentally induced stimulus. We investigated the neurobiological substrates associated with chronic low back pain using [ Chronic low back pain (CLBP) is a common neurological disorder in the lumbosacral segment and persists over 12 weeks after its onset. CLBP affects about 10–20% of patients who do not present pain resolution  and douleur neuropathique en 4 questions (DN4).This study aimed to investigate the neurobiological substrates associated with chronic low back pain using Tc-ECD (ethyl cysteinate dimer) was injected at a maximum dose of 1,295 MBq (35 mCi). SPECT was performed during resting state, with eyes open, in a quiet and darkroom, refrained from talking and listening.All patients underwent cerebral SPECT scans, and the tracer Tc-ECD brain SPECT in a small sample of 14 patients. The results revealed significant rCBF increase in the right prefrontal and dorsolateral frontal, occipital, and posterior cingulate areas, and rCBF decrease in the superior parietal lobe and middle cingulate cortex in patients with CLBP. These findings highlight the contribution of the perfusion SPECT in the identification of brain areas involved in chronic pain and may contribute to future therapeutic challenges in patients with CLBP, similar to previous studies in Fibromyalgia  covers the anterior portion of the frontal lobe and deserves attention in pain processing. The medial prefrontal cortex (mPFC) is involved in two opposite roles, mediating antinociceptive effects and becoming chronic the pain . fMRI studies with CLBP patients showed rest activation in the mPFC and cingulate cortex (DMN) . The mPFC has been extensively studied in pharmacological and psychosocial pain management such as the use of antidepressants, acupuncture, cognitive behavioral therapy, meditation, music therapy, physical exercise, prayer, and others  . A study showed the good performance of DN4 in screening for various neuropathic pain syndromes. However, sensitivity varies by the syndrome. A positive DN4 was associated with greater pain catastrophizing, disability, and anxiety/depression, which may be explained by the severity of the disease  of pain was inversely and moderately correlated with the intensity of rCBF increase in the right frontal lobe, and no correlation was observed between rCBF changes and In summary, neuroimaging studies involving the evaluation of neuropathic pain show heterogeneous patterns of brain activation. Etiology of pain, lesion topography, symptoms, and stimulation procedures for activation neuroimaging studies are possible sources of heterogeneity (Watanabe et al. Similarly to CLBP patients, patients with fibromyalgia present changes in perfusion SPECT (Kwiatek et al. Particularly, and compared to responders to gabapentin, poor responders with fibromyalgia exhibited hyperperfusion in several brain and cerebellar regions, including frontal and cingulate cortices, with high positive likelihood ratios (Usui et al. The present preliminary study contributes to the investigation of the neurobiological substrates of chronic lumbar back pain. Knowing the brain systems involved in CLBP and the functional activation and deactivation of these structures during the pain may represent the background for future pharmacokinetics and pharmacodynamic modeling studies. A limitation is the small sample of patients and healthy controls undergoing the study. However, the quantitative SPM technique offered sophisticated analysis tools that dispensed large samples, avoiding unnecessary exposure of patients to radiation. The group of participants with CLBP had a slightly older mean age than the control group.


Spondylodiscitis is a rare illness and serious complication of the vertebral column. The suitable type of surgery is debatable for these patients. This study describes a series of cases that are treated with modified interbody fusion for the treatment of spondylodiscitis by combining allograft and autograft bone chips with posterior segmental fusion.This was a retrospective study. The clinical deficit was evaluated with ASIA, VAS, and JOABPEQ scores before and after surgery. Radiological parameters were assessed with local kyphosis angle (degree), segmental height correction, and loss of correction. Post-operative bone union was evaluated as suggested by Tan et al. The mean age of patients (n=34) was 52.3(SD=13.6) years and 67.6% were males. The mean follow-up duration was 25.8 (2.3) months. In the last follow-up, VAS back pain 4.9(0.77), VAS leg pain 4.6(0.78), JOABPEQ low back pain 68.1 (9.3), JOABPEQ lumbar function 81.3 (8.9), and JOABPEQ walking ability 72.8 (8.3) shows a significant difference when compared with preoperative scores. According to ASIA grading, none of the patients deteriorated neurologically . The average segmental height correction and loss of correction were observed 7.5(3.7) % and -1.8(3.6) %, respectively, indicating improvements in the patients. A high union fusion rate (82.4%) was observed in the last follow-up.This modified method can be a safe and effective technique for surgical intervention in patients with spondylodiscitis. Spondylodiscitis is a condition that involves the intervertebral disc space and adjacent vertebrae by infective process . It is aEthical approval was obtained from the Research Ethics Committee of the Isfahan University of Medical Sciences (ref nr: IR.MUI.MED.REC.1400.567).This was a retrospective study. It was conducted on 34 patients with spondylodiscitis who had undergone posterior lumbar/thoracic interbody fusion using compressive bone graft with the combination of autograft and allograft bone chips at a single medical center from December 2018 to October 2021. All surgeries were performed by a single surgeon. Data were collected through a review of patient records and relevant imaging. The diagnosis was according to clinical findings, radiological imaging, and laboratory results  bone chips were impregnated with one gram of vancomycin powder. After mild distraction, it was inserted in the interbody space and impacted under the intraoperative neuromonitoring recording. Then compression was applied to increase bone-bone interface and further correction of spinal alignment. After fixation of rods and posterolateral fusion, the wound was closed in the traditional layer manner.Measures: (I) Clinical outcomes were evaluated by visual analogue scale (VAS) (le (VAS)  for backle (VAS)  for neurle (VAS) . The JOAle (VAS) , was catClinical and radiographic  investigations were conducted preoperatively, early postoperatively, and late postoperatively (last follow- up). Statistical analysis of the data was performed using PASW Version 18 . For continuous values, the mean was considered to derive the central tendency of the data. Comparison of ASIA scales before surgery and the final follow-up were assessed by χ2 test. Grouped values were evaluated using a Pearson chi-square test; values of ≤ 0.05 were considered significant.Ethics: The Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran, approved the study.Characteristics of patients are shown in Regarding pain and functional improvement, the average change in VAS score and JOABPEQ subscales scores shows a significant difference when compared with preoperative scores . According to the ASIA scale criteria, 16 (47.1%) patients and 14 (41.2%) patients had Grade D and Grade E, respectively . No caseTo our knowledge, we reported the first case series of patients with spondylodiscitis undergoing allograft and autograft combination bone chips interbody fusion with the posterior approach. This is a good technique to obtain spine pain relief, improve functional outcomes, and have good bone union with low complication rates.The average change in VAS score for back pain was 4.9, while that for leg pain was 5.1. Our study results are comparable with the results of Zhao et al. , which mPee et al. , was preSpine infection normally affects the anterior vertebral elements, and an anterior surgical technique is recommended to debride the infected material. However, anterior spinal surgery is limited by the perceived seriousness of the potential complications, in particular major vascular injury. The posterior approach is recommended, as this has more advantages compared to the anterior approach, and faster fusion attained with posterior instrumentation . In thisThe current study had some limitations. First, the low sample of patients should be addressed in further studies. Second, a new technique may or may not be better than an existing one and a clinical trial is can be performed to find the best technique. Third, due to biomechanical problems, this method is not considered for patients with more than 40% vertebral body height involvement. Other surgical methods such as titanium or mesh cages can be recommended. However, strengths of the study include a long-term follow-up study was presented of 34 cases with spondylodiscitis undergoing interbody fusion surgery. Additionally, titanium cages as PEEK cages are expensive compared to this method. Finally, our experience demonstrates that this method can significantly improve clinical outcomes.This study shows that this technique can result in a successful bone union of the spine, improved pain assessment, and neurological outcomes in patients with spondylodiscitis. Future prospective randomized controlled trials are required to further evaluate this method using surgical and patient-reported tools.


Background: We aimed to prospectively assess the role of needle length in improving the tolerability/safety profile of OnabotulinumtoxinA (BoNTA) for chronic migraine (CM) prophylaxis, with a specific focus on neck pain, based on patients’ body habitus and other variables. Methods: BoNTA was administered quarterly for two consecutive cycles, using the standard 0.5-inch 27 G needle at all pre-defined PREEMPT injection sites, except the left-hand side trapezius and paraspinal muscles, which were injected using longer needles of 1-inch 23 G at first and 1-inch 27 G at second infusion. Participants were interviewed at day 14 following each session for evidence of neck pain. The predictive significance of Body Mass Index (BMI) and other variables with neck pain was also examined. Results: A total of 100 consecutive CM patients were evaluated, and each patient served as her/his self-control. The incidence, duration and intensity of neck pain did not significantly differ using either 1-inch needle compared with standard 0.5-inch 27 G needle, although the incidence and characteristics of neck pain with the use of longer needles appeared slightly higher and more intense. The BMI index and other tested variables remained unrelated to neck pain. Conclusions: We were not able to identify significant differences or correlations in the incidence, characteristics and location of neck pain with the use of different needle length to inject BoNTA, although the use of the longer 1-inch needles likely increased the risk of this adverse event. Migraine appears to be the seventh most common disease worldwide, with an estimated global prevalence of 15.3% . AccordiOnabotulinumtoxinA (BoNTA) stands worldwide among the established treatment options for CM prophylaxis, following the publication of pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT  clinical program . These pThe role of patients’ body habitus and its potential impact on tolerability profile of BoNTA injections for the prevention of migraines has been minimally explored. Wu-Fienberg et al.  were the2) patients. In addition, the semispinalis capitis muscle lay deeper than can be reached using the standard 0.5-inch needle in both the obese (BMI 30–35 kg/m2) and the severely obese (BMI > 35 kg/m2) patients of the study population. Thus, a 0.5-inch needle is insufficient to allow intramuscular BoNTA injection into the trapezius and semispinalis capitis muscle in a majority of overweight and obese patients [The results showed that the temporalis and trapezius muscles lie deeper than can be reached using the standard 0.5-inch needle in severely obese  of them achieved treatment with the 2nd BoNTA course, according to the study’s schedule. Each of these 100 patients served as her/his self-control, and no additional patients were used for comparison. Patients were treated quarterly with BoNTA, strictly adhering to the fixed-dose, fixed-sites PREEMPT paradigm  and usinThe study sample consisted of 14 males (14%) and 86 females (86%) with a mean age of 44.5 ± 10.3 (range: 19–60) years. Patients had failed a median number of three (range: 1–7) previous oral prophylactic medications. A total of 18/100 (18%) enrolled patients were BoNTA naïve, with the remaining 82 patients previously exposed to a median of four (range: 1–16) BoNTA quarterly administered sessions. Among these 82 pre-treated patients, six (7%) reported neck pain during their previous exposure to BoNTA therapy. Psychiatric comorbidities were common, being evident in 69/100 patients (69%). Of those 69 patients, 24 (34.8%) had anxiety disorder; 22 (31.9%) had depression; 20 (29%) were diagnosed with mixed anxiety and depression disorder; and 3 (4.3%) had bipolar disorder. At first BoNTA administration, the use of a 1-inch 23 G needle in the left-hand side trapezius and paraspinal muscles resulted in 16 (16%) patients reporting neck pain: 8 at left, 3 at right and 5 bilateral. At second repeated infusion using the 1-inch 27 G needle to inject BoNTA in the left-hand side trapezius and paraspinal muscles, there were 11 (11%) patients reporting neck pain: 6 at left, 3 at right and 2 bilateral. The difference in the incidence and location of neck pain between the first and second BoNTA infusion remained insignificant a,b. Figup = 0.09) days. Similar to the first infusion, the left-hand side vs. other side neck pain was slightly higher in duration at the second infusion with the use of a 1-inch 27 G needle. The reported severity of neck pain was comparable between the first and second BoNTA infusions, being rated at first infusion as minor in five patients, moderate in eight and severe enough to require prescription of NSAIDs in three patients vs. minor (n = 6), moderate (n = 4) and severe (n = 1) at phone interviewing conducted three weeks after the second BoNTA course (The duration of neck pain without taking into account the side of the neck pain was 7.1 ± 6.7 (range: 1–14) days, while at second BoNTA infusion, the duration was shorter than that observed at the first infusion, but without reaching significance (4.5 ± 4.4 (range: 1–14) vs. 7.1 ± 6.7 (range: 1–14); A course .p = 0.6) to the clinical benefit experienced by patients, as this was expressed by the reduction in mean migraine days. PGIC scorings after both first and second BoNTA infusions are shown in In any case, the duration and severity of neck pain at first infusion influenced the BoNTA-attributed perception of change and satisfaction of affected patients, as 8 of 11 patients experiencing moderate/severe intensity remained dissatisfied with a score ≤ 4 on “Patient Global Impression of Change” (PGIC). The remaining 92 patients reported an at least clinically meaningful benefit (PGIC ≥ 5) with the first BoNTA treatment course. At second BoNTA infusion, all five patients experiencing moderate/severe intensity scored PGIC ≤ 4 to express their dislike. It is worth noting that rating PGIC ≤ 4 after both the first and second BoNTA infusion attributed to moderate/severe neck pain remained unrelated  to inject BoNTA or when using the 1-inch 27 G needle (p = 0.74). The logistic regression analysis failed to identify predictors being able to independently predict the manifestation of neck pain at either of the two BoNTA infusions. Specifically, gender (p = 0.335 with 1-inch 23 G needle and p = 0.676 with 1-inch 27 G needle); age (p = 0.284 with 1-inch 23 G needle and p = 0.433 with 1-inch 27 G needle); BMI (p = 0.611 with 1-inch 23 G needle and p = 0.851 with 1-inch 27 G needle); the number of previous BoNTA cycles in pre-treated patients (p = 0.483 with 1-inch 23 G needle and p = 0.452 with 1-inch 27 G needle) and the evidence of neck pain during previous exposure to BoNTA therapy (p = 0.393 with 1-inch 23 G needle and p = 0.576 with 1-inch 27 G needle) failed to significantly correlate with the left-hand side vs. other location of neck pain.There was no significant difference in the location of neck pain (left-hand side vs. other) either with the use of the 1-inch 23 G needle  is generally in line with previous studies . It shouIt is generally considered that patients with preexisting neck pain might be more liable to experience neck pain exacerbation after BoNTA injection in the cervical paraspinal muscle group, whereas patients of smaller frames may be also more prone to neck pain and weakness . NeitherOur study has some limitations, which are related to its observational design and might relate to the relatively overall small sample size and the corresponding low numbers of patients experiencing neck pain, likely resulting in insufficient power to detect medium effect sizes. However, provided that this is a self-controlled study, because each patient serves as her/his own control, we might suggest that we were able to produce results that are statistically and clinically valid with far fewer patients than would otherwise be required; a similar outcome is expected to occur with the use of larger sample size.2 and semispinalis capitis muscle of patients with BMI of <30 kg/m2) or injecting the toxin to the belly of the selected muscle . More specifically, the length of the used needle at the left-hand side trapezius and paraspinal muscles was 1-inch, which converts into 25.4 mm, and the depth of the muscles under investigation is considerably lower based on measurements of the median muscle depth with the use of computed tomography scans of the head and neck [Finally, it is important to clarify that longer needles would under no circumstances result in PREEMPT protocol violation, as based on the available data they would result in injecting the toxin deeper within the selected muscle  were over 18 years of age at enrolment (ii) had been diagnosed with CM with or without medication overuse (iii) were either BoNTA treatment-naïve or treatment-experienced, (iv) agreed to keep headache diaries as per their treating physicians’ instructions and (v) were consistent in conducting phone interviews according to the study needs. Otherwise, general inclusion and exclusion criteria were the same as previously described ,17,18.2), overweight (BMI 25–30 kg/m2), obese (BMI 30–35 kg/m2) and severely obese (BMI > 35 kg/m2) based on their BMI index [® 100UI/fl, Allergan-Abbvie, Hellas) was administered quarterly from certified BoNTA injectors throughout the study’s period, according to the PREEMPT paradigm [For the purposes of the current study, eligible patients were classified at baseline as normal weight  questionnaire PGIC, where 1 stands for “no change” and 7 for “considerable improvement” . A cut-op < 0.05.Descriptive statistics were generated for all variables, depending on the nature of the variable, using the SPSS for Windows . Non-parametric statistics using the Kruskall–Wallis one-way analysis of variance were computed to ascertain potential differences in the occurrence of left- vs. right-hand side neck pain at each of the two consequent BoNTA infusions. A linear regression analysis using the left-side neck pain as the dependent variable was performed to identify predictors of its occurrence. All tests were two-sided, unless otherwise stated, and significance was set at


There is no consensus about the mechanism and efficacy in alleviating pain of the lower-level laser therapy (LLLT) during orthodontic treatment. This study aimed to evaluate the LLLT effectiveness clinically in reducing pain caused by orthodontic movement that occurs in the early stages of treatment.  The sample consisted of 54 patients in need of orthodontic treatment divided into two groups. A 28 experimental patients group  was undergone gallium-aluminum-arsenide infrared laser application on 12 points for each tooth immediately after the installation of the first alignment archwire, and a 26 patients control group  was undergone to no pain control intervention at all. Pain intensity was measured by using a visual analog scale, which was marked pain level (mm) reported in 06, 24, 48, and 72 hours. The perception of pain  was evaluated by filling up a questionnaire. To compare the intensity and perception of pain between groups, a nonparametric Mann–Whitney has been performed. p < 0.001), 24 (p=0.004), and 48 hours (p=0.007) and perception of pain (hours) in the peak (p=0.026), decline (p=0.025), and absence (p=0.008) significantly lower compared to the group control.  The experimental group showed levels (mm) at 6 ( Low-level laser therapy is effective in reducing pain severity caused by orthodontic forces activation, and it promotes the analgesic action lasting effect during the most painful feeling time. Patients undergoing orthodontic treatment may experience significant levels of pain, a common condition in orthodontic fixed appliance therapy –3, even The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the preferred method by orthodontists to control pain caused by tooth movement , 6. PresAchieving an effective pain management method without drug administration is a common goal of research in all areas of the health sciences , 13. ForLasers are classified according to the power of their radiation emission, which can be high, medium, and low intensities. Low-level lasers (LLL), also called cold, therapeutic, or soft-laser lasers, have a photochemical action of analgesia, anti-inflammatory, and tissue biostimulation , 14 suchDifferent parameters of various types of lasers, such as time, intensity, energy density, number of irradiated points, and others, have been proven to be effective , 16, 17 Thus, this study aimed to clinically evaluate the effectiveness of low-level laser therapy in reducing pain caused by orthodontic movement in the early stages of treatment.This study was approved by the Ethics Research Committee of the Ingá University Center (protocol no. 768.652).Sample size calculation was based on an alpha of 5% and a beta of 20%, using a standard deviation of previous research , of 15.6The sample consisted of 54 individuals, selected according to the following inclusion criteria: need for nonextraction orthodontic treatment performed with the preadjusted fixed appliances, 0.022″ slot; installation of the 0.012″ thermoactivated nickel-titanium archwire as the beginning of the alignment and leveling phase ; no-use medication that interferes with the results; good oral and general health conditions, and signed informed consent, agreeing with the research procedures.The patients were randomly divided into two groups: laser group (LG) and control group (CG). The LG was composed of 28 patients: 13 male and 15 female, mean initial age of 26.84 years (SD 13.83), who received low-lever laser irradiation right after the installation of fixed appliances. The CG with 26 patients, 11 male and 15 female, mean initial age 29.13 years (SD 13.39) received no intervention for pain control after the appliance installation.The laser used was a gallium-aluminum-arsenide (GaAlAs) infrared laser with a wavelength of 808 nm and a cross-sectional beam diameter of 2 mm  adjusted to 40 mW.2 (0.78 J) per point, totaling 12 irradiations in each tooth, with a total energy of 9.36 J per tooth.Laser therapy was performed only once, immediately after brackets bonding and installation of the first archwire of the orthodontic treatment (0.012″ thermoactivated nickel-titanium). The average time for irradiation of all teeth was 19.5 minutes, on the distal region of the first molar to the distal region of the opposite first molar. Three points between the roots and distal spaces of the first molar  of the buccal and lingual/palatal sides where the orthodontic appliance was installed  were irrThe level of pain was evaluated through a visual analog scale (VAS) with 100 mm horizontal line, delimited in three points with descriptors (expressions of smiles) in each marking: 0 (zero) meant no pain; 5 (five) representing moderate pain, and 10 (ten) representing severe pain. On this scale, the patient was instructed to mark a vertical risk at the location corresponding to the level of pain experienced at 06, 24, 48, and 72 hours after the orthodontic appliance installation.The patients answered a questionnaire, with the VAS score at times evaluated, and indicated the perception of pain in relation to the amount of time from the laser therapy , the highest intensity (maximum), and decline and absence of pain. Each patient indicated when (day and hour) these levels of pain was felt by them.All research participants were told that it was not forbidden to take painkillers, but if they did, they should inform in the questionnaire which was the painkiller used, and these patients were excluded from the sample.The compatibility between the groups for some characteristics that could influence the pain levels between the groups was also evaluated: age, Little' irregularity index to measure the crowding, sex, and type of malocclusion.Little irregularity index measurements were obtained from the patients' dental casts by summing the linear displacements of the contact points between the incisors and between the lateral incisors and the mandibular canine . Measuret-tests, at p < 0.05.To assess the reliability of Little' irregularity index , new meaNormal distribution of the variables was evaluated with Kolmogorov–Smirnov tests.t-tests. Intergroup comparability regarding sex distribution, malocclusion classification, and skeletal component was evaluated with chi-square tests. The level of pain symptomatology and pain perception between the two groups was evaluated with the Mann–Whitney test.Intergroup comparability regarding ages and Little's irregularity Index at the initial stage was evaluated with p < 0.05.All statistical tests were performed with Statistica software . Results were considered statistically significant at There was no systematic error, and the casual error was of 0.21 mm (Little' irregularity index).The groups were comparable regarding initial ages, Little irregularity index, sex distribution, and type of malocclusion .Patients that received laser therapy reported significantly lower levels of pain at 6, 24, and 48 hours than patients from the control group . At the The laser group showed the maximum, decline, and absence of pain in significantly shorter periods of time than the control group .Both groups were comparable regarding initial ages, Little irregularity index, sex distribution, and type of malocclusion . TherefoThe allocation of patients in each group was done consecutively and randomly, in a ratio of 1 : 1. The patients were sequentially distributed until each group reached the minimum amount required by the sample size calculation. One of the inclusion criteria was the no-use medication that interferes with the results, i.e., nonsteroidal anti-inflammatory drugs (NSAIDs) or painkillers. However, it was not prohibited for patients to take such medications if they felt it necessary. No patient took these medications, and there was no withdrawal.The assessment of pain levels using the visual analog scale is a subjective method, but it is also one of the best available methods used to assess pain perception, used in several studies in the literature , 22–26. 2) administered within 72 hours of the injury. Another aspect considered was the time of 2-3 minutes per tooth, defined by Harazaki et al. [The lower-level laser therapy (LLLT) irradiation protocol was based on the dosages used in the literature , 22. A si et al.  as necesi et al. , 30. A si et al. , 32. Howi et al. , 34 repo2 or by the cross-sectional area of the beam [2 in most devices.The “Arndt-Schulz Law” is widely used to describe the effects of light parameters . Energy the beam . In factIn the present study, the laser was applied intraorally. However, transcutaneous  use can also be necessitated in some cases due to the size of some kinds of laser device or operator preference. It is an essential question since the intra and extraoral administration of LLLT may have affected the results. The differences between the skin and mucosa affect the results, i.e., the effect of LLLT depends on the fact that laser light penetrates tissues and tissue fluids . Aras anThe average time for irradiation of all teeth was 19.5 minutes, distal from molar to distal from opposite molar. Celebi et al.  completeTherapy with nonsteroidal anti-inflammatory drugs is the method most used by orthodontists to control pain caused by fixed appliances . Howeverp < 0.001, p=0.004, and p < 0.001), which is in line with previous research on the effectiveness of LLLT [p=0.235); however, the control group showed a quite intense decrease in pain levels in the interval between 48  and 72 hours . According to the patients' perception of pain progression and decline (p=0.025 and p=0.008) of 97% and 99%, respectively. The patients showed improvement due to the anticipation of the attenuation and the absence of discomfort. Pain relief happened earlier and was even less intense during the comparison period between groups. If pain perception is examined only from the perspective of pain levels marked on the visual analog scale  reported some level of pain in the first 24 hours, decreasing progressively in 48 and 72 hours , while SHowever, other studies with randomized clinical evaluation did not detect positive effects of laser therapy on reducing pain in the orthodontic treatment , 22. TheIt is known that pain intensity is generally more prevalent in the inflammatory phase, during the first hours and days after the injury, and in most cases, the pain decreases as tissue repair processes occur . To contEven though the pain levels were lower, a considerable portion of the sample experienced some discomfort during the initial phase of treatment. The forces applied to produce tooth movement can generate high levels of pain since it is subjective and related to each patient's experiences. It is up to the orthodontist to provide relief for the discomfort resulting from simple procedures such as installing intermaxillary elastics or leveling wires, as this undesirable effect can influence patients not to use important devices for therapy and even take them to abandon orthodontic treatment.Low-level laser therapy showed to be effective in reducing pain severity in the early stages of orthodontic treatment, promoting long-lasting analgesic action during the period of greatest pain sensitivity.


Back pain is a main driver of disability and the most prevalent reason why people in Demark visit a general practitioner (GP). However, little is known about back pain management in primary care. For new strategies to be sustainable and to accommodate the recommendations for evidence-based practice, patients’ perspectives are paramount to complement clinical expertise and research evidence.This study aimed to identify recommendations for systematic data collection in a nationwide cohort regarding the management of back pain in general practice from the perspectives of GPs and patients.We applied an adapted exploratory sequential design using focus groups and individual interviews. Seven GPs and ten patients with back pain participated, and four focus groups and seventeen individual interviews were conducted. Data were analyzed using abductive reasoning.Both GPs and patients with back pain found that 1) recruitment to a cohort should take place through the GPs, 2) the heterogeneity of patients with back pain and their need for individualized treatment and care should be considered, and 3) data from the cohort should feed into a flowchart or guideline to illustrate a generic patient pathway and visually assist both the patient and GP to obtain an overview and, thus, structure the patient pathway.GPs and patients with back pain both considered the nationwide cohort with the overall aim to investigate back pain management as being extremely relevant in relation to improve t the patient pathway. User perspectives should be explored and integrated into health care interventions. Back pain is an unpleasant condition, and although the prognosis of back pain episodes is good, the prospect of curing persistent back pain is poor –3. With Large scale data collections are, therefore, required to achieve insights into back pain care, understand the drivers of treatment decisions and plan new strategies, and systematic data collection is recommended . For newOur study was carried out to contribute to the development and design of a national general practice cohort for patients with back pain. The overarching aim of the project is to improve health care for people with back pain through the investigation of the content of care, patient- and clinician-level drivers of variation in care and the decision processes in the management of back pain in Danish general practice. Further, the project aims to investigate how management strategies relate to patient outcomes.To increase end-user value and feasibility, the present sub-study was conducted with the purpose of informing the data collection and contributing to co-creation of the final cohort.Thus, this study aimed to identify recommendations for systematic data collection in a nationwide cohort regarding the management of back pain in general practice from the perspectives of GPs and patients.This study is reported according to the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist .We applied an adapted exploratory sequential design using focus groups and individual interviews and, again, focus groups to provide context and enhanced understanding of the findings. We did not include quantitative data as conventional in the sequential analysis; we did, however, collect and analyze the data sequentially ; thus, tBecause the back pain cohort is anchored in general practice nationwide, we planned to include patients and GPs from all five regions in Denmark. However, due to the COVID-19 pandemic, we had to approach recruitment pragmatically. Thus, the members of the steering group for the back pain cohort who were GPs acted as gatekeepers in the GP recruitment process, which took place, therefore, as snowball sampling. Regarding patients, contact was established with key people in two local patient associations (focusing on exercises for back pain), who also acted as gatekeepers during patient recruitment. The two key persons were both listed as contact persons for their patient association and both were a board member, too. Possible participants were then contacted by email or phone (by STM), informed about the study and asked for final acceptance of participation.A total of 7 GPs (from three regions) and 10 patients with back pain (from one region) were recruited. None of the approached participants refused to participate. In the following, the GPs are labelled GP1-GP7 and the patients as P1-P10.Through a total of four focus groups, two with GPs and two with patients, as well as seventeen individual interviews, one for each participant, the users' perspectives were uncovered. All interviews were based on a generic semi-structured interview guide Table , prepareTo facilitate a safe space and minimise power imbalances, the data collection process was carried out separately for GPs and patients, respectively—yet with similar procedures. A female research assistant (STM) trained in both health care  and qualitative research (MSc) conducted all interviews. During recruitment, the interviewer was presented for all informants in terms of educational background, affiliation and role in the study.Data collection took place from September to November 2021 and was initiated and finalized with a focus group (still separately) to facilitate interactions, reflections and discussions across the participants when they reacted and commented on each other’s perspectives, experiences and understandings. Thus, the outcome of focus groups depended on this social interaction –16.Both the initial and final focus groups with the GPs were conducted online to accommodate the participants' busy working day and enable as many informants as possible to participate. The sessions lasted 60–90 min and were all recorded for the analysis. In the initial focus group, five GPs participated, whereas six participated in the final focus group; two GPs participated in both focus groups.The participating patients with back pain wanted the focus groups conducted onsite, and one of the informants offered his/her house as a location. In the initial focus group, ten patients participated, whereas eight participated in the final focus group; five patients participated in both focus groups.The initial focus group focused on the topics and questions presented in Table During the final focus group, core issues and themes found across the initial focus groups and the individual interviews were presented to the informants, and they were asked to reflect on these findings, discuss them and validate or improve them. Both GPs and patients were presented with their own results only.In between the initial and final focus groups, individual interviews with all participants were conducted, comprising a total of 17 interviews. The main purpose of these individual interviews was to uncover in-depth perspectives and reflections on key findings from the initial focus groups in a safe space.The individual interviews were conducted from September to November 2021; they lasted 30–45 min and were all recorded for the analysis. All individual interviews were conducted via telephone—both due to the COVID-19 pandemic and to flexibility towards the informants’ time schedules.Data were analyzed using abductive reasoning, as described by Revsbæk and Tanggard (2015). During such reasoning, which is neither data nor theory driven, but a ‘breakdown-driven’ process, repeated playbacks of the interviews contributes to further understanding when the empirical material was ‘opened up’ to the listening researcher. Thus, our data material consisted only of the audio-recorded interviews (no transcripts) and unstructured handwritten notes from the interviews – the latter to support recall of immediate impressions and nonverbal reactions. The initial step, listening to the interviews, was carried out by STM. Subsequently, two researchers  discussed the findings and underlying patterns, and the selection of quotes was discussed. Abductive reasoning is a pragmatic approach that allows the researchers to take note of situations that may generate a breach of understanding followed by a new understanding that occurs. This research approach is particularly suitable for experienced professionals within the field because it allows the incorporation of prior understandings in the analysis .Following the sequential design, data form each interview round  and for GPs and patients, respectively were analyzed separately. As described above, all informants provided feedback on the findings in the sequential design.The study was approved by the Research Ethics Committee of the University of Southern Denmark (21/43008), in agreement with both research ethics and General Data Protection Regulation (GDPR) legislation , and allInformed consent to participate in the study was obtained from all participants. Before inclusion, all potential participants received written information about the purpose of our study, contact information, anonymity, confidentiality and the responders’ right to withdraw from the study at any time. Before each interview, this information was repeated orally, and an informed consent was signed by all informants, including consent for publication. According to Danish legislation, no further approval was necessary.Recruitment, data and data collection and Contribution to the patient pathway. We present the results separately for the GPs and patients, respectively.Corroborating the aim of our study, the results are presented under the headings: Of the participating seven GPs, three identified as male and four as female. They ranged in age from 31 to 75 years and presented up to 35 years of experience in general practice. All stated being experienced with patients with back pain in general practice.Regarding the recruitment of GPs to a nationwide cohort, the GPs suggested various strategies, including Facebook, their professional clusters and the medical doctors in specialist training to become a GP. According to the GPs, Facebook would provide a broad and nationwide recruitment strategy—however, only for GPs actively engaged in relevant Facebook groups.‘So, I guess that many would say that it is totally in line with that you want to contribute, and the clusters are an optimal place for recruitment, and it is easy to find the boards or chairmen; you can just ask for a mailing list… ‘ (GP1)An even more relevant strategy would be through the professional clusters in which GPs organize nationwide in Denmark. Each of these clusters are organized with a board and a chair, and they could assist by distributing information material regarding a nationwide cohort and arranging oral presentations on meetings.Regarding the medical doctors in specialist training to become a GP, the informants stated that it should be at the end of their training (phase 3)—that is, when they are experienced and confident about becoming a GP but still have a bit more time left in their schedule compared to the GPs and, thus, could find the time to contribute to the nationwide cohort.Regardless of which strategy is chosen, it is considered paramount that the information is provided by a GP—‘… a god and conscientious colleague…’ (GP4)—and that what is expected of the participating GPs is unambiguous.For a nationwide cohort to be beneficial for the GPs, they suggested striving for maximum variation and, thus, data from as many patients with back pain as possible and across various social and economic conditions. Moreover, they suggested data collection from the beginning of a patient’s pathway from diagnosis to treatment and from both short and longer and more complex pathways. Regarding the specific data, they suggested, among others: description of the first contact to health care, number of contacts to health care per year, description of diagnostic procedures and treatment, coherence, collaboration, satisfaction, well-being and quality of life.‘…if a template was available for the medical record that roughly contains what you normally discuss with the patients, it would be as easy as if you document conventionally…’ (GP4)The GPs commented that some of the data for a nationwide cohort could be captured from the patient records if informed consent could be obtained from the patients. Because the GPs document during medical examination and treatment anyway, data capturing was preferred as the data collection strategy; thus, the GPs could document as usual instead of contributing additional data to the cohort. They did, however, acknowledge that heterogeneity in documentation could pose a challenge and that a prerequisite for data capturing would be an agreement on the form and content of the medical records for example in terms of a template.Hence, they underscored that the GPs participating in a nationwide cohort should not be expected to write ‘long prose texts’, and it would be preferable if they could contribute using a pre-printed template or answering a few questions by checking off.‘(…) because you can have some patients who do not really have that much pain, but where the impact is great, where it's just about their everyday life, the job, the relationship and everything…’ GP6)Overall, the GPs agreed that the patients should provide information to the cohort—because they would possess core knowledge regarding living with back pain.Hence, the GPs considered it relevant that the patients respond to appropriate questionnaires regularly. The patients could access the questionnaires either through a webpage or via a personal email. Diaries were also mentioned as a possible data collection method for patients; in diaries, the patients could document, for example, pain, exercises and drug use continuously and more thoroughly than a questionnaire would allow.‘… I find it relevant as a tool so that we early in the process can identify whether people will follow a conventional pathway with progress, or we can tell from the beginning that it might be a difficult case to handle…’ GP7)The GPs underscored the heterogeneity of patients with back pain. However, they also recognized some common features that, in their opinion, increased the relevance of the nationwide cohort. They wanted the cohort to contribute with knowledge about the generic patient pathway, both for the patients doing well and those doing less well over time. They mentioned that data could inform the development of generic patient profiles to indicate specific attention points during medical examination and treatment.‘It would be really nice to have such an algorithm-based guideline (…) well, it would be really nice with a flowchart…’ (GP4)This mentioned tool could, according to the GPs, be a flowchart or algorithm-based guideline for medical examination and treatment.This flowchart or guideline should act as an illustration of the patient pathway and visually assist both the patient and the GP to obtain an overview and, thus, structure the patient pathway. Furthermore, this illustration could serve as an engaging communication tool during consultations and help align expectations and coordinate decisions. It was, however, highly important for the GPs that a guideline or flowchart should guide an individual and tailored pathway and not act as a ‘one-size-fits-all’ kind of truth.A total of ten patients participated; seven identified as female and three as male, and they were aged 48–73 years. Some were still working, others on either early retirement or conventional retirement. They presented their back pain condition as various forms of arthritis, disc herniation and work accidents; all stated that they had had back pain for several years and all trained regularly in specific back training teams as members of a local gymnastics club.The patients found that recruitment to a nationwide cohort through their GP was most convenient. They suggested that information material should be accessible in the waiting rooms for the patients to sign up for the cohort, if interested, or the GP could inform and include the patients during the consultation. They mentioned that if their GP asked them for inclusion, it would positively affect their desire to participate.The patients also suggested recruitment through local clubs for yoga, water gymnastics or (back) gymnastics. They have all met a lot of peers with back pain in these clubs and anticipated that many would be interested in contributing to a cohort. These clubs could be approached through information material distributed in the teams, through the boards or by an oral presentation at a board meeting or a joint event. To reach the younger group of patients with back pain, they suggested including reflexologists, osteopaths, physiotherapists and chiropractors, as well as pain clinics and gyms in the aforementioned information strategy.“The doctor is so busy; I do not remember that I have been asked how I feel about being in pain, what I could do to not be in pain – besides taking painkillers and doing back exercises…” (P4)The patients underscored that data should capture ‘… the whole person…’ as this quote illustrates:The patients recommended that data should include the pathway on a timeline, pain profile, description of contacts to health care, list of diagnosis, diagnostic procedures and treatment, collaboration among health professionals, who coordinates, knowledge dissemination between health professionals, what is good for your back, determinants of compliance , what the patient does him/her self to take care of his/her back, ergonomics at home and at work and personal burden of the back pain .“It should be written in a plain language – no Latin expressions that ordinary mortals do not understand, and not the same questions again and again.” (P5)The patients stated that data collection preferably could be via electronically distributed questionnaires. The ‘not-too-long’ questionnaires should include short and precise questions in clear, plain and respectful language without patronizing the respondents.“I just need to think twice, maybe read the question several times before answering” (P6)It should be possible to complete the questionnaire within 20 min, and contact information should be provided. Furthermore, adequate time should be provided for answering the questionnaire.rd month, would be relevant.The patients also mentioned dairies as a relevant data collection method . Finally, the patients found that interviews, for example every 3‘The doctor who knows you personally is the best doctor ever…’ (P2)In the contact with their GPs, it was considered paramount for the patients to be seen by a GP who knows them personally and who knows what they have been through regarding their back pain. The want to be taken seriously and to be seen, heard, met and understood.Thus, the patients wanted the cohort to contribute to a better flow during diagnosis and treatment because they experienced too many obstacles and waiting time in their pathways.‘Doctors can’t know everything, of course they can’t (...), and they are just as different as we are (…),’ but it is important to know because you are uncertain about what will happen next (…) Yes, because you simply feel let down, it's just like you do not mean anything… it is important to feel taken seriously’ (P9)They wanted the cohort to contribute with an overview and a guideline or catalogue with inspiration and recommendations regarding treatment and care.‘It is always cool if your GP is familiar with the possibilities in the community.’ (P10)The patients wanted the guideline to systematize the pathway and visualize for both patients and GPs where the individual patient is on a timeline and provide information about possibilities for the patients to be active themselves.Furthermore, they wanted the guideline to focus on follow-up and collaboration with the GPs.Both GPs and patients with back pain found a nationwide back pain cohort extremely relevant in relation to improving diagnosis and treatment and also found it relevant that their perspectives were integrated into a future solution. Overall, the similarities between the GPs’ and patients’ perspectives were striking.Both groups found that recruitment to a cohort should take place through the GPs. Our results thus corroborate the perception of the GP as being a gatekeeper and treatment coordinator for patients with chronic diseases – roles that contribute to both safety and compliance in terms of following the treatment due to a long-standing and trusting GP–patient relationship –21. HoweFurthermore, both GPs and patients highlighted the heterogeneity of patients with back pain and the need for individualized treatment and care showing the complexity in care for chronically ill patients. The fact that patients want individualized treatment and care—and GPs want to provide this—is far from new; regardless of the diagnosis, patients want to be seen as individuals, and studies have demonstrated improved health outcomes when patients are involved in the management of their own health conditions and when their individual needs are taken into account, including increases in satisfaction , qualityPatients also face various challenges during encounters with their GPs. Multiple studies report on GPs’ lack of time to deal effectively with patients’ concerns and their beliefs, and patients experiencing that their GPs are rushed and tend to be preoccupied with their own agendas under time-pressure constraints. Another challenge for the patients occurs when they do not see the same GP every time and, thus, experience a lack of continuity .Finally, both GPs and patients suggested that knowledge from the cohort should feed into a flowchart or guideline to illustrate a generic patient pathway and visually assist both the patients and GPs to develop an overview and, therefore, structure the patient pathway—both for patients doing well and those doing less well over time. Being positive that both GPs and patients miss this overview and want an evidence-based instrument to structure the pathway and facilitate collaboration, this approach might include some challenges. First, research suggests that GPs might experience a number of barriers towards using guidelines or evidence-based recommendations to guide their treatment of patients with back pain –32. SecoDue to the COVID-19 pandemic, it was challenging to recruit informants as widely  as initially planned. However, we consider the number of informants appropriate (seven GPs and ten patients with back pain), particularly because patterns emerged early in the data collection process. Furthermore, we believe that the sequential design contributed to nuanced and rich data and also to valid and trustworthy results. On the other hand, we are aware that our informants might be less representative due to our sampling strategy. The GPs were found by snowball sampling, potentially meaning that they represent a more positive group towards both the topic (back pain and systematic data collection) and our method (interviews). Furthermore, the patients with back pain were identified through two local patient associations focusing on exercises for back pain, meaning that they might represent a more active and self-determined segment of patients with back pain. We do, however, rely on our data, and we believe that our results contribute valuable knowledge on both GPs’ and patients’ perspectives on systematic data collection regarding the management of back pain in general practice.Both GPs and patients with back pain found a nationwide cohort for back pain relevant, and they appreciated that their perspectives were explored. They found that 1) recruitment to a nationwide cohort should take place through the GPs, 2) the heterogeneity of patients with back pain and their need for individualized treatment and care should be taken into consideration, and 3) data from the cohort should feed into a flowchart or guideline to illustrate a generic patient pathway and visually assist both the patient and GP to obtain an overview and, thus, structure the patient pathway.


Prostant effectively improved the urination status, lower abdomen symptoms, time to urinate and score of VAS, and the reduction of TNF-α and IL-6. Similarly, Prostant can ameliorate the outcome of urodynamics in urinary retention mice. Mechanically, Prostant reversed the urinary retention-elevated the serum level of hs-CRP and TNF-α, reduction of IL-2, imbalance of Treg/Th17, and level of JAK2 and phosphorylated STAT3. Besides, Prostant ameliorated the pain as shown by the reduction of writhing response, and the elevation of threshold of pain and degree of swelling. Moreover, Prostant antagonized the pain-induced dysregulation of Treg/Th17. Therefore, Prostant can treat patients and mice with anal pain and urinary retention by modulating the balance of Th17/Treg to regulate the secretion and production of inflammatory factors. We hope our results can establish a scientific treatment approach for solving anal pain and urinary retention after PPH surgery of mixed hemorrhoids.Anal pain and urinary retention are the two most outstanding complications of the procedure for prolapse and hemorrhoids (PPH) surgery. This study intended to assess the clinical effect and mechanism of Prostant on urinary retention and anal pain after the PPH. Here, 30 patients received PPH surgery. The role and mechanism of Prostant in patients and mice with urinary retention and anal pain were evaluated. ANOVA tests were executed and differences between groups were regarded as statistically significant when  Hemorrhoids are one of the remarkable diseases manifested as the anal mucosa prominences that are generated by loose connective tissue, venous and arterial vessels, and smooth muscle . In the The procedure for prolapse and hemorrhoids (PPH) surgery was first mentioned in 1998 by Longo, which then has been widely utilized in the therapy of hemorrhoids . HoweverCortex Phellodendri (Huang Bai), Rhizoma Polygoni Cuspidati (Hu Zhang), Fructus Gardeniae (Zhi Zi), and Radix et Rhizoma Rhei (Da Huang) [“Treating different diseases with the same treatment” is an important fundamental theory of traditional Chinese medicine (TCM), which indicates that the same approach of treatment can be used to treat diverse diseases with analogical pathological alteration during various stages of the progression . TCM thea Huang) . The maia Huang) , 14. In a Huang) . ProstanHere, the clinical effects of Prostant on anal pain and urinary retention after PPH surgery of damp-heat mixed hemorrhoids were evaluated based on the “Treating different diseases with the same treatment” theory combined with the “precision medicine” theory. Moreover, the mechanism of action of Prostant was investigated in animal models. We hope our results can enrich the TCM theory of “Treating different diseases with the same treatment,” as well as provide a scientific treatment method for solving anal pain and urinary retention after PPH surgery of mixed hemorrhoids.n = 15) through the randomized single-blind control method. Both patients in two groups obtained PPH surgery. Patients in the treatment group received Prostant before the end of the operation and placed 4 cm inside the opening of the rectum. Then, patients obtained Prostant treatment at 4 cm inside the opening of the rectum in the morning and evening after the operation for consecutive 7 days. Patients in control group did not receive any treatment. All subjects accredited the written informed consent. The study was approved by the Board and Ethics Committee of our Hospital.Data of the present study were from 30 patients who were diagnosed with damp-heat mixed hemorrhoids admitted to our hospital. The diagnostic criteria were according to the “Guidelines for the Clinical Diagnosis and Treatment of Hemorrhoids” jointly stipulated by the Colorectal and Anal Surgery Group of the Chinese Medical Association Surgery Branch, the Anorectal Branch of the Chinese Society of Chinese Medicine, and the Anorectal Branch of the Chinese Society of Integrative Medicine in 2006. The diagnostic criteria for the damp-heat mixed hemorrhoids were as follows: bright red and thick blood in the stool followed by discharge or swelling of the abscess, feeling of burn pain or nourishing water, dry and loose excrement, yellow or small urine, dry mouth and tongue, yellow and dark fur, and stringy or floating pulse. A total of 30 patients with damp-heat mixed hemorrhoids were allotted into control group and treatment group  (0–10 points) to directly record the score with 0 point indicating no pain and 10 points indicating maximal pain.α and IL-6 was also measured through the enzyme-linked immunosorbent assay (ELISA) assay.The degree of dysuria and pain of patients in the two groups was scored and analyzed. Three times were recorded at 3 h, 6 h, and 12 h after operation. After that, it was recorded again every morning and evening for 7 days. If the patient was discharged early, follow-up records would be given by telephone. In addition, the serum level of TNF-SPF male BALB/C mice (18–22 g) were obtained from Guangdong Medical Experimental Animal Center. All mice were bred in the SPF environment of the Animal Experiment Center of our hospital and acclimated for 3 days before experiments. Mice were offered a 12 hour/12 hour light-dark cycle and provided with water ad libitum and a standard diet at (21 ± 2)°C. All experiments were authorized by the Animal Ethics Committee of our hospital. The experimental operations and materials were conducted following the Guiding Opinions on the Treatment of Experimental Animals, Laboratory Animal Management Regulations, and Laboratory Animal Licensing Management Measures, and were consistent with the guidelines of the National Institutes of Health and Health.After perianal disinfection of the mice, 0.05 mL of 75% glacial acetic acid was injected into the skin around the anus. Ulcers were formed after 24 hours. Then, 2–3 mice were randomly selected and scored the perianal area based on the local symptom scoring criteria  to evaluMice were intraperitoneally received with 40 mg/kg sodium pentobarbital. The mouse lies in the supine position on the dissection table with a hole at the bottom. After anesthesia, the bladder is opened from the middle, and the indwelling needle is punctured and used for bladder perfusion. One end of the indwelling needle is connected to the 50 mL syringe on the micro syringe pump through a three-way valve, and the other end is connected to an amplifier through a pressure sensor. Then, the urodynamic indexes including the urination interval, maximum urination pressure, basal bladder pressure, and urination threshold pressure were recorded via the LabChart software in real-time. Next, the bladder was perfused with saline at 6 mL/h for 60 minutes to determine the urodynamic data of the bladder under normal conditions. After the last urination, the external urethra was ligated to result in obstruction and perfused with saline at 12 mL/h for two urination cycles. The acute urinary retention model was built 2 hours later.n = 6). H&UR mice models were established as described above, while mice in control group obtained no stimulation. Mice in H&UR + Prostant-low and H&UR + Prostant-high groups were administrated with 0.5 g/kg and 1.0 g/kg Prostant, respectively. Therapeutic effect indexes were recorded and analyzed, including the basal pressure of the bladder during urinary retention, the time of first bladder contraction urination, the base pressure of the bladder after the first contractile urination, urination pressure, and urination threshold pressure for the first contraction of bladder urination, the base pressure of the bladder within 30 minutes after the first bladder contractile urination, urination pressure and urination threshold pressure within 30 minutes after the first bladder contraction, urination pressure during the first contraction of bladder urination, urination pressure 30 minutes after the first urinary bladder contraction and the number of unstable contractions after urination. In addition, the expression level of serum inflammatory factors, the function of T cell, the protein expression level, and the expression of VEGF in mucosa were determined by ELISA, flow cytometry, western blot, and immunohistochemistry assays.Mice were randomly divided into control group, hemorrhoids combined with urinary retention model group (H&UR model group), hemorrhoids combined with urinary retention model treated with low-concentration of Prostant (H&UR + Prostant-low), and hemorrhoids combined with urinary retention model treated with high-concentration of Prostant (H&UR + Prostant-high) ((1) A mouse Model of hemorrhoids Combined with Urinary Retention and Pain was Induced by Glacial Acetic Acid. Mice were randomly divided into control group, H&UR&P-GAA model group, H&UR&P-GAA + Prostant-low group (0.5 g/kg), and H&UR&P-GAA + Prostant-high group (1.0 g/kg) (n = 6). 0.6% glacial acetic acid was injected into the abdominal cavity of the hemorrhoids combined with urinary retention model mice, and then mice received chemical stimulation for 15 minutes to obtain the hemorrhoids combined with urinary retention and pain (H&UR&P-GAA) model mice. After Prostant was placed into the rectum for 20 minutes, the number of writhing reactions in the mice was recorded to indirectly evaluate the analgesic effect of Prostant.(2) A Mouse Model of Hemorrhoids Combined with Urinary Retention and Pain was Induced by Pressure. Mice were randomly divided into control group, H&UR&P-pressure model group, H&UR&P-pressure + Prostant-low group (0.5 g/kg), and H&UR&P-pressure + Prostant-high group (1.0 g/kg) (n = 6). The tails of hemorrhoids combined with urinary retention model mice were depilated, and then the mice were placed in a fixed tube with the tail exposed. The tails were marked at 1 cm from the base of the tail, and the tail retraction was indicated as the pain response gradually increased the pressure. The pain response of mice at 0.5 h, 1 h, and 2 h after administration was measured 5 times in total, and the analgesic effect was evaluated by calculating the percentage increase in pain threshold.(3) A Mouse Model of Hemorrhoids Combined with Urinary Retention and Pain was Induced by fresh Egg Whites. Mice were randomly divided into control group, H&UR&P-egg whites model group, H&UR&P-egg whites + Prostant-low group (0.5 g/kg) and H&UR&P-egg whites + Prostant-high group (1.0 g/kg) (n = 6). A mark was made on the right hind foot joint of the mouse, and 0.1 mL of 1% fresh egg white was injected into the foot plantar aponeurosis to cause inflammation. After 30 min, Prostant intervention was carried out and measured at 1, 2, 3, 4, and 5 hours after inflammation. The volume of the feet, the degree of swelling, and the inhibition rate of inflammation were calculated.γ, and transcriptional expression level of T-bet, RORγt, GATA3, and Foxp3 was detected by ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), severally.In addition, cytokines secreted by Th cells in serum including IL-4, IL-10, IL-17A, and IFN-α and IL-6 were measured via Human IL-6 ELISA Kit (EK0410) and Human TNFα ELISA Kit (EK0525), and the mouse serum levels of IL-2, TNF-α, hs-CRP, IFN-γ, IL-4, IL-17A, and IL-10 were determined by Mouse IL-2 ELISA Kit (EK0398), Mouse TNFα ELISA Kit (EK0527), Mouse IFN gamma/IFNG ELISA Kit (EK0375), Mouse IL-4 ELISA Kit (EK0405), Mouse IL-17A ELISA Kit (EK0431), and Mouse IL-10 ELISA Kit  in line with the manufacturer's protocol. The mouse serum levels of hs-CRP were analyzed through Mouse C Reactive Protein ELISA Kit  based on the working instructions. The absorbance at 450 nm was measured using a microplate reader .The human serum levels of TNF-μg/ml) plus protein transport inhibitor (BD Biosciences) for 5 hours. Cells were then fixed, permeabilized, and stained with anti-IL-17A . Finally, cells were analyzed using a flow cytometer . Fluorescence minus one (FMO) samples and unstained samples were used as internal controls to set positive and negative gating. Cell gating and data collection were performed in a blinded manner.Mouse peripheral blood was collected and prepared into lymph node single cell suspension for flow cytometry assay. Cells were harvested and stained with anti-CD4 antibodies . FoxP3 staining was performed using Foxp3/Transcription Factor Fixation/Permeabilization Concentrate and Diluent Kit  according to manufacturer's instruction. Then, cells were stained with anti-FoxP3 antibody (eBioscience). Regarding intracellular cytokine staining, spleen cells were cultured in media containing PMA (50 ng/ml) and Ionomycin . Protein concentration was determined by a Pierce® BCA Protein Assay Kit (Thermo Fisher). Subsequently, protein samples were dissolved using 10% SDS-PAGE and then transferred onto PVDF membranes . The membranes were sealed in 5% skimmed milk powder at room temperature for 2 h and then hatched with primary antibodies overnight at 4°C, followed by introduction with the corresponding secondary antibody (BOSTER) for 1 h at room temperature. An ECL chemiluminescence kit (EMD Millipore) was used to visualize the bands, and Image-ProPlus software  was utilized for the analysis of the gray value. Protein levels were calculated relative to GAPDH. The primary antibodies used in this study were as follows: GAPDH , JAK2 , and phospho-STAT3 (Tyr705)  at 1 : 1, 000 dilutions.f at room temperature for 24 h. After dehydrated, embedded, and cut, the sections (5 μm) were obtained for IHC experiment. Sections were stained with anti-VEGFC antibody . Subsequently, the slices were assessed with a light microscope  and Image-Pro Plus 6.0 (Media Cybernetics).Internal hemorrhoid-damaged mucosal tissues were immobilized with 4% paraformaldehyde μl quantum involving 2 μl of the cDNA, 12.5 μl 2 × SYBR® Premix Ex Taq™ II (Tli RNaseH Plus) (TaKaRa), 2 μl of the 10-μM upstream and downstream primers as well as 8.5 μl ddH2O, using the ABI PrismTM 7500 (Thermo Fisher). The RT-qPCR conditions were as follows: 30 s at 95°C, followed by 40 cycles between 95°C for 5 s and 60°C for 30 s, 95°C for 10 s, and 65°C for 5 s. The relative expressions of T-bet, RORγt, GATA3, and Foxp3 were calculated using the 2−ΔΔCT method and normalized to the GAPDH. All the primers used in the present study were listed in Total RNA from perianal tissues was enriched through TRIzol reagent  and then reversely transcribed into cDNA by PrimeScript™ RT reagent Kit with gDNA Eraser  (TaKaRa) following the operating instruction. RT-qPCR was performed in a 25 t-test with only two groups, whereas differences were determined via one-way analysis of variance and Duncan's test among various groups. All the count data were displayed as a percentage and detected by the chi-square test. The differences were regarded as statistically significant when p < 0.05. Figures were generated using Graphpad Prism 8.0 software.Data in the present study were determined using SPSS 25.0 statistical software . Data were first analyzed using Shapiro‒Wilk test. All the measurement data were presented as means ± SD when measurement data conformed to normal distribution. Data were tested by a rank sum test or student's p > 0.05).30 patients who accorded with the inclusion and exclusion criteria were included and allocated into control and treatment groups. As shown in α of the two groups was no statistical difference before operation, while IL-6 and TNF-α levels in patients administrated with Prostant were observably reduced on the first day and the second day after the operation  . Thus, smmation,  experimemmation,  rheumatommation, , and chrmmation, . In lineenotypes , 31. Takγt, and reduction of FoxP3. ROR γt is a pivotal transcription factor for Th17 cells differentiation, and it also regulates the expression and secretion of IL-17, [γ, while Th2 cells can relieve pain based on the generation of anti-inflammatory cytokines IL-4, IL-5, IL-10, and IL-13 [γ and T-bet, and reduction of IL-10 and GATA-3. In brief, combined with the improvement of pain with Prostant treatment as indicated by the reduction of writhing response, and the elevation of threshold of pain and degree of swelling, we concluded that Prostant can alleviate urinary retention and pain through regulating the balance between T cell subpopulations in mice. Nevertheless, no statistical difference was detected in the serum level of IL-4 relative to that in the control, which might suggest that Prostant mainly alleviated urinary retention and pain through regulating the balance of Th17/Treg.In addition, the balance of Th17/Treg has also been demonstrated to be associated with pain, such as neuropathic pain,  bone canf IL-17,  while Fof IL-17, . Moreovend IL-13 . T-bet and IL-13 . Thus, iIn conclusion, Prostant can treat patients and mice with anal pain and urinary retention. Mechanically, Prostant may regulate the balance of Th17/Treg to modulate the secretion and production of inflammatory factors, which ameliorated anal pain and urinary retention. However, our study still has a few limitations. First, the clinical sample size of this study is small, thus more sample numbers are needed in subsequent observations. Next, the potential and further molecular mechanisms  involved in pain need to be inquired about in further study. Additionally, the lack of validation of jak2/stat3 inhibitors and/or agonists is indeed another shortcoming of our study, which need to be supplemented in the following experiments. Briefly, we hope the results can establish a foundation for therapeutic drugs to treat anal pain and urinary retention after surgery.


To evaluate high-frequency (10-kHz) spinal cord stimulation (SCS) treatment in refractory painful diabetic neuropathy.A prospective, multicenter randomized controlled trial was conducted between Aug 28, 2017 and March 16, 2021, comparing conventional medical management (CMM) with 10-kHz SCS+CMM. The participants had hemoglobin A1c level of less than or equal to 10% and pain greater than or equal to 5 of 10 cm on visual analog scale, with painful diabetic neuropathy symptoms 12 months or more refractory to gabapentinoids and at least 1 other analgesic class. Assessments included measures of pain, neurologic function, and health-related quality of life (HRQoL) over 12 months with optional crossover at 6 months.The participants were randomized 1:1 to CMM (n=103) or 10-kHz SCS+CMM (n=113). At 6 months, 77 of 95 (81%) CMM group participants opted for crossover, whereas none of the 10-kHz SCS group participants did so. At 12 months, the mean pain relief from baseline among participants implanted with 10-kHz SCS was 74.3% , and 121 of 142 (85%) participants were treatment responders (≥50% pain relief). Treatment with 10-kHz SCS improved HRQoL, including a mean improvement in the EuroQol 5-dimensional questionnaire index score of 0.136 . The participants also reported significantly less pain interference with sleep, mood, and daily activities. At 12 months, 131 of 142 (92%) participants were “satisfied” or “very satisfied” with the 10-kHz SCS treatment.The 10-kHz SCS treatment resulted in substantial pain relief and improvement in overall HRQoL 2.5- to 4.5-fold higher than the minimal clinically important difference. The outcomes were durable over 12 months and support 10-kHz SCS treatment in patients with refractory painful diabetic neuropathy.clincaltrials.gov Identifier: NCT03228420 Investigations with low-frequency SCS report modest pain relief; however, this treatment has not been widely adopted in clinical practice. This study assesses long-term effects of high-frequency 10-kHz SCS on pain, neurologic function, and health-related quality of life (HRQoL) in patients with PDN with refractory symptoms.,,Methods have been described previously.2) of less than or equal to 45 kg/m2. Investigators assessed comorbidities to determine participant suitability for SCS procedures.Participants were aged 22 years or older with PDN symptoms for at least 12 months, currently or previously taking pregabalin or gabapentin plus at least 1 other class of analgesics; lower limb pain visual analog scale (VAS) of greater than or equal to 5 of 10 cm; hemoglobin A1c (HbA1c) level of less than or equal to 10%; and body mass index  or 10-kHz SCS+CMM was completed at sites by blocks with concealed assignment. The participants were stratified by glycemic control (HbA1c level of <7% or ≥7%) and pain severity (VAS <7.5 cm or ≥7.5 cm). Assessments were completed at baseline and at 1, 3, 6, 9, and 12 months. The participants were eligible for crossover at 6 months if they had less than 50% pain relief from baseline, were dissatisfied with treatment, and the investigator approved it as medically appropriate.,Lower limb pain was assessed on a 10-cm VAS.,A thorough neurologic examination was designed by 2 independent neurologists who trained the investigators to assess the lower limb motor strength, reflexes, light touch, and pinprick and 10-g monofilament sensation at 10 test sites per foot with Neuropen (Owen Mumford).Patients continued their current therapy, and further optimization was permitted. The treatments included the usual noninvasive or minimally invasive therapies.Temporary trial SCS lasting 1 to 2 weeks evaluated whether a participant obtained greater than or equal to 50% pain relief to be eligible for permanent implantation of the 10-kHz SCS system (Nevro Corp). During trial stimulation, 2 octopolar percutaneous leads were inserted into the thoracolumbar epidural space and connected to an external pulse generator. For permanent device implant, 2 leads were placed into the epidural space with electrodes spanning T8 to T11 vertebral bodies and connected to an implanted pulse generator (IPG). Stimulation was delivered at a 10-kHz frequency and 30-μs pulse width, with amplitude typically ranging from 0.5 to 4.0 mA.Randomized participants who completed the 3-month primary end point visit were included in the per-protocol population for analysis. Those who did not complete the primary end point assessment remained in the study but were included only in the safety outcomes.t tests assessed the significance of the mean percentage change from baseline to 12 months within the treatment groups. For categorical variables, the numbers in each category are presented by the treatment groups and compared with the distributions across categories using the Fisher exact test.For continuous variables, descriptive statistics are reported. Paired P values were considered significant at α level of 0.05. Given the exploratory and hypothesis generating nature of the analyses, P values were not adjusted for multiplicity. Statistical analyses were carried out using SAS version 9.4.Two-sided 2 .In total, 103 participants were assigned to continue CMM and 113 were assigned the addition of 10-kHz SCS to CMM . The parP<.001). Baseline characteristics for the resulting 3 analysis groups present at 12 months are reported in http://www.mcpiqojournal.org).Temporary trial SCS was completed for 104 participants assigned to 10-kHz SCS+CMM. In the group that was assigned CMM, there were 95 who completed the 6-month follow-up visit and 81% (77 of 95) crossed from CMM to 10-kHz SCS+CMM, compared with none from the 10-kHz SCS+CMM arm  participants having success, defined as at least 50% pain relief from baseline, and being eligible for permanent device implant. Among the original 10-kHz SCS+CMM group and those who crossed over from CMM, 154 participants proceeded with permanent implant. The full subject disposition is shown in P<.001) and across all Short-form McGill Pain Questionnaire-2 subscales   or 74.3%  .Figure 2The NNT for 50% pain relief with 10-kHz SCS was 1.3  on the basis of the proportion of pain responders among original treatment assignments at 6 months (74 of 87 in the 10-kHz SCS+CMM group vs 5 of 93 in the control arm).At 6 months, 43 of 73 (59%) participants in the 10-kHz SCS+CMM group demonstrated improved neurologic function on examination, and this result was maintained through 12 months  on the EQ-5D-5L VAS . This imThe mean total Diabetes Quality of Life score at baseline was 2.5 of 5  for the 10-kHz SCS+CMM group participants. The patients reported improvements across all 4 subscales by 6 months that were sustained through 12 months . The croPoor sleep quality was evidenced by baseline scores on the Pain and Sleep Questionnaire 3-Item Index of 5.9 of 10  for the 10-kHz SCS+CMM group and 6.7  for the crossover group C. TreatmPain interference with daily living as measured by the Brief Pain Inventory for Painful Diabetic Peripheral Neuropathy was 6.2 of 10  for the 10-kHz SCS+CMM group and 5.9  for the crossover group D. TreatmClinicians rated patients’ social, occupational, and psychological functioning by Global Assessment of Functioning, reporting mean baseline score of 63.1 of 100  that improved by 18.4 points  at 6 months and 20.7 points  at 12 months for the 10-kHz SCS+CMM group E. For thParticipants reported high satisfaction with 10-kHz SCS at 12 months: 46 of 142 (46%) were “satisfied” and 85 of 142 (60%) were “very satisfied” among all implanted patients F. Both cIn total, 154 participants received a permanent 10-kHz SCS device implant. The most common study-related adverse event was surgical site infection : 3 infections resolved and patients continued, whereas 5 (3.2%) patients required surgical explant, with 4 patients discontinuing and 1 later reimplanted and remaining in the study. There were neither stimulation-related neurologic deficits nor any explants for loss of efficacy. Two (1.3%) participants underwent surgical revision of the IPG location and lead migration for 1 (0.6%) participant required a revision procedure, but all 3 continued in the study.Several participants discontinued because of health reasons unrelated to the study, consistent with the presence of significant comorbidities; however, retention was good among patients in the 10-kHz SCS group; of participants medically able to proceed with trial SCS, 154 of 181 (85%) received permanent device implants, and 148 of 154 (96%) of those remained in the study at 12 months.This is the largest RCT to date for SCS treatment of PDN. Compared with pharmacotherapy and low-frequency SCS, 10-kHz SCS resulted in more profound pain relief and pronounced HRQoL improvements. Additionally, 10-kHz SCS does not induce continuous paresthesias as is required by conventional SCS, an advantage for patients with PDN who frequently already suffer uncomfortable paresthesia because of diabetic neuropathy.A lack of sensation in the feet of patients with PDN limits activities of daily living and can result in debilitating sequelae, including injury from falling, fractures, foot ulceration, and lower limb amputation. Over half of the patients treated with 10-kHz SCS had notable improvement on neurologic examination, particularly improved sensation, and this was durable over 12 months. This potentially disease-modifying effect could have tremendous benefit for the safety and quality of life of patients with PDN and merits further research.The estimates for the minimally important difference in EQ-5D-5L index specifically for individuals with type 2 diabetes range from 0.03 to 0.05.There have been 2 prior RCTs evaluating SCS for PDN, both requiring continuous-induced paresthesias in the painful area using low-frequency SCS.,,The effectiveness of low-frequency SCS attenuates over time.,Procedure-related complications observed in this study aligned with expected SCS complication rates.Patients with PDN medically appropriate for implant procedures have a high likelihood of success with 10-kHz SCS. Finnerup et alLong-term controlled pharmacotherapy studies are lacking; few extend beyond 12 weeks. Nonetheless, initial pharmacological management of PDN is appropriate and supported by guidelines.The optional crossover study design provided a unique data set wherein patients serve as their own controls. Pain, health, and HRQoL measures remained unchanged or deteriorated over 6 months of CMM. Results for crossover patients postimplant are similar to those originally assigned to 10-kHz SCS. The participants in this study represent a large patient population who has exhausted the best available medical treatments and need effective alternatives.,55The results for PDN are similar to those reported with 10-kHz SCS treatment of other chronic pain conditions. There were 85% pain responders at 12 months, which aligns with prior prospective studies with 10-kHz SCS reporting the proportion of responders at 12 months for neck pain (85%-89%), pelvic pain (77%), upper limb pain (76%-95%), back pain (79%), leg pain (79%), chronic postsurgical pain (78%), abdominal pain (82%), and nonsurgical back pain (90%).This study was unblinded, which may influence the participants and investigators. Steps to minimize bias included concealed treatment allocation and random sequence generation. The treatment groups were well-matched for baseline characteristics, missing data were unlikely to affect the outcomes, and prespecified end points have been reported.,The detailed neurologic examination has been previously described.Comparing a surgical intervention to medical management has potential for greater placebo effect in the active treatment arm; however, stable results with 10-kHz SCS over 12 months mitigate concerns about the placebo response.In conclusion, 10-kHz SCS provided substantial and durable pain relief, improved HRQoL, better sleep quality, and neurologic improvements over 12 months. These data should support the use of 10-kHz SCS for patients with PDN with symptoms refractory to conservative care.Dr Petersen has received consulting fees from Abbott, Medtronic, Neuros Medical, Nevro, Saluda, and Vertos and research support from Medtronic, Neuros Medical, Nevro, ReNeuron, and Saluda. Dr Scowcroft has received research support from Boston Scientific, Nevro, Saluda, and Vertiflex. Dr Brooks is an employee of Nevro Corp. Dr White has received consulting fees from Lilly and CALIBR. Dr Sills has received research support from Nevro. Dr Amirdelfan has received consulting fees from Nevro, Nalu, Saluda, Biotronik, and Medtronic and research support from Nevro, Biotronik, Vivex, Saluda, and SPR Therapeutics. Dr Guirguis has received consulting fees from Nevro, Saluda, Avanos and research support from Abbott, Saluda, Neuros, Nevro, Nalu, and Avanos. Dr Xu has received research support from Nevro, NIH K08 Grant CA228039. Dr Yu has received research support from Nevro. Dr Nairizi has received consulting fees from Flowonix and Nevro and research support from Nevro. Dr Patterson has received consulting fees from Abbott, AIS, Allergan, Amgen, and CornerLoc and research support from Abbott, Biotronik, Flowonix, Nevro, Nuvectra, and Vertiflex. Dr Mehta has received consulting fees from Nevro, Salix Pharma, Biodelivery Sciences, and Averitas and research support from Boston Scientific, Medtronic, and Nevro. Dr Sayed has received consulting fees from Abbott, Boston Scientific, Nevro, Vertos, Vertiflex and research support from Abbott, Biotronic, Nevro, Vertos, Vertiflex. Dr Lad has received consulting fees from Nevro. Dr Goree has received consulting fees from Stratus Medical and Abbott and research support from SPR Therapeutics and Mainstay Medical. Dr Argoff has received consulting fees from Nevro, Vertex, Lilly, Pfizer, and Teva and research support from Allergan, Amgen, DSI, Lilly, Novartis, and Teva. Dr Nasr has received consulting fees from Siemens Healthineers, Horizon Therapeutics, Nevro, Neurogastrx, and Exelixis. Dr Taylor has received consulting fees from Medtronic, Nevro, and Saluda. Dr Caraway is an employee of Nevro Corp. Dr Mekhail has received consulting fees from Boston Scientific, Sollis Therapeutics, Saluda Medical, Nevro, Abbott , Vertos Medical, Nuvectra, and Relievant Medsystems; is a Medical Monitor for Mainstay’s RESTORE clinical trial; and has received research support from Avanos “Halyard,” Mallinckrodt, Mesoblast, and Neuros Medical. Other authors report no competing interests.