Previous reports concerning deep surgical site infection (SSI) after posterior spinal instrumentation treated with vacuum-assisted closure (VAC) system indicated that most patients must suffer from a delayed incision suture. To date, there are no published reports about the application of incisional VAC following a one-stage incision suture in the treatment of spinal infections. The purpose of this study was to evaluate the feasibility and efficacy of using an incisional VAC system following a one-stage incision suture combined with continuous irrigation to treat early deep SSI after posterior lumbar fusion with instrumentation.Twenty-one patients who were identified as early deep SSI after posterior lumbar fusion with instrumentation were treated by incisional VAC following a one-stage incision suture combined with continuous irrigation at our spine surgery center between January 2014 and March 2020. Detailed data from medical records were collected and analyzed, including age, gender, primary diagnosis, original operation, number of VAC dressing changes, duration of continuous irrigation, hospital stay, risk factors for infection, bacteria type, and laboratory data. Clinical efficacy was assessed using the pre- and postoperative visual analog scale (VAS) for back pain and Kirkaldy-Willis functional criteria by regular follow-up.All the patients were cured and retained implants with an average of 1.9 times of VAC dressing replacement, and an average of 10.2 days of continuous irrigation. There were significant differences between pre-operation and post-operation in ESR, CRP, and VAS score of back pain, respectively (P < 0.05). The satisfactory rate was 90.5% according to Kirkaldy-Willis functional criteria. One patient developed a back skin rash with itching around the wound because of long-time contact with the VAC dressing. There was no recurrent infection or other complications during follow-up.Our preliminary results support that the treatment protocol is feasible and effective to treat early deep SSI following posterior lumbar fusion with instrumentation. Postoperative surgical site infection (SSI) is a common and potentially devastating complication following spinal surgery. It is associated with prolonged hospitalization, increased morbidity, excess expenditure, and poor outcomes . SSI is The treatments of deep SSI after posterior spinal instrumentation are varied and controversial, including sensitive antibiotics alone, surgical debridement, continuous suction irrigation, vacuum-assisted closure (VAC) system, hyperbaric oxygen therapy, temporary implantation of antibiotic cement, local tissue flap coverage, and removal of instrumentation if necessary –6. AmongTo date, there are no published reports about the application of incisional VAC following a one-stage incision suture in the treatment of spinal infections. Mediouni et al. , 14 propThis was a retrospective study. The study was performed in compliance with ethical standards and was approved by the institutional review board of our hospital. Informed consent documents were obtained from all patients prior to surgical treatments. The data were prospectively collected in 21 consecutive patients who were identified as early deep SSI after posterior lumbar fusion with instrumentation, treated by incisional VAC following a one-stage incision suture combined with continuous irrigation at our spine surgery center between January 2014 and March 2020. The cases consisted of 20 patients who underwent initial surgical treatments at our hospital and 1 patient who had received the initial surgery at another hospital. The initial diagnoses included lumbar isthmic spondylolisthesis, lumbar degenerative spondylolisthesis, lumbar disc herniation, and lumbar spinal stenosis. Patients with superficial SSI, late deep SSI, or those younger than 18 years of age were excluded from the study.The definition of SSI was based on the guidelines from the United States Centers for Disease Control and Prevention , 15. DeeAfter the diagnosis of early deep SSI Fig. A, patienIn the operation described above, the inflow velocity of solution for continuous irrigation was set at a minimum of 150 ml per hour on the first day after the operation and then was adjusted to 100 ml per hour for the next 2 days and to 50 ml per hour for the following 2 days. When the drainage was clear and the bacterial culture of the drainage was negative for three consecutive times, the VAC system was removed, the continuous irrigation was terminated, and the inflow tubes were transformed into drainage tubes  and C-reactive protein (CRP) level were examined periodically. Clinical efficacy was assessed using the pre- and postoperative visual analog scale (VAS) for back pain and Kirkaldy-Willis functional criteria . During P < 0.05 considered to be statistically significant.The statistical analysis was performed using SPSS Statistics software . The values of VAS, ESR, and CRP were summarized using mean ± standard deviation (SD). The differences of the above continuous variables before and after surgery were analyzed using Dunnett t test, with Twenty-one patients in this study all received follow-up for an average of 19.2 months (range 13–38 months). All patients underwent a posterior lumbar fusion with instrumentation. The mean age of 21 patients, including 12 males and 9 females, at surgery was 62.9 years (range 34–79 years). The mean hospital stay was 30.4 days (range 24–53 days). The mean number of VAC dressing changes was 1.9 times, with 1 time for 4 patients, 2 times for 16 patients, and 3 times for 1 patient. The mean duration of continuous irrigation was 10.2 days (range 5–16 days) , 4 strains of methicillin-resistant Staphylococcus aureus (MRSA), and 1 strain of Staphylococcus epidermidis. In addition, 8 strains of gram-negative pathogens were found, including 5 strains of Escherichia coli and one each strain of Enterobacter cloacae, Acinetobacter baumanni, and Pseudomonas aeruginosa.Table P < 0.05). ESR and CRP returned to normal levels within 3 months in most patients.In this study, the levels of ESR and CRP in each patient were higher than normal before debridement. The mean ESR level declined from 58.4 ± 32.3 pre-operatively to 34.1 ± 14.5, 10.6 ± 6.3 and 9.1 ± 4.2 at 1 week, 3 months post-operatively, and the last follow-up, respectively .All patients were cured of the early deep SSI with implant retention. One patient developed a back skin rash with itching around the wound because of long time contact with the VAC dressing for 16 days, which was relieved after taking antiallergic drugs and removing the VAC dressing. There was no recurrent infection or other complications during follow-up. There were 7, 12, and 2 patients who had excellent, good, and fair outcomes, respectively, and no patients got poor outcomes according to Kirkaldy-Willis functional criteriaDeep SSI after posterior spinal fusion with instrumentation is a troublesome and undesired complication, which may result in pseudarthrosis, spondylodiscitis, correction loss, spinal instability, adverse neurological sequelae, and implant removal if not treated timely . Early dThe application of a continuous irrigation suction system can improve local microcirculation, remove necrotic tissues and inflammatory factors, decrease the bacterial adhesion and recontamination, avoid secondary wound closure, and reduce the number of postoperative operating room visits. Lian et al.  reportedThe VAC system has been widely used to treat deep SSI after posterior spinal instrumentation because of its advantages of reducing tissue edema, promoting granulation tissue formation and angiogenesis, increasing blood flow, decreasing bacterial presence in the wound, and removing necrotic tissue , 9, 18. In recent years, unlike many previous clinical applications of the VAC system for secondary wound closure, the incisional VAC system following primary wound closure has been successfully used for the prevention of SSI in spine surgery , 12. HowThe treatment method we adopt in this study combined the advantages of a continuous irrigation suction system and VAC system and eliminated the disadvantages of each other. In our study, the incisional VAC system application can remove drainage and infectious material around the closure wound, prevent fluid leakage from inflow or outflow tubes, avoid skin erosion around inflow or outflow tubes, decrease the risk of retrograde infection, increase microcirculation and tissue regeneration, protect the closure wound from external infectious sources as a sterile barrier, decrease lateral tissue tension, and promote incisional apposition in case of dehiscence . All theWith regard to laboratory testing related to SSI, ESR and CRP, as inflammatory markers, are two commonly used indicators to indicate improvement or progression of infection, especially CRP with more sensitivity , 26. UndMany scholars , 14, 26 We acknowledge there are some limitations to this study. First, the sample size of early deep SSI patients was relatively small. Second, there was no control group to further highlight the advantages of the treatment protocol in the study. Furthermore, this is a single-center retrospective study. To overcome these shortcomings, a multicenter prospective randomized controlled trial with a larger sample size should be performed to identify the efficacy of the treatment protocol used in this study.This study explores the feasibility and efficacy of an incisional VAC system following a one-stage incision suture combined with continuous irrigation for early deep SSI after posterior lumbar fusion with instrumentation. Our preliminary results support that the treatment protocol is feasible and effective to treat early deep SSI following posterior lumbar fusion with instrumentation. A multicenter prospective randomized controlled trial with a larger sample size should be conducted in the future.


BackgroundRadioneuromodulation (RNM) can explain the immediate pain relief experienced by a subgroup of patients after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). In this study, our main objective was to demonstrate that a minimum of a 50% reduction in TN pain can be achieved consistently in under 72 hours by targeting the affected nerve, the contralateral centromedian nucleus, and parafascicular complex in patients experimenting a prolonged refractory pain crisis.MethodologyWe treated eight patients experiencing severe TN pain crisis in whom percutaneous procedures had failed or were unwanted with SRS with an intention to procure pain relief in under 72 hours. The affected trigeminal nerve was targeted using a 4-mm collimator with an 80 to 90-Gy dose; an additional target was defined in the mesial portions of the thalamus and irradiated using the 4-mm collimator with a 120 to 140-Gy dose.ResultsThe median duration of TN was 60 months, the median duration of pain crisis was 10.7 weeks despite the best medical treatment, and the mean presenting visual analogue score (VAS) was 10 at the time of treatment. The median follow-up was 135 days . Twenty-four hours after treatment, two (25%) patients had no pain (VAS 0), three (37.5%) had mild pain (VAS 1 to 3), and three (37.5%) had moderate pain (VAS 4 to 7). Forty-eight hours after treatment, all patients reported pain relief, seven (87.5%) reported >50%, and one (12.5%) patients reported 30% relief. The three-month median VAS score was 3 . At the last follow-up, there were no adverse events to report.ConclusionsDual irradiation to the affected trigeminal nerve and contralateral mesial structures of the thalamus may provide fast pain relief for patients experiencing a prolonged pain crisis from TN, which veers away from the concept that the SRS pain relief effect is generally delayed and holds no place in the management of such patients. Although this is a small series with a limited follow-up duration, no adverse effects were noted.RNM can be defined as the capacity to alter neuronal activity through targeted delivery of a stimulus of radiation at a duration too brief to be explained by the development of a focal lesion. The immediate pain relief and its habitual oscillatory nature of lesser pain recurrence in most patients until enough time elapses for pain stabilization clinically demonstrates that the pain circuitry is altered and remains functional, thus accomplishing a neuromodulation effect even at the face of an apparent doses suspected to be ablative. Further research is needed to understand if this clinical effect is achieved with a suspected sub-ablative dose. Neuromodulation is the alteration of neuronal activity through the targeted delivery of an electrical or chemical stimulus. It can be achieved through minimally invasive techniques  or noninvasively by repetitive transcranial stimulation to a larger area of the brain ,2. An alRégis et al. proposed that SRS could produce a nonablative neuromodulation effect in epilepsy patients and other pathologies where radiological evidence failed to demonstrate a lesion, but the therapeutic effect remained ,9. EmpirIdeally, radioneuromodulation (RNM) achieves a long-lasting therapeutic effect or alteration of viable neurons’ function at a dose that would not produce tissue ablation via focalized radiation . TherefoRefractory TN, especially in patients experiencing a pain crisis, can become a multidisciplinary challenge. Most patients with a long history of pain progression are usually heavily medicated or are medicated by multiple first-line or second-line regimens. Many of these patients also receive invasive treatment modalities such as percutaneous rhizotomy or microvascular decompression .Gamma Knife is a safe and effective minimally invasive treatment modality commonly used to treat medically refractory TN . Its higSchneider et al. postulated a concept for RNM that alters neural activity if radiation is focally delivered to brain tissue at subablative doses . TherefoThis study investigated the RNM pain-relieving effect within 72 hours using SRS in refractory TN patients in a pain crisis. To our knowledge, this is the first series to deliberately elicit the RNM effect to alleviate pain using multiple targets and in areas other than the hypophysis.Patient selectionWe analyzed a small group of patients with refractory TN who were experiencing a severe pain crisis at the time of treatment. The study included patients aged 18 years or older who reported a VAS of 10 at the time of treatment. All patients had been declared refractory to medical treatment, including opioids, were unaffected by other invasive treatment modalities, and no other therapy was feasible or desired. The primary endpoint was to achieve an RNM effect within 72 hours of treatment by reducing the VAS score by at least 50%. VAS 0 indicated no pain, VAS 1 to 3 was considered mild pain, 4 to 7 was moderate pain, and 8 to 10 was intense pain. Pain measurement was based on the quality of pain assessment reporting , and parAdditionally, patients’ pain crises had to be constant for at least four weeks and without adequate pain control via regimens prescribed by a specialist . Moreover, included patients needed to have sufficient family support to understand treatment expectations, evaluate VAS changes after SRS, and report changes during the follow-up period. On the day of the treatment, patients were asked about their TN pain history including time of pain since diagnosis, exact pain location, VAS at the time of SRS, BNI prior to treatment and at last follow-up, and history of previous treatments including procedures and medication use. Patients were asked to continue using their regular medicine as prescribed before SRS, and their regimens were later adjusted depending on their response to SRS. The study was approved by the institution’s ethical committee, and all patients provided written consent.Radiosurgical techniqueOn the day of the procedure, patients were placed under local anesthesia and slight sedation, and a stereotactic frame  was placed by a neurosurgeon with the aid of ear bars searching for frame parallelism to the anterior and posterior commissure line or the intercommissural line (ICL). Magnetic resonance imaging (MRI) was performed using a 1.5-Tesla Avanto  as a T1 and T2 constructive interference in steady-state of 1-mm slices with no space covering the thalamus to the superior border of the corpus callosum and below the trigeminal nerve. Images were later transferred to the treatment planning station. For treatment planning, the anterior commissure and posterior commissure (PC) were identified in the axial plane, the images were then transformed into a sagittal plane using fusion tools, and the ICL was drawn between the T1 and T2 sequences. The distance from the PC was taken anteriorly along the ICL ; this measurement was tagged as Y. A 90° angle was traced from the PC to the Y along the ICL, and Z was usually determined 4-5 mm above the ICL. Images were then reoriented to axial views, and X coordinates were 5-6 mm lateral from the contralateral thalamic border to the side of the pain. Using a 4-mm collimator, a single shot was placed, and a 120 to 140-Gy dose was delivered. Finally, using T1-weighted multiplanar gradient recall gadolinium with 1-mm slices in axial orientation, a single 4-mm isocenter positioned at the retrogasserian zone (RGZ) of the affected trigeminal nerve with an 80 to 90-Gy dose was prescribed. Plans were reviewed and approved by the radiation oncology and neurosurgery teams  specifically within 72 hours of SRS. Patients were asked to assess their pain during every follow-up call and report any increase in pain despite the use of their usual medication.From January 2021 to September 2021, eight  patients were eligible for the treatment protocol and follow-up. The mean patient age at treatment was 63.2 years , and the median duration of the pain crisis was 10.7 weeks . The most affected side was the right side in seven (87.5%) patients, and all patients presented pain in more than one of the trigeminal branches . One (12.5%) patients had postherpetic TN in CNV1, and all other patients (87.5%) had primary TN.Regarding previous treatments, one (12.5%) patients had received a microvascular decompression of the trigeminal nerve and experienced pain relapse within a few months after the procedure. Four (50%) patients had received percutaneous radiofrequency procedures, and the other three (37.5%) had received medical treatment with primary line drugs (neuromodulators), nonsteroidal anti-inflammatory drugs (NSAIDs), or opioids. Two of these three (66%) patients declined other forms of invasive procedures  due to age and comorbidities. Presenting VAS score at the time of treatment was 10; thus, all patients presented with a BNI of 5. The median follow-up was 135 days .At 24 hours after treatment, two (25%) patients had no pain (VAS 0), three (37.5%) reported mild pain (VAS 1 to 3), and three (37.5%) had moderate pain (VAS 4 to 7). At 48 hours, all patients reported some level of pain relief (100%), seven (87.5%) had more than 50% relief, and one (12.5%) patient reported 30% pain relief according to VAS  patients experienced increased pain with a VAS 4 at 48 hours, VAS 5 at 72 hours, and VAS 7 at 96 hours. All other patients (87.5%) maintained pain levels between VAS 0 and VAS 5 within 96 hours of treatment. The RNM effect was seen in all patients 48 hours after treatment, with a mean VAS of 2 . The pain relief effect was monitored for at least 60 days after treatment  patients presented with short pain crises (VAS 8 to 10) within the follow-up period and were managed with other medications.The median score at three months was VAS 3 . Three months after treatment, one (12.5%) patient had an excellent response (BNI I), and seven (87.5%) patients had good results . The total success rate per BNI score was 100% (BNI I to IIIb). Two patients (25%) had moderate pain scores at the last follow-up (VAS 4 to 7), but they confirmed pain alleviation with complementary medication use. Six (75%) patients reported no pain to mild pain in their last follow-up examination. No complications, including facial paresthesia, were documented.Treatments for TN are generally divided into the following three categories: medical treatment, surgical treatment , and SRS. Craniotomy and microvascular decompression emerged as the gold standard treatment for medically refractory TN by the end of the 20th century . UnfortuPeripheral transmission and central areas of pain integration participate in the complex mechanisms regarding severe attacks of TN, which may account for the difficulty of treating refractory TN with a single target approach. Thalamotomy using SRS dates to the origins of Gamma Knife SRS with Leksell . This blThe rationale for targeting the TN, the contralateral CM nucleus, and PFc of the thalamus lies in the anatomy and pathophysiology of facial pain. The ventral posteromedial nucleus is adjacent to the CM-PFc region and is a relay center for the main sensory nucleus and the spinal nucleus of the trigeminal nerve that receives direct afferents from the spinal tract. The CM-PFc region also receives afferents from the ventral posterolateral and spinothalamic tract and the trigeminal lemniscus and finally gives efferent connections to the anterior cingulate cortex. This might explain the affective aspects regarding pain perception and, possibly, the RNM effect when this area is irradiated. Peripheral targets in the trigeminal nerve vary; some studies targeted the dorsal root entry zone (DREZ), where the anatomical transition in myelin characteristics is present, and others targeted the RGZ. In our experience, targeting the RGZ was more effective in pain control than the DREZ with similar adverse events, and the RNM effect was most often seen when targeting the RGZ. However, the maximum therapeutical effect was noted three months after treatment .Due to its delayed therapeutical effect, SRS does not traditionally play an important role in TN acute pain management. The results of this small series challenge the classical perception and open the possibility of SRS as an acute pain management approach for non-oncological pain such as refractory TN. RNM or most likely radio-neuro-endocrine-modulation has been documented in 70-80% of terminally ill oncology patients with refractory pain from bone metastases. Pain relief (as >50% VAS reduction) often occurs in less than 72 hours when a high dose of radiation is delivered to the hypophysis -14. GiviDespite achieving rapid pain relief after SRS in all patients, some experienced recurrent pain of different intensities that required additional pain management with NSAIDs, and two patients required an occasional intravenous phenytoin bolus (500-600 mg). Although our series is too small to assess the impact of these additional medical treatments, it indicates that the RNM effect does not result in complete pain relief for all patients, and possibly clinically proving that the neuronal circuitry responsible for pain transmission even at expected ablative doses remains viable but its function is altered and modulated. Physicians should monitor patients closely during additional pain management treatments until they achieve a permanent response, which can take up to three months in our experience.Regarding safety, no patient experienced facial numbness as of this writing, but additional follow-up is necessary. Irradiating the mesial structures of the thalamus is safe; Urgosik et al. and our group found no neurological disturbances associated with this procedure ,27, alonIn animal studies for epileptic models, high doses of radiation delivered with a Gamm Knife have shown a decrease of up to 55% of neuronal firing compared to the control animals; the rats receiving <50 Gy had no signs of necrosis . SmallerThe doses used in this study can be reduced, especially to the nerve, as other groups reported similar outcomes using a lower dose to the nerve (80 Gy) . This haOur study was limited by its small number of patients; however, it provides a clinical proof of concept that speaks to the potential for SRS to treat functional diseases with a multitarget approach in appropriate patients.Dual irradiation to the affected trigeminal nerve and contralateral mesial structures of the thalamus may provide fast pain relief for patients experiencing a prolonged pain crisis from TN, which veers away from the concept that the SRS pain relief effect is generally delayed and thus no place in the management of such patients. Although this is a small series with a limited follow-up duration, no adverse effects were noted. From our previous experience and this recent series, the combination of targets might be a safe alternative for patients experiencing prolonged pain crisis in refractory TN.RNM has yet to be fully explored and defined that includes understanding which areas should be treated and the doses are truly ablative and needed to achieve RNM. Although suspected ablative doses were used in most patients, this series provides a clinical proof of concept of the consistency of RNM in obtaining quick pain relief. Further research is needed to determine doses that can provide similar results outside of what is expected to be the ablative spectrum.


Video-assisted thoracoscopic lobectomy is the prior recommended treatment for non-small cell lung cancer (NSCLC), with the advantages of small trauma, less postoperative pain, and quick recovery. However, a large number of patients may suffer chronic postsurgical pain (CPSP), which makes the patients unwilling to practice pulmonary exercises, and it would directly affect patient's cough, sputum expectoration, and mobility. Opioids could greatly improve the quality of postoperative analgesia and the quality of life after surgery, but it is accompanied with obvious side effects. A number of clinical studies have proved that acupuncture could improve postoperative pain and reduce opioid use. In this study, we try to conduct a randomized controlled study to evaluate the efficacy and safety of plum-blossom needle acupuncture combined with Tramadol in improving CPSP after lobectomy in NSCLC patients.Patients will be randomly divided into treatment group (acupuncture plus Tramadol) and control group (sham acupuncture plus Tramadol) with a random number table in 1:1 ratio. The patients, outcome assessor, and statistician will be blinded. The outcomes are changes of numerical rating scale, Karnofsky performance score, brief pain inventory, blood routine, liver and kidney function. The data will be analyzed by SPSS 22.0.The results will help to evaluate the efficacy and safety of plum-blossom needle acupuncture in improving CPSP after lobectomy in NSCLC patients. Nowadays, the rapidly emerging technique, video-assisted thoracoscopic lobectomy (VATL) is the prior recommended treatment for NSCLC, with the advantages of small trauma, less postoperative pain, quick recovery, and better patient satisfaction.–8 Recently, VATL continues to improve with the decreasing working port size and incisions. The conventional multiportal VATL with several incisions was alternated to triportal, and recently biportal, or even uniportal VATL.,10Lung cancer is one of the most common malignant tumors, with the highest morbidity and mortality rate worldwide, which seriously threatens human health and life.–13 The occurrence and severity of CPSP after lobectomy is an important factor to influence the recovery of patients with NSCLC. CPSP makes the patients unwilling to practice pulmonary exercises, and it directly affects patient's cough, sputum expectoration, and mobility. Patient with CPSP may even complicate with atelectasis, lung infection, hypoxemia, which greatly lower the quality of life.,14However, in patients undergoing lobectomy, a large number would suffer chronic postsurgical pain (CPSP), the most common complication after chest surgery. The biportal or uniportal VATL approach has been proposed to perform feasibly and safely in lobectomy with less incisions and quicker recovery, but many patients may still complicate with CPSP.Conventional analgesia methods for CPSP after lobectomy mainly include patient controlled analgesia, regional analgesia, and analgesic pumps. Patient controlled analgesia, involving opioids such as morphine and fentanyl, as well as anti-inflammatory drugs, could greatly improve the quality of postoperative analgesia and the quality of life after surgery, but it is accompanied with obvious side effects, such as urine retention, vomiting, and allergies. Therefore, to seek a safe and effective combined therapy is important for the treatment of CPSP. and a number of clinical studies have proved its efficacy for postsurgical pain. Acupuncture could improve postoperative pain and reduce opioid use. However, there are fewer studies on acupuncture against CPSP after lobectomy. Our group preliminarily found that plum-blossom needle percussion, one of the acupuncture therapies in traditional Chinese medicine, combined with analgesic could significantly relieve CPSP in NSCLC patients and reduce the side effects of analgesic. Therefore, in this study, we try to conduct a prospective, randomized controlled study to evaluate the efficacy and safety of plum-blossom needle combined with Tramadol Hydrochloride Sustained Release Tablets in improving CPSP after lobectomy in NSCLC patients.Acupuncture, a traditional alternative therapy, has been used to treat pain for many years,22.1The randomized, controlled trial will be carried out in Chongqing Steel General Hospital, and it has been approved by the Health Research Ethics Board of Chongqing Steel General Hospital. The study has been registered in open science framework with registration number of DOI 10.17605/OSF.IO/RJEYB. All patients will provide a signed written informed consent at enrollment.The inclusion criteria for participants are as follows:(1)diagnosis of CPSP after lobectomy in NSCLC patients;(2)being aged between 35 and 75 years old;(3)with 3 < numerical rating scale (NRS) < 7;(4)with Karnofsky performance score > 60;(5)with signed written informed consent.Patients will be excluded with the following criteria:(1)with previous history of thoracic surgery;(2)who had undergone targeted therapy or chemoradiotherapy before;(3)with peripheral structures invasion;(4)with contraindication plum-blossom needles, such as wounds, ulcers, scars at the puncture site;(5)with abnormal renal or liver function;(6)with other surgical contradictions.2.2Patients will be randomly divided into treatment group (acupuncture plus Tramadol) and control group (sham acupuncture plus Tramadol) with a random number table in 1:1 ratio , 100 mg, and twice a day for 14 days.In the treatment group, plum blossom needles  percussion will be performed on pain area, 70 to 90 times per minute for 10 minutes, with moderate percussion intensity, once every 2 days, and the treatment course will be 14 days.While in the control group, plum blossom needles  percussion will be performed around the pain area, 70 to 90 times per minute for 10 minutes, with moderate percussion intensity, once every 2 days, and the treatment course will be 14 days.2.4The primary outcome is the change of NRS at day 0, day 7, and day 14. The secondary outcomes are Karnofsky performance score, brief pain inventory, blood routine, liver and kidney function before and after the treatment. The change of Tramadol application will be recorded. All adverse events will be also recorded.2.5In our preliminary trial, the changes of NRS in treatment group and control group are 2.65 ± 1.25 and 1.8 ± 1.31, respectively. Taking α = 0.05, β = 0.2, 30 cases will be needed in each group. Considering a loss to follow-up of 20%, the estimated sample size will be 72.2.6t test or Mann–Whitney U test will be applied accordingly. P < .05 will be considered statistically significant.The data will be analyzed by SPSS 22.0 . The count data will be described by number and percentages, and the comparison between groups will be performed by chi-square test; The measurement data will be presented as mean ± standard deviation. Repeated measures analysis of variance will be applied for repeated data, considering normality and homogeneity. For the changes between groups, 3,17,18 However, patients may still suffer from CPSP. CPSP refers to the continuous or intermittent pain, mainly caused by surgery. In most cases, CPSP lasts longer than 2 months, and it could seriously affect the rehabilitation and quality of life of patients. CPSP could lower the respiratory rate and tidal volume to cause atelectasis and pulmonary infection. Opioids, such as Tramadol, could improve the quality of postoperative analgesia and the quality of life after surgery, but it is accompanied with obvious side effects.Lobectomy is an important treatment for patients with NSCLC lung cancer. With the increasing enhancement of equipment and technology, VATL could greatly lower the incidence of mortality and complications. and reduced opioid use. Plum blossom needle is an important acupuncture method in traditional Chinese medicine, and it has the advantages of low cost, high tolerance, convenience, and minimal adverse reactions. In this study, we try to conduct a prospective, randomized controlled study to evaluate the efficacy and safety of plum-blossom needle combined with Tramadol Hydrochloride Sustained Release Tablets in improving CPSP after lobectomy in NSCLC patients. Also, there are several potential limitations of the trial. First, the single-blinded design may cause inevitable bias. Second, the limited patients’ source may cause some biases.Many studies have showed that acupuncture can be useful for the postoperative pain managementData collection: Congyi Wang and Ling Xiao.Data curation: Congyi Wang.Funding acquisition: Gang Li.Funding support: Gang Li.Investigation: Congyi Wang and Ling Xiao.Literature retrieval: Changxi Zhang and Congyi Wang.Software operating: Congyi Wang.Supervision: Ling Xiao.Writing – original draft: Gang Li and Changxi Zhang.Writing – review & editing: Gang Li and Gang Li.


To the Editor,International Journal of Emergency Medicine :10), we want to first congratulate the authors for the successful publication of this article. Additionally, we hope to contribute some of our findings to further enhance this line of research.After reading the review article titled “The emergency department care of the cannabis and synthetic cannabinoid patient: a narrative review” by Kevin Takakuwa and Raquel Schears published in the As the legalization of cannabis continues to spread in North America, it has become increasingly important for physicians to recognize and treat cannabinoid-related syndromes. In this secondary analysis of a randomized controlled trial that studied the effect of topical capsaicin on patients presenting to the emergency department (ED) with cannabinoid hyperemesis syndrome (CHS), we describe symptomatology and return visits in patients suffering from CHS .Our study population consisted of 29 participants with a mean age of 30 years. Most patients were Black (90%) and hypertension was the most frequent comorbid condition (28%). All participants experienced nausea and vomiting. Other reported symptoms included abdominal pain (90%), chills (52%), and diarrhea (27%). Abdominal pain was mild  2.7 ± 1.2 cm) compared to nausea (mean VAS 7.3 ±2.5 cm). Sixteen patients accounted for 41 repeat ED visits and 10 hospitalizations for CHS-related symptoms within 6 months.Data indicates that the increased accessibility of cannabis in the USA is associated with an increase in cannabis-related conditions presenting to the ED . Many ofWhile the majority of published studies of CHS obtain retrospective data or present small case series, this prospective data provides an accurate assessment of patient symptoms and high rates of return visits. It also includes data on a largely Black cohort, whereas most published literature on CHS is inclusive of White patients. We present quantified data on the degree of nausea common among CHS patients and the degree of abdominal pain. Contrary to prior studies, we found that abdominal pain severity is overall mild to moderate, especially when compared to nausea severity . Given tIn this cohort of CHS patients, it was found that nausea was a larger concern for patients than abdominal pain and that repeat encounters for related symptoms were common. As cannabinoid use becomes more mainstream, physicians in all settings should include CHS in their differential when faced with GI symptoms.


Three of the women who demonstrated a significant VAS reduction at T7 retained such VAS improvement at T30. VAS decreased by six points (95% CI 1.3–10.7) at T30 ). This coupled approach seems promising for pain management in adult women with refractory CPPS and paves the way for future randomized controlled trials.Chronic pelvic pain syndrome (CPPS) affects about 4–16% of adult women, and about one-third of them require medical assistance due to severe symptoms. Repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) has been shown to manage pain in refractory CPPS. Focal muscle vibration (FMV) has also been reported to relieve pelvic pain. The objective of this study was to assess the feasibility and effect of rTMS coupled with FMV to reduce pain in seven adult women with refractory CPPS. This pilot, open-labeled, prospective trial examined treatment by 5 Hz rTMS over SMA and 150 Hz FMV over the perineum, suprapubic, and sacrococcygeal areas, with one daily session for five consecutive days for three weeks. We assessed tolerance and subjective pain changes  until one month post-treatment, with a primary endpoint at day 7. No patients experienced serious adverse effects or a significant increase in pain. Six out of seven patients experienced a VAS improvement of at least 10% at T7; three of these individuals experienced a VAS improvement of more than 30%. Overall, we found a significant VAS reduction of 15 points (95% CI 8.4–21.6) at T7 (t = 6.3,  Chronic pelvic pain syndrome (CPPS) is a centralized and disabling pelvic region disorder that is diagnosed when pain has persisted for at least six months. In women, the prevalence of CPPS is between 4 and 16%, and about one-third of them require medical assistance due to severe gastrointestinal and gynecological symptoms, as well as the psychological burden associated with these symptoms ,3. TheseThe management of CCPS is challenging given that pharmacological and rehabilitative treatments , aimed at promoting muscle relaxation and increasing analgesia, are often unsatisfactory . MoreoveTranscranial magnetic stimulation (TMS) and muscle vibration (MV) are among the complementary approaches to relieve pain ,8,9. RepMV has generated good results concerning muscle strengthening, the normalization of basal muscle tone, and pain relief. However, it has been mainly employed as whole-body vibration , whereasMV has been combined with other rehab strategies to improve functional outcomes . CombiniIn this study, we consecutively enrolled female patients attending our rehabilitation institute, who complained of refractory CPPS, between January 2018 and March 2020 (when the enrollment was interrupted due to the COVID-19 pandemic).The inclusion criteria were the following: (i) A diagnosis of CPPS , refractory to the most common treatments, including drugs  and surgical treatments; the diagnosis had to be corroborated by a careful clinical examination with urodynamic, laboratory, and urinalysis testing and the exclusion of other syndromes with similar symptoms . (ii) PaThe exclusion criteria were the following: (i) prior, recent treatment with rTMS; (ii) new medications initiated during the month prior to study entry; (iii) contra-indications to rTMS; (iv) severe pain syndromes other than CPPS; (v) unable to give written informed consent; and (vi) being in the menstrual phase .All study aspects conformed to the principles described in the Declaration of Helsinki and its subsequent amendments, and they were approved by our Institutional Review Board (IRCCSME ID: 32/2017). All participants provided their written informed consent.Patients were assessed daily for one month  (T0) using a visual analog scale (VAS) with a range from 0 to 100, the short form of the Brief Pain Inventory (BPI) , the PatThe primary outcome was the percentage of patients who reported serious adverse effects and who did not complain of a significant decrease in pain (using VAS with a 0–100 range) at T7 compared to T0. A variation of 10% was considered significant ,17,38,39Secondary outcome measures included the pain variation (as per VAS) between T30 and T0, and the variations in BPI, PGIC, BDI, and QOL at T7 and T30 compared to T0.Patients underwent an rTMS-MV paradigm every day in the late morning/early afternoon, once a day, five days a week, for three weeks a. Patien2 fixed to the suprapubic and sacrococcygeal areas by a Velcro strap and a pen-like probe positioned over the perineum, held by the therapist who carried out FMV . The device is equipped with cup-like probes of 2 cm out FMV b. MV wasOnce the MV began, we applied a high-frequency rTMS over SMA. In this regard, we first determined the motor hot spot for the relaxed abductor hallucis of the right foot (AH) and first dorsal interosseous of the right hand (FDI) using single magnetic pulses delivered through a figure-of-eight coil ) placed tangentially over the scalp with the handle pointing backward with a 45-degree angle to the midsagittal for the FDI hotspot and along the sagittal midline with the handle pointing to the right for the AH hotspot c 40], w, w40], wConcerning SMA rTMS, we adopted a facilitatory 5 Hz stimulation protocol using the TMS setup mentioned above. Trains of 50 pulses at 5 Hz (10 s) every 50 s, repeated ten times for a total of 500 pulses (in 10 min), were delivered over SMA at 110% AMT of FDI b. We adoThis pilot study aimed to assess the feasibility and safety of rTMS-MV treatment for refractory CPPS, paving the way for future randomized controlled trials. Therefore, the study sample size was estimated concerning the primary outcome measure (the percentage of patients undergoing the treatment who reported serious adverse effects and did not complain of a significant decrease in pain). A conservative estimate of this effect size was assumed (d = 0.3), given that it widely varies across the published studies ,43. TherContinuous data are presented as the mean ± standard deviation or the median (interquartile range) according to statistical distribution .The assessment of patients tolerating the protocol and showing pain reduction at T7 compared to T0 is presented with a 95% confidence interval and was statistically assessed at the individual level using the reliable change indicator (RCI) , which it-test or Wilcoxon test. The tests were two-sided, with type I error set at α = 0.05. The Hedges’ g effect size (ES) was calculated [Paired comparisons were carried out using the Student paired lculated  and estilculated .The statistical analysis was performed using Stata software, version 13 .Seven women diagnosed with refractory CPPS were enrolled in this pilot study. They all complained of severe pain, mainly localized at the suprapubic region, the pelvis, and the lower abdomen and back. In addition, urinary symptoms, including urgency, frequency, and nocturia, were also reported. VAS individually varied during the one-month baseline assessment by no more than 6 ± 2%, although there were some exacerbation days. However, both these aspects were consistent with the diagnosis of CPPS. Baseline data are summarized in All enrolled patients completed the protocol and were assessed at the one-month follow-up. All patients tolerated the protocol, and none reported any significant side effects or discomfort following each rTMS session, but, occasionally, mild headache and neck pain were reported; in such a case, we slightly increased (+5%) the interval time or slightly reduced (−5%) the duration of stimulation to minimize any side effects. In addition, no pain increase was reported either during or after each rTMS session. Data are summarized in p = 0.001; ES = 2.3 (1.1–3.9); Six out of seven patients experienced a VAS improvement of at least 10% at T7; three of these individuals experienced a VAS improvement of more than 30% . OverallThus, the main outcome was achieved with a tolerance rate of 100%  and a significant pain reduction  in 86% of participants.p = 0.02; ES = 1.5 (0.2–2.6); Three of the individuals who demonstrated a significant VAS improvement at T7  retained such improvement at T30 (43% of participants). Specifically, VAS decreased by about eight points at T30 (95% CI 1.3–10.7), which was statistically significant at both the group level  and T30  (p = 0.002), whereas such an improvement was not significant at T30 (p = 0.2) (p = 0.001), whereas such an improvement approached statistical significance at T30   . QOL sigp = 0.2) . BDI sig = 0.06) . Finally = 0.06) .For the first time ever, our pilot study suggests that combining rTMS over SMA with FMV to PFM is a safe and effective add-on treatment to alleviate pain and improve QoL in women with refractory CPPS. Pain intensity, as per VAS scoring, was reduced by about 30% in the majority (six out of seven) of patients, with a small effect size  that, however, corresponded to a minimal clinically important difference for chronic pain conditions ,49,50.To date, no studies have investigated rTMS over SMA and FMV to PFM applied together. We can, thus, only compare our preliminary findings with the currently available data on stand-alone rTMS over SMA and FMV to PFM. The pain-relieving effects of rTMS applied to PFM representation in SMA are well known, but they require large-scale confirmatory studies . In partOverall, these studies suggest that rTMS over SMA may increase or decrease M1 excitability, depending on the SMA conditioning protocol, thus affecting PFM tone . FurtherFMV is a validated approach to manage pain and spasticity-related pain in different neurological conditions, including stroke, multiple sclerosis, and cerebral palsy ,32,56,57The aftereffects of the 15 rTMS and FMV sessions that we employed were longer than those reported in the abovementioned rTMS studies ,17,18,51Finally, we have to acknowledge the potential interaction among neuromodulation and concomitant pharmacological therapy. Even though we did not assess or observe  a decrease in “drug consumption for pain” or “number of days taking drugs for pain”, an interaction between the treatments is plausible. In fact, there could be a synergic effect between neuromodulation and conventional therapy, including cyclo-oxygenase inhibitors, tricyclic antidepressants, and neuromodulation drugs , which can all affect pain-processing-related synaptic plasticity ,71,72,73The main study limitations are the lack of a control group and the limited sample size. However, this study was intended as a pilot one to preliminarily assess the safety and feasibility of the approach. In addition, the importance of a placebo effect deserves further investigation, even though there were no evident BDI changes, thus suggesting that the clinical alleviation of pain was not preponderantly due to improvements in the patients’ psychological statuses .The management of refractory CPPS is still challenging despite the availability of several pharmacological and non-pharmacological approaches, thus raising the need for new treatment options. Our pilot study suggests that coupling high-frequency rTMS over SMA with FMV to PMF is feasible, effective, and well tolerated in patients with refractory CPPS. A consistent proportion of the patients reported a significant improvement in individually estimated pain and PGIC up to 30 days following the end of the stimulation protocol. The coupled approach, together with actual pharmacological therapy, may positively influence pain by mediating a functional reorganization of the pain-related plasticity processes related to the emotional component of pain, the pain processing mechanisms, and the descending inhibitory pathways. Furthermore, this combined approach potentially fits with other therapies, as it has no pharmacological or surgical side effects and does not interfere with concomitant pharmacological treatments. Consistent with the limited sample and the pilot nature of the study, our data pave the way for future, larger, randomized clinical trials to support this approach as a new analgesic technique to be applied in daily clinical practice. This will also allow more accurate and thorough knowledge of the neurophysiological correlates of rTMS and FMV concerning pain reduction in CPPS.


Our data show that SF-36 has validity and reliability and can be used in patients with endometriosis. Surgery improved the QoL and digestive function.Morbidity and mortality alone are not comprehensive measures of evaluating the benefits of surgical interventions in endometriosis patients, thus, subjective patient-reported instruments are required. The 36-tem Short Form Survey (SF-36) is a Health-Related Quality of Life (HRQoL) instrument that has not been validated yet for women with endometriosis. The aims of this study are to evaluate the validity and reliability of the SF-36 in patients with colorectal endometriosis and to compare the HRQoL before and after surgery, using different Quality of Life (QoL) instruments: the Gastrointestinal QoL Index (GIQLI) and Knowles–Eccersley–Scott Symptom Questionnaire (KESS). We conducted a retrospective study using prospectively recorded data in the North-West Inter-Regional Female Cohort for Patients with Endometriosis (CIRENDO) database. The assessment was performed on four hundred and eighty-eight patients before and 12 months after the surgery. Preoperative and postoperative item-internal consistency and Cronbach’s α proved evidence for good reliability showing that SF-36 is a useful instrument for endometriosis patients’ QoL. The domains of Role (limitation) physical, Bodily pain and Role (limitation) emotional showed the most remarkable improvements (difference before vs. one year after surgery) with  Deep endometriosis (DE) is characterized by the presence of endometriosis lesions that infiltrate the peritoneum by >5 mm . It occuEndometriosis affects the quality of life (QoL) of young, active women by disrupting their ability to work, their sexual functioning and their social relationships . The HRQThe aim of this study is to evaluate the validity and reliability of SF-36 in patients with endometriosis before and after surgical treatment. A second objective is to compare the HRQoL pre and postoperatively, using different instruments apart from SF-36, such as the Gastrointestinal Quality of Life Index (GIQLI) and Knowles–Eccersley–Scott Symptom (KESS) questionnaire, which are validated and suitable for endometriosis-related gastrointestinal symptoms and the Visual Analogue Scale (VAS), as shown by Bourdel N. et al. in an exhaustive systematic review, which is considered the “gold-standard” for pain-measurement .The present study is a retrospective analysis of prospectively recorded data from June 2009 to November 2016 at Rouen University Hospital, Rouen, France and includes patients with surgical procedures for DE nodules of the rectum or sigmoid colon. The procedures, both laparoscopies and laparotomies, were performed by our team, which has significant experience in the surgical management of colorectal endometriosis. The women were enrolled in the CIRENDO database , a prospective cohort with financial support by the G4 Group . Prospective data recording and analysis were approved by the French authorities CNIL  and CCTIRS . Of the patients enrolled in CIRENDO, we selected for analysis those with histologically confirmed endometriosis and one-year follow-up visit. The surgical and histological records, as well as the self-assessment questionnaires completed before and after the surgery, provide information for the study. Data were recorded by a clinical researcher in charge of evaluating patients’ follow-up. All patients filled in baseline standardized questionnaires, i.e., SF-36, GIQLI, KESS, before surgery and one year after, as implemented by the CIRENDO protocol. The Visual Analog Scale (VAS) was also used for the evaluation of dysmenorrhea and dyspareunia, with and without pain relief medication. The French-language versions of the SF-36, GIQLI and KESS questionnaires were validated long ago on large cohorts .The SF-36 self-administered questionnaire incorporates 36 standardized items evaluating the generic health status of a patient . This suThe GIQLI and KESS questionnaires are used when describing, comparing and differentiating the outcomes of surgical treatment in patients with gastrointestinal diseases. The GIQLI survey consists of 36 questions targeting intestinal dysfunctions, with scores ranging from 0 (worst) to 144 (best) . The KESThe baseline and management characteristics and questionnaire results before and after surgery are presented as absolute and relative frequencies for qualitative variables and as mean and standard deviations for quantitative variables. Two techniques were used for the evaluation of the internal consistency of the SF-36 questionnaire: item-scale correlation and Cronbach’s α. The item-scale correlation was assessed by using item-internal consistency and item-discriminant validity. Item-internal consistency estimates the correlation between the implied item and the sum of the other items on the same domain; its value must be greater than 0.4 . Item-diConstruct validity was evaluated by comparing the SF-36 scores and pain  intensity levels, both pre and postoperatively. The Pearson correlation coefficient was used for evaluating the relationship between HRQoLs as measured by the SF-36 and pain intensity as measured by the VAS.A paired T-test of differences before and one year after surgery was used to determine changes in the SF-36 , the KESS and GIQLI scores and in the pain intensity VAS score. Observed differences between pre-op and one-year post-op values were described using 95% confidence intervals (95% CI). For the patients whose KESS and GIQLI scores showed a worsening of digestive symptoms, the evaluation of the HRQoL was compared separately using a T-test for means comparison. Statistical analysis was performed using the software IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY, USA: IBM Corp.We enrolled 488 patients from the CIRENDO database. Patients’ characteristics at baseline are presented below in The most important intraoperative findings and surgical procedures are represented below. Postoperative complications were reported in the order of their appearance, as follows: ureteral fistula 7%, digestive tract fistula 2.2%, pelvic abscess  0.6%, bladder atony 0.6%, pelvic abscess (conservative management) 0.4% and others 1.8% .p < 0.001) at one year post-surgery compared to preoperative evaluations. This intensity decreased from 8.4 ± 1.5 to 2.1 ± 3.2 points without PRT and from 4.7 ± 2.3 to 2.9 ± 2.1 with PRT. A similar evolution was noticed in dyspareunia intensity without PRT. We observed a significant decrease in VAS score (p < 0.001) from 5.6 ± 2.4 preoperative to 1.9 ± 2.8 post-op at one year. Dyspareunia with PRT only slightly decreased after surgery, from 4.0 ± 2.3 to 3.8 ± 2.3, without achieving statistical significance (p = 0.657) , which primarily consisted of nonsteroidal anti-inflammatory drugs (NSAIDs), decreased significantly (= 0.657) .Item-internal consistency exhibited preoperative values of 0.472 , 0.760 (Bodily Pain dimension) and signaled good internal consistency. Item-internal consistency had better postoperative values for all of the eight domains of the SF-36.Scaling success rates were used to evaluate item-discriminant validity. The preoperative scaling success rate had values greater than 98.2%. The postoperative scaling success rate showed values greater than 99% for 7 of the 8 domains of SF-36. The values of this reflected higher correlations with their hypothesis scales than with other scales, both pre and postoperatively, except the Vitality domain, which slightly decreased in postoperative, from 98.2% to 97.7%, due to high correlation between the vitality item (VT) and distinct scales.Internal consistency measured with Cronbach’s α was greater than 0.7 for all of the eight domains of the SF-36, both pre- and post-op. Cronbach’s α for pre and postoperative PF and for postoperative BP exceeded the 0.9 threshold, meeting the recommended standard criteria for individual comparisons .p < 0.001), than the preoperative mean scores. The most remarkable improvements were observed in the domains of Role (limitation) physical (26.9), Bodily pain (25.4) and Role (limitation) emotional (20.8).All of the SF-36 domains and the summary scales  revealed significantly higher mean values postoperatively . All of the SF-36 domains scored inferior values for the HRQoL compared to a nationally representative sample of healthy French women aged 25–34, both preoperatively and postoperatively .All SF-36 domains correlated negatively with dysmenorrhea (with and without treatment) and dyspareunia (without treatment), as measured by the VAS, both preoperatively and postoperatively. The scores for dyspareunia with treatment were significantly correlated with the preoperatively Bodily Pain scores and with the postoperatively General Health and Social Functioning scores .p < 0.001). The KESS score dropped from 10.6 ± 7.6 to 9.1 ± 7.1 and the GIQLI score increased from 76.6 ± 35.9 to 90.5 ± 38.5 (Both KESS and GIQLI scores significantly improved one year after surgery (5 ± 38.5 . The KES5 ± 38.5 .p = 0.006), in addition to the Physical component score (p = 0.047). Patients with worsened GIQLI scores also experienced higher scores for the Physical Functioning and Role (limitation) physical domains , without statistical significance.The GIQLI score improved in 66.8%, worsened in 21.3% and remained stationary in 11.9% of the patients. The 104 patients whose GIQLI score decreased also experienced a decrease in the scores for most HRQoL domains but without statistical significance. Bodily Pain is the only SF-36 domain that recorded a statistically significant increase  [The domains that exhibited the largest improvement 12 months after surgery were Role Limitation (RP) , Role Limitation (RE) , and Bodily Pain (BP). These domains exhibited some of the lowest preoperative scores . Our results are in line with most of the other studies ,21,22. Rctively) . Anotherctively) . Meulemactively) ,27.It can be challenging for patients to deal with gastrointestinal symptoms due to colorectal endometriosis or surgical treatment procedures . In our p < 0.001). Therefore, pain intensity in the form of either dysmenorrhea or dyspareunia, with or without treatment, represents an important component of diminished self-perceived HRQoL. In a prospective study on patients with colorectal excision for endometriosis, Bailly et al. showed significant improvement in postoperative VAS scores for dysmenorrhea (p < 0.0039), dyspareunia (p < 0.0084), chronic pelvic pain (p < 0.0002) and dyschezia (p < 0.0312) [p < 0.080 and p < 0.173, respectively). Hence, the same study proved that dysmenorrhea and chronic pelvic pain VAS median scores improved one year after surgery  and reached statistical significance  [Previous studies on the topic mainly emphasize the improvement in pain after laparoscopic surgery for colorectal DE ,35. In tctively) .Our study corroborates the findings of most of the literature. SF-36 is a valid and reliable survey instrument. It confirms the improvement in the overall HRQoL in women who undergo surgery for colorectal DE. It is of note that surgery also improved HRQoL in patients without objective improvement in digestive function. Our results confirm that surgically-treated colorectal endometriosis associates with better HRQoL and improvement in digestive function, as evaluated with SF-36, GIQLI, KESS and VAS questionnaires. The decision to perform a surgical procedure should be a consideration in symptomatic patients with colorectal DE.


In comparison to asymptomatic controls (n = 69), machine learning revealed three bladder pain phenotypes with unique, salient features. The first group chiefly describes urinary frequency and pain with the voiding cycle, in which bladder filling causes pain relieved by bladder emptying. The second group has fluctuating pelvic discomfort and straining to void, urinary frequency and urgency without incontinence, and a sensation of incomplete emptying without urinary retention. Pain in the third group was not associated with voiding, instead being more constant and focused on the urethra and vagina. While not utilized as a feature for clustering, subjects in the second and third groups were significantly younger than subjects in the first group and controls without pain. These phenotypes defined more homogeneous patient subgroups which responded to different therapies on chart review. Current approaches to the management of heterogenous populations of bladder pain patients are often ineffective, discouraging both patients and providers. The granularity of individual phenotypes provided by unsupervised clustering approaches can be exploited to help objectively define more homogeneous patient subgroups. Better differentiation of unique phenotypes within the larger group of pelvic pain patients is needed to move toward improvements in care and a better understanding of the etiologies of these painful symptoms.Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as an unpleasant sensation perceived to be related to the bladder with associated urinary symptoms. Due to difficulties discriminating pelvic visceral sensation, IC/BPS likely represents multiple phenotypes with different etiologies that present with overlapping symptomatic manifestations, which complicates clinical management. We hypothesized that unique bladder pain phenotypes or “symptomatic clusters” would be identifiable using machine learning analysis (unsupervised clustering) of validated patient-reported urinary and pain measures. Patients ( Interstitial cystitis/bladder pain syndrome (IC/BPS) is a frequently debilitating, chronic condition whose central diagnostic feature is pain attributed to the bladder . Direct While the central feature of IC/BPS is the perception of bladder pain, patients exhibit a diverse range of accompanying genitourinary (GU) symptoms such as urinary urgency, frequency, nocturia, dyspareunia , pelvic pain, and incontinence . These tDespite this large symptomatic diversity, IC/BPS is typically managed and studied as a single clinical condition. The combination of inconsistent mechanistic data, the large diversity of symptom expression, and the inability of any specific treatment to prove effective in more than a subset of patients suggest that IC/BPS is not a single clinical condition, but instead may reflect several unique pathologies that manifest with similar, overlapping symptoms , 11. It n = 145), we enrolled premenopausal women (maximum age of 45) suspected of having IC/BPS by their treating provider at initial consultation. Diagnosis was made by one of four board-certified, Female Pelvic Medicine and Reconstructive Surgery specialty urologists from a detailed history and physical exam using the definition established by the American Urological Association (AUA)/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU): IC/BPS is “an unpleasant sensation  perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than 6 weeks duration, in the absence of infection or other identifiable causes” (n = 69) were recruited independently from patients seen in the same clinic who had been referred for urologic evaluation for a range of benign, asymptomatic findings, such as renal cyst or microscopic hematuria. All of these subjects had a BPCI score <3 and asymptomatic responses on all additional questionnaires.After approval from the local Institutional Review Board (IRB# Pro00046154), 521 sequential patients complaining of any element of pelvic pain were evaluated from the Cedars-Sinai Women's Urology Clinic for possible inclusion. For the IC/BPS cohort , current smoking, or a vaginal pessary. As worsening pain in association with menstrual cycle can be a common feature of IC/BPS, subjects who experienced flares or worsening pain during phases of the menstrual cycle were allowed to participate, but were excluded if they complained only of isolated cyclic pain at menses . Baseline demographics and clinical data including age, body mass index (BMI), comorbidities, past surgeries, and medication usage, including hormonal medications, were captured at enrollment.After signing informed consent, subjects completed the female Genitourinary Pain Index (fGUPI)  and InteFigure 2A). This provided an estimation of the number of likely clusters within the studied population of IC/BPS subjects, of which two or three groups appeared the most appropriate. The elbow method, in which the explained variation in the data is plotted as a function of the number of possible clusters . Second, we applied the K-means machine learning algorithm (k determined in step 1) subgroups using phenotypic variables derived from the symptomatic assessment instruments. All measurements were standardized using z scores for continuous variables and 0 or 1 for categorical variables. Continuous variables were log transformed to approximate a normal distribution where indicated. Patient cluster distribution visualized by principal coordinate analysis with the Bray-Curtis dissimilarity measure.Cluster analysis methodology utilized a two-step approach to generate symptomatic clusters for the IC/BPS population. Controls were not included in the derivation of clusters. First, hierarchical clustering using Ward's method generated a cluster dendrogram , an unsupervised technique of clustering and dimensionality reduction, consist of an arbitrary number of nodes where each node represents a point in the original, multi-dimensional input space. As new points are added, they are classified by pairwise Euclidean distance with the nearest neighboring node. The grid of nodes is trained such that nearby nodes resemble each other more than nodes that are further away. A final step uses hierarchical clustering to group the nodes into a user-defined number of metaclusters, which is then visualized in two-dimensional space . This anK-means randomly assigns observations to a new cluster given an arbitrary number designation; thus, an emergent cluster of the same observations may be assigned a different cluster number in the bootstrapped sample. To account for differences in cluster number assignment when determining these metrics, we reassigned cluster numbers based on the highest interrater reliability (kappa) between the original cluster and the bootstrapped clusters.To ensure cluster assignment stability, we resampled a large number of replications  with replacement (bootstrapping) and identified the cluster assignments for each iteration. The Rand  and JaccTo determine if there were additional features common to each symptom cluster that could not be captured by the patient-reported outcomes administered in this study, we performed a modified thematic analysis approach. Descriptions of patient complaints and features were captured from the history of present illness and assessment of the specialist's initial consultation within the electronic medical record. Primary patient complaints/bothersome symptoms as well as anticipated symptomatic features  were cataloged by two reviewers blinded to both subject cluster assignment and the nature of the characteristic cluster symptomatic features.For the 145 IC/BPS subjects, treatment responses were assessed by chart review for therapies prescribed after inclusion. Response to treatment was noted to be positive if the immediate post-treatment note documented a positive patient perception of improvement with therapy (yes/no). Medical charts were reviewed by one of two researchers who were blinded to both subject cluster assignment and cluster features. While patients were categorized to specific clusters from data obtained prior to their treatments, there was no communication with the patients about this categorization or its hypotheses; patients chose their care plans and reported their responses according to the typical standard of care with their treating provider. Only those patients for whom a determination about responses to treatment could adequately be made were included in the analysis. Only 105 subjects could be included in this analysis, as we did not have adequate information to determine treatment responses for 40 subjects (27%), either because they were unable to complete the course of treatment or to follow-up with their treating provider after treatment due to clinic closures associated with the SARS-CoV2 pandemic. A proportion of the subjects within each phenotype responding to each treatment was determined  as was the proportion of total responders to each therapy for each phenotype .U-tests for independent data as appropriate (2-tailed). Differences in proportions were compared using the two-sample z-test. Results are considered significant at an alpha level <0.05.The R Studio integrated development environment was used for the unsupervised clustering analysis with the stats (version 3.6.1), cluster (version 2.1.0), mclust (version 5.4.7) randomForest (version 4.6–14), kohonen (version 3.0.10), and popsom (version 5.2) packages. Differences in patients' demographic and clinical characteristics were compared by using the Wilcoxon signed rank tests for paired data and the Pearson chi square, Fisher exact, or Mann-Whitney and also scored 4 or higher on the BPCI, a measure of pain selectively associated with the bladder. Sixty-nine age-matched, asymptomatic subjects with BPCI < 3 were selected from the potential subject pool as controls. As the hormonal changes in the peri- and postmenopausal period add an additional level of complexity and obscure the relation of symptomatology to bladder pain, only pre-menopausal women were included. This selection avoids the complicating comorbidities and co-existing genitourinary symptoms, such as detrusor underactivity and overactive bladder, common in post-menopausal women. The combination of narrow inclusion criteria using clinician diagnosis in conjunction with objective scoring on the BPCI corrected for confounders within and between study groups to reliably identify IC/BPS subjects and separate symptomatic patients from controls  were assigned a diagnosis of IC/BPS. Although pain levels in this group were significantly elevated in comparison to control subjects, identification of subject groups by diagnosis was not sufficient to separate IC/BPS patients from controls symptomatically . In addicontrols . The basbladder pain in the absence of infection or other organic pathology, difficulties discriminating pelvic visceral sensation and a lack of well-defined language describing pelvic pain complicate IC/BPS diagnosis and subclassification. As a quantitative approach to identifying more homogeneous IC/BPS subpopulations, we used K-means clustering, an unsupervised machine learning approach, to recognize distinct phenotypes based on the patient-reported measures examining GU symptomatology from the 145 IC/BPS subjects. K-means clustering necessitates defining k, the fixed number of clusters you anticipate within the dataset. To define this value, we first applied hierarchical Ward's clustering to the symptomatic assessment instruments alone, revealing that a three-cluster solution best fit the dataset of patients with perceived bladder pain  clinical phenotypes based only on the patient responses to symptomatic questionnaires. This cluster solution assigned 56 subjects to group 1, 31 patients to group 2, and 58 patients to group 3. The meaningful separation of these groups by symptomatic assessment measures was visually confirmed by principal coordinate analysis using Bray-Curtis dissimilarity measures . In these patients, the fGUPI revealed higher levels of pain localized to the vagina and urethra , coexisting with both dyspareunia and dysuria  . NUPP suThe third group, designated as myofascial pain (MFP), exhibited a wide range of symptoms that were elevated, such as urinary frequency, bladder discomfort, and pelvic pressure, in comparison to controls. This group was distinguished by significantly more defecatory symptoms (PFDI20 questions 7–14), an increased sensation of incomplete emptying of the bladder , and small amounts of urine leakage (PFDI-20q18), typically without awareness. While these subjects expressed similarly elevated “pain below the waist” (fGUPI1d) as the other groups, they had the lowest proportions of pain in other pelvic locations specified on questions 1 and 2 on the fGUPI, which specify types of pain in the pelvis through a set of eight yes/no questions . HoweverSubjects in this group had nearly identical pain levels, urinary symptoms and severity, and quality of life impact as the BPS group. The major difference in their symptoms was the associated defecatory symptoms. The symptomatic questionnaires, however, include multiple questions describing the nature of the pain . ICPI4 aTo ensure the stability of our cluster assignment, we resampled (500) with replacement (bootstrapping) a large number of replications  and identified the cluster assignments for each iteration. From these we computed the percent observed agreement (Rand Index) and percent overlap (Jaccard Coefficient), for which values over 0.7 indicate good cluster stability. The Rand indices were 0.86 (95%CI: 0.85–0.87) for BPS, 0.85 (95%CI: 0.084–0.86) for NUPP and 0.75 (95%CI 0.74–0.76) for MFP, demonstrating high percent observed agreement of the bootstrapped samples. The clusters had Jaccard coefficients of 0.68 (95%CI: 0.67–0.69) for BPS, 0.55 (95%CI: 0.53–0.57) for NUPP and 0.49 (95% CI: 0.47–0.52) for MFP. These measures of agreement suggest that for the NUPP and MFP clusters, the high observed percent agreement was driven by the absence of observations being assigned to these clusters. However, the BPS cluster showed stability based on both percent agreement and percent overlap. Overall, the cluster stability measures indicate that only the BPS cluster would be likely to be detected using a similar definition in a different sample.K-means algorithm  to allow for meaningful groups of similar patients to emerge. Only a portion of the total subjects  including the pain groups and controls fell into a “pure” phenotype category . These “pure” phenotypes, in which a single symptomatic feature (or “pie slice”) was clearly dominant, are designated by a colored ring surrounding the bin. The red heat map in While most IC/BPS subjects displayed only one predominant symptom cluster, some individuals exhibited features of more than one group. These overlapping symptoms raised the question of whether these phenotypes could manifest independently. We utilized a Kohonen SOM , a type p < 0.001 for both). We observed that the NUPP group consistently demonstrated low response rates to all therapies. In contrast, MFP subjects responded well to PFPT, with almost 80% of those who could be assessed responding positively to this therapy . Unfortunately, the number of patients in this group that were not seen in follow-up after PFPT was enriched due to clinic closures associated with the pandemic. Regardless, these findings are suggestive that IC/BPS phenotypes can be identified that require different therapeutic strategies to achieve symptomatic control.After observing segregation of the original IC/BPS population into phenotypes with divergent clinical features, we hypothesized each would respond differently to IC/BPS therapies. We performed retrospective chart review of subjects for each group to determine patient-perceived responder rates for four common IC/BPS therapies: oral bladder analgesics, intravesical instillations, pelvic floor physical therapy (PFPT), and oral amitriptyline . Of patiDeeper clinical characterization of female premenopausal patients with the subjective sensation of bladder pain reveals three distinct phenotypes which suggest divergent sources of perceived pain. Each of the phenotypes had recognizably different clinical features as well as different responses to the various treatments frequently employed for IC/BPS patients, data which support differing pathophysiologies underlying these phenotypes.For many chronic pain conditions, such as IC/BPS, the condition is defined by a process of exclusion of other organic pathologies. The exclusion of other conditions does not, however, mean that the remaining affected individuals are homogeneous. Depending on the inclusion criteria, patients endorsing the sensation of bladder pain or discomfort may include multiple symptomatologies: true pain deriving from aberrant sensation in the bladder, other forms of pelvic pain referred to the bladder, centralized or systemic allodynia including features of pain ascribed to the bladder, or other localized pelvic pain misattributed to, but unrelated to the bladder. These different symptom origins may be described similarly by patients but are unlikely to represent a single clinical condition or respond to identical treatment approaches. While there is growing consensus that the recognition of Hunner's lesions in IC/BPS should prompt different considerations for medical and surgical management , phenotyIn addition, subjects with IC/BPS are at high risk for experiencing other forms of pelvic pain or dysfunction, such as irritable bowel syndrome, which has been attributed to neuronal cross-talk at the level of the spinal cord –30. IC/BSeveral previous classification systems, such as UPOINT , 35, havIn fact, even the necessity of pain for a diagnosis of IC/BPS is not universally accepted. European Association of Urology (EAU) guidelines consider pain attributed to the bladder a key diagnostic feature , while tThe differing definitions of IC/BPS have significant consequences in the study of this condition. Our phenotypes reveal that a subset of patients may define their symptoms more as pressure or discomfort than frank pain. This discomfort was more constant and associated with myofascial dysfunction, which was distinct from the perception of pain in the bladder related to voiding cycle. Given the subjective nature of the definitions of IC/BPS, there may be very different populations included if the definition requires a description of “pain” instead of “pain, pressure or discomfort.” As no objective markers of IC/BPS exist, attempting to discover an underlying pathologic mechanism in a pooled, inclusive population of subjects with any form of pressure, pain, or uncomfortable frequency may prevent any potential discoveries.We focused on identifying the subtle differences in bladder-related symptoms in a population of premenopausal women with a narrowly-defined perception of bladder pain to characterize possible phenotypes that could represent different pathologies. Only by defining more homogeneous populations will we be able to improve therapeutic assignment and outcomes. This has even more significance for future research attempting to discover the underlying molecular mechanisms related to bladder or pelvic pain in each population, a requirement for identifying new approaches to improving patient care. A lack of such homogeneous groups may well be the primary confounding factor affecting studies to date. Only with such knowledge will we be able to define the pathways we can target for better treatment and prevention. While it will be necessary to validate the classification system and optimize the associated phenotypic measures in larger populations, this study is a first step toward those goals.The clear differences seen in these populations in terms of their responses to treatment support the concept that these phenotypic groups represent distinct, independent disease categories or etiologies. The mechanisms of each of these therapies suggests possible origins of the pain seen in each group, which we hope to evaluate further in additional studies. Most responders to bladder-directed therapies, such as bladder analgesics and intravesical instillations were those with bladder-centric pain related to the voiding cycle categorized to the BPS group. This finding implicates a bladder-derived pathology in these patients, as could be mediated by local inflammation , 39 or uThe myofascial pain group is challenging to recognize without more accurate metrics, because it is common for patients with bladder pain to have some myofascial pain that accompanies their bladder-centric symptoms and frequently will respond to PFPT . This isThis may be the explanation underlying why the Jaccard coefficient (JC) of the MFP group (0.51) is significantly lower than the BPS group (0.69). A “stable” or “excellent” cluster, in which subjects can be consistently assigned to this group in multiple sub-samplings of the population, will have a Jaccard coefficient of more than 0.70. While the symptoms of these patients were highly similar, the presence of pain with bladder filling was highly specific for the BPS group, which likely aided in the stability of group assignment. In contrast, no single clear symptom was consistently found in all MFP subjects. Regardless of this finding, the difference in treatment responses suggests that the differentiation of the MFP subjects from BPS-dominant groups is clinically relevant and pathologically meaningful. Additional studies with more extensive phenotyping may be helpful in identifying more discriminatory symptomatic features, but we propose that MFP be suspected in IC/BPS subjects without clear pain with bladder filling who complain of POP-like symptoms without objective signs of visceral or pelvic floor descent on exam.The NUPP group exhibited milder urinary symptoms than the other two groups but was still highly bothered by the pain. The pain was prominent in the distal vagina/urethra and was associated not with bladder filling but with voiding. It is easy to see how these painful symptoms could be attributed to the bladder, despite the distinct pattern in their manifestation. These patients do not respond to the bladder-directed therapies of the BPS group, or indeed any of the other typical IC/BPS therapies documented in this study. A large limitation to understanding the nature of this group was the limited exploration of vaginal and urethral symptoms present in the fGUPI. The questions distinguishing the NUPP group were yes/no questions merely describing pain location or aggravating factors, without a more subtle assessment of these pain manifestations or their severity. These symptoms may have been missed or even overemphasized in some. A more detailed exploration of uncomfortable vaginal and pelvic symptoms in combination with a detailed exam is needed to understand the range of symptoms and the relationship of this phenotype to other pain conditions, such as vestibulodynia.Interestingly, we did observe the expression of features characteristic of multiple phenotypes by smaller numbers of subjects. This may mean these phenotypes are not sufficiently defined. It has been noted elsewhere that patients often find the language of urology unfamiliar at best and have difficulty describing their symptoms accurately , which mIt was common for the BPS subjects to manifest at least some MFP symptoms. Pelvic floor hypertonicity and tenderness is hypothesized to be a consequence of local pelvic pain and is seen in a variety of pelvic pain conditions , 41. TheThe group with high levels of all types of pain comprises a small, but not insignificant portion of the overall population. Patients with more domains of pain typically have more severe symptoms , 44, sugThe details of the phenotypic classification determined in this study highlight the challenges in attempting to identify more homogeneous phenotypes of perceived bladder pain, even when narrowly defined by multiple inclusion criteria. It is possible that a larger sample size would identify additional phenotypes that were not recognized here and that are less common or inadequately assessed by the information collected in these questionnaires.The responder analysis was not anticipated in the original study; thus, the utility of this data is limited by its retrospective acquisition, the absence of more detailed, quantitative outcome measures, and lack of standardized care pathways. In addition, lack of follow up for a subset of the population secondary to reduced clinical access as a result of the SARS-CoV2 pandemic also limited these data. Therefore, while treatment response data are suggestive that the groups respond differently, more detailed prospective studies are needed to validate these preliminary findings.As this study only included pre-menopausal women, it is not known whether this approach will be generalizable to other age groups or genders. Postmenopausal women can commonly experience a range of genitourinary symptoms associated with that state of relative hormone deficiency, including pain, burning, and dysuria which may complicate this phenotypic classification.Finally, the IC/BPS subjects included in this analysis did not routinely undergo cystoscopic evaluation as part of their initial treatment course, making it difficult to determine whether a subset of these subjects may have had Hunner's lesions. As Hunner's ulcers are present only in a minority of IC/BPS cases and tend to occur predominantly in older patients, we anticipate that this is a minor portion of this population –47. We cGoing forward, it will be necessary to validate these phenotypes in larger, multicenter populations. It will be especially important to confirm prospectively that these phenotypes are reliable and accurate predictors of response to treatment. Finally, we must determine if these phenotypes are applicable to other populations such as older women and men. We expect both additional and different symptoms in these groups. Additional studies must determine if new phenotypes are required and how well the model described here can be adapted.As with all chronic pain conditions, multimodal treatment remains the most effective approach. It is important to address the accompanying extra-pelvic symptoms and recognize the psychosocial and systemic manifestations of this chronic pain condition to improve overall health-related quality of life. We believe, however, that a simple IC/BPS phenotyping into the categories defined here could help focus both initial treatment assignment as well as better facilitate mechanistic studies that could provide insight into disease etiology and promotion. Progress in the care and management of this highly impactful condition is sorely needed; refining our diagnostic categories is a necessary next step in moving toward that goal.In conclusion, expanded clinical phenotyping of patients reporting perceived bladder pain can identify distinct phenotypes. The different patterns of associated symptoms suggest that these phenotypes may reflect unique pathophysiologies. Further, the varying response of each phenotype to traditional therapies for IC/BPS suggests the utility of such phenotyping and, if validated in prospective studies, may provide a useful approach to understanding the underlying pathophysiologies and improving the diagnosis, treatment, and prevention of bladder pain.The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by Pro00046154. The patients/participants provided their written informed consent to participate in this study.PM assisted in the development of the study, conduct of the research, data analysis, and drafting the manuscript. FK and AC conduct of the research and editing of the manuscript. NJ development of the study, data analysis, and editing of the manuscript. JW, VS, KE, and JTA development of the study, conduct of the research, and editing of the manuscript. DU development of the study, direction of the research, and editing of the manuscript. JEA data management and editing of the manuscript. ALA development of the study, conduct of the research, data analysis, and final approval of the manuscript. All authors contributed to the article and approved the submitted version.This study was funded by a Department of Defense Peer-Reviewed Medical Research Program Discovery Award (PR161914).ALA is an expert witness for Cynosure and a consultant for Watershed Medical. KE is a consultant for Allergan and Coloplast. The remaining 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.