BackgroundPostoperative pain is a significant problem encountered by patients after a surgical intervention, and there is a crucial need for effective postoperative pain control. The studies have shown that multimodal analgesia and wound infiltration are effective ways to reduce this pain and have a substantial role in the reduction of postoperative medications requirement. This study aimed to evaluate the effect of subcutaneous infiltration of bupivacaine hydrochloride and intravenous (IV) diclofenac as postoperative pain relief in adults undergoing inguinal hernia repair.MethodsA single-center retrospective study included 104 patients aged 18-65 undergoing unilateral inguinal herniorrhaphy at the selected hospital. The patients were in two groups of 52 each. Group A received a 75 mg dose of IV diclofenac plus a subcutaneous injection of 10 mL of bupivacaine hydrochloride (HCl) 0.5% while Group B only received the IV diclofenac without the bupivacaine injection. The postoperative pain was assessed at one, two, three, six, and 12 hrs after the operation using the visual analog scale (VAS), which exhibited a range of pain from zero (no pain) to 10 (extreme pain).Results2. American Society of Anesthesiologists physical class I was similar in both groups (90.4% versus 84.6%). Patients in Group A had significantly lower VAS pain scores at one, two, three, six, and 12 hrs after the operation and a longer emergence time than Group B . Subcutaneous bupivacaine infiltration and IV diclofenac were also found to be an effective analgesic technique in open hernia repair with mesh .Of a total of 104 patients, 92% of patients were male. The patients' mean age was 36 ± 11 years, and the mean body mass index (BMI) was 22 ±3 kg/mConclusionSubcutaneous injection of bupivacaine combined with IV diclofenac provides superior analgesia to monotherapy intravenous diclofenac after inguinal hernia repair. Postoperative pain is the most common adverse event encountered by patients after surgery. Almost 80% of patients experience postoperative pain after surgical intervention, with 75% complaining of pain after receiving a single dose of analgesic . The paiInguinal hernia repair is a common surgery in all ages worldwide, with thousands of people seeking treatment for surgical hernia repair to relieve abdominal pain and limitations in physical activity. However, due to postoperative pain, symptoms frequently persist after surgery . MoreoveWith the advances in perioperative pain management, multimodal analgesia has become essential for pain control . MultimoA single-center retrospective study was conducted in the department of General Surgery, Algerian Hospital, Gaza, Palestine. The data of 104 patients undergoing inguinal hernia repair were obtained from the hospital data records through the period from September 2020 to August 2021. The hospital officer-in-charge chose patients in both groups according to the medications they received intraoperatively, one case per one control. Elective patients undergoing only unilateral inguinal hernia and aged between 18 and 65 with American Society of Anesthesiologist (ASA) physical health status classifications I and II were included in this observation. Patients with bilateral inguinal hernia and those who did not receive the previously mentioned drugs intraoperatively were excluded from the study.Demographic data , and marital status), in addition to clinicopathological data, i.e., chronic diseases, previous surgery, ASA, type of surgical repair, as well as the time of anesthesia and surgical procedure were collected. Furthermore, because this project was a retrospective medical record review and quality improvement study, patient-informed consent was not required, and ethical approval was granted under the supervision of Universiti Sains Malaysia with the protocol code USM/JEPeM/21110757. The study was conducted with proper permission from the hospital.All procedures were performed by the same surgical team at the Algerian hospital. All patients received general anesthesia. Fentanyl citrate , propofol , and atracurium besilate  were used for induction of general anesthesia, and a 50% mixture of oxygen/nitrous oxide and isoflurane 1.15%  were used for maintenance. Patients in Group A (n= 52) received a 75 mg dose of intravenous diclofenac, and intraoperatively, a single shot of 10 mL of 0.5% bupivacaine HCl was subcutaneously administered beneath the incision margins after the closure of the skin layer, whereas Group B (n=52) only received 75 mg of intravenous diclofenac. The intravenous diclofenac was given slowly in a solution for up to 20 mins.At the end of the surgery, patients were transferred to the post-anesthesia care unit (PACU), and the postoperative pain score was assessed using VAS (0-10) at one hr and two hr. Then, patients were transferred to the ward, and the VAS score was assessed at three, four, six, and 12 hrs postoperatively. Patients who submitted a VAS pain score of 3 or above have received painkillers accordingly. Examples of pain control regimens followed in the hospital are intravenous acetaminophen, diclofenac, ketorolac, and meperidine as needed. At discharge, scheduled oral analgesics like acetaminophen 1 gr, ibuprofen 400 mg, or diclofenac 50 mg were prescribed as part of the postoperative pain control regimen.Outcome measuresThe primary purpose of this study was to evaluate the effect of subcutaneous bupivacaine HCl infiltration added to the pain control regimen. The secondary outcome includes the effect of SBI on postoperative pain in the presence of the mesh repair technique. The average pain scores in the PACU and surgical wards were obtained using VAS, which exhibited a range of pain from zero (no pain) to 10 (extreme pain).Statistical analysisStatistical analysis was done using SPSS®  version 26.0 . Data were demonstrated as means with standard deviation and counts with percentage as appropriate. Continuous data, such as age, BMI, anesthesia duration, and surgery duration, were analyzed using the dependent t-test. The associations in categorical data, such as gender, ASA physical health status classification, and type of surgical repair, were determined using the chi-square test or Fisher's exact test where applicable. A p-value < 0.05 was considered statistically significant. The postoperative pain score was analyzed using the Mann-Whitney test. All the tests were two-tailed.Study size calculationThe highest sample size calculation based on general and specific objectives is 104 participants. This is using specific objectives, for example: Identify the postoperative pain of a patient undergoing inguinal herniorrhaphy within six to 12 hours after the operation.Sample size independent t-testBased on the paper "Local Wound Infiltration with Ropivacaine for Postoperative Pain Control in Caesarean Section" .Of a total of 280 patients who had undergone inguinal hernia repair from 2020-2021, only the data of 104 patients were obtained from the hospital records. Ninety-six patients were male (92.3%), and eight were female (7.7%). The patients' mean (SD) age was 36 ± 11, and the mean BMI was 22 ± 3. ASA physical health status class I was similar in both groups (90.4% versus 84.6%), and the differences were statistically insignificant (p = 0.38). The patients were divided into two equal groups of 52 each. Group A received SBI in addition to IV diclofenac. Group B received only IV diclofenac monotherapy. Both groups were well-matched in the most basic characteristics such as gender, age, BMI, duration of surgery, and ASA classification. However, there was a statistically significant difference in the duration of anesthesia and the median anesthesia duration for SBI with IV diclofenac and IV diclofenac monotherapy was 72 ± 13 and 61± 7 mins, respectively. This is due to the need to perform and administer local anesthesia postoperatively. The descriptive characteristics of the study groups are summarized in Table The VAS differences between the groups were statistically significant throughout the five intervals of time Figure . A signiThe study also noted that out of 104 patients, 81 (77.9%) patients received mesh repair for their inguinal hernia. A comparison of postoperative pain between the two analgesic groups in the presence of a mesh was analyzed, and the analysis was statistically significant. The mean pain score was found to be reduced in Group A compared to Group B. Group A had significantly lower pain scores in the first 12 hrs after the operation with all p-values < 0.001 Table .2, which interprets that patients were at normal body weight. Therefore, our finding is inconsistent with other studies, which indicate that patients with lower BMI are at higher risk of inguinal hernia [Of a total of 104 patients undergoing inguinal hernia repair, 96 (92.3%) were male. KS and Rao found that inguinal hernia is a common surgical procedure that accounts for approximately 75% of all abdominal hernias and the majority of patients were males . To the l hernia ,13.Inguinal hernia repair is usually performed to avert or reduce the hernia's side effects. However, postoperative pain after inguinal hernia repair remains a significant challenge for healthcare providers, and the need for appropriate postoperative pain control is crucial. Postoperative pain control is the primary clinical and patient-desired outcome issue that needs proper attention and intervention. Efficient postoperative pain management significantly reduces the need for postoperative analgesia and rescue, improves patient satisfaction, allows for early recovery after surgery, improves physical activity, and speeds up hospital discharge . The AmeAnother study demonstrated that it is essential that surgical site infiltration is combined with other non-opioid analgesics to attain the maximum analgesic effect . Local aIn this study, we observed the analgesic effect of SBI and IV diclofenac (A) on postoperative pain relief in patients undergoing inguinal hernia repair compared with a monotherapy diclofenac administration (B). A single shot of subcutaneous bupivacaine infiltration and intravenous diclofenac was given intraoperatively. The results showed statistically significant differences in VAS scores between the two groups. The VAS score in the bupivacaine group was significantly lower compared with the diclofenac group at one, two, three, six, and 12 hrs postoperatively. The lower pain score reflects that the bupivacaine group had a higher satisfaction level and less analgesic consumption. These findings correlate well with the present studies, which demonstrated that bupivacaine infiltration reduces postoperative pain in the first 24 hours of surgery without adverse cardiological or neurological effects ,20. The Surgical wound infiltration is a component of multimodal analgesia that plays a substantial role in the reduction of acute postoperative pain. Andersen et al.  observedAdditionally, inguinal hernia repair using mesh is the preferred method when the prevention of recurrence is the primary goal. However, mesh implantation is associated with increased complications for patients, particularly postoperative pain, for this reason, some patients request non-mesh hernia repair -28. In oThe study concludes that subcutaneous infiltration with bupivacaine HCl plus intravenous diclofenac can improve postoperative pain control after inguinal hernia repair and reduce the acute postoperative pain after mesh implantation. SBI and IV diclofenac markedly reduce the total postoperative analgesia consumption. This simple, safe, and effective analgesic technique can be applied in most surgeries to reduce acute postoperative pain.


Conclusions: This meta-analysis reveals that Pilates may have positive efficacy for pain relief and the improvement of functional disorders in CLBP patients, but the improvement in quality of life seems to be less obvious. Registration: PROSPERO CRD42022348173.Background: Chronic low back pain (CLBP) is a common health problem. Pilates is a unique exercise therapy. This meta-analysis aims to evaluate the efficacy of Pilates on pain, functional disorders, and quality of life in patients with chronic low back pain (CLBP). Methods: PubMed, Web of Science, CNKI, VIP, Wanfang Data, CBM, EBSCO, and Embase were searched. Randomized controlled trials of Pilates in the treatment of CLBP were collected based on the inclusion and exclusion criteria. The meta-analysis was performed using RevMan 5.4 and Stata 12.2. Results: 19 randomized controlled trials with a total of 1108 patients were included. Compared with the controls, the results showed the following values: Pain Scale [standard mean difference; SMD = −1.31, 95%CI ,  Low back pain (LBP) has been a prevalent health problem for adults. The incidence is as high as 84%. In modern society, with the accelerated pace of life and the increased pressure of work, the incidence of LBP is increasing year by year. From 2006 to 2016, the incidence of LBP increased by 18% . The lifPilates, as an exercise therapy, is widely used in clinical rehabilitation. Pilates has been proven to have positive effects in relieving shoulder–neck discomfort and low back pain, enhancing joint mobility, improving physical balance ability, reducing the risk of falling in the elderly, and so on ,11,12,13Some clinical studies have found that Pilates had positive effects on pain relief and improvement of functional disability in CLBP patients ,19,20, whttp://www.crd.york.ac.uk/PROSPERO, accessed on 1 August 2022) with the registration number CRD42022348173.This meta-analysis was planned and implemented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The proIn this study, PubMed, Web of Science, CNKI, VIP, Wanfang Data, CBM, EBSCO, and Embase were searched. The search time ranged from the date of database construction to November 2022. The last retrieval date is 20 November 2022. The literature search was conducted using a combination of subject terms and free terms. The search terms included “Pilates”, “Pilates training”, “low back pain”, “back pain”, “low back ache”, “nonspecific low back pain”, “chronic nonspecific low back pain”, “chronic nonspecific lumbago”, “chronic nonspecific lower back pain”, “chronic nonspecific lumbar pain”, and “non-specific lower back pain”. In order to obtain all the randomized control trials related to Pilates intervention in the treatment of CLBP patients, we also traced the references of the retrieved literature to supplement the relevant literature. The full search strategy for each database is presented in Participants—CLBP patients , regardless of race and nationality, whose physical examination showed tenderness or pain in the lumbosacral region but no positive result in the straight leg raising test and the strengthening test, while excluding low back pain caused by other diseases, such as fracture, infection, and tumor, and ensuring no structural lesion in the lumbar spine in the imaging examination;Study design—randomized controlled trials (RCTs);Primary treatment methods—Pilates alone or in combination with other treatment methods;Treatment methods for the controls—any other treatment methods, including routine treatment, sham treatment, and no treatment;Literature data—the literature with complete data, which is able to effectively extract data and obtain original texts;Languages—the literature published in English or Chinese;Literature type—journal articles.The primary outcome indicators were as follows:Pain Scale, which was used to evaluate the pain intensity, including the Visual Analogue Scale (VAS) (ICC = 0.76–0.84) and Numerical Rating Scale (NRS) ,28,29;Oswestry Disability Index (ODI). The ODI was used to evaluate lumbar vertebra function disorders in CLBP patients, consisting of 9 questions with 6 options per question, corresponding to 0 to 5 points, thus, giving a maximum score of 50, with a final score equal to actual score/45 × 100%. The higher the final score, the more severe the lumbar vertebra dysfunction (ICC = 0.99) ,31;Roland–Morris Disability Questionnaire (RMDQ). The RMDQ was used to evaluate self-test dysfunction in CLBP patients. Scores ranged from 0  to 24 , with higher scores indicating more pronounced function disorders ,33,34.The secondary outcome indicators were as follows:A 36-item Short-Form (SF-36). The SF-36 was used to evaluate the quality of life in CLBP patients, including eight dimensions of Physical Function (PF), Role Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotion (RE), and Mental Health (MH). Scores ranged from 0 to 100, with higher scores indicating better quality of life (ICC > 0.85) ;Quebec Back in Disability Scale (QBPDS). The QBPDS was used to assess fear of reinjury following a sports injury. The scale consists of 17 items with scores ranging from 17 (no fear) to 68 (highest fear), and the scale has good reliability and validity in CLBP patients ,37,38,39Sit-and-reach test. The test was used to evaluate hamstring tendon flexibility as well as lower back flexibility and lumbar extension (ICC = 0.94) ,41.The eligibility criteria were as follows:www.endnote.com). Step 2—exclude duplicate materials. Step 3—perform the first round of screening by reading titles and abstracts. Step 4—after downloading full texts, conduct the second round of screening to determine if the inclusion criteria were met.Step 1—import the retrieved literature to the literature management software Endnotex9 . If the results included in the literature were continuous variables and from the same assessment method, we used the mean difference (MD) and 95% confidence interval (CI) for statistics. If the results were not from the same assessment method, the standard mean difference (SMD) and 95% confidence interval (CI) were conducted. The analysis . The α vThe initial search resulted in a total of 537 studies, and 6 studies were selected in other ways. EndNote X9 was used to remove duplicate documents, and there were 416 studies left. After reading the titles and abstracts, 41 studies were selected. Then, after reading the full texts, 22 studies were discarded because they did not meet the inclusion and exclusion criteria, and 19 studies were finally included ,53,54,55A total of 1108 patients were included in the 19 RCTs. The average disease duration ranged from 86 days to 11.6 years. The sample size of each study ranged from 17 to 101 patients. The average intervention cycle is 6.8 weeks (ranging from 4 to 13 weeks), with training 3.1 times a week on average (ranging from 1 to 6 times per week). A total of 16 articles were published in the past 10 years (2013 to 2022), accounting for 84%. In 12 RCTs, the treatment method in trial groups was Pilates alone. In the remaining 7 RCTs, the treatment methods in trial groups were Pilates respectively combined with usual care, home exercise, physical therapy treatment, a standardized education program, infra-red radiation and back care, tendon puncture, the suspension training method, and non-steroidal anti-inflammatory drugs. For the controls, the treatment methods were conducted after the removal of Pilates in seven included RCTs, and there were six RCTs using the method of no treatment. Furthermore, usual care, home exercise, physical therapy treatment, as well as infra-red radiation and back care were, respectively, conducted in one, three, one, and one of the included RCTs. The details of the research characteristics are shown in Of the included 19 RCTs, 17 RCTs ,53,54,55Cochrane Handbook for Systematic Reviews. The results are shown in The risk of bias assessment was performed using RevMan5.4 software, according to the p < 0.00001], ODI , and RMDQ  in CLBP patients. The results of the meta-analysis are presented in According to the results of the heterogeneity assessment, the random effects model meta-analysis was conducted to analyze the efficacy of Pilates in the context of the Pain Scale, ODI, and RMDQ of CLBP patients. The results showed that there were statistically significant differences between trial groups and control groups, which indicated that Pilates has a positive improvement on Pain Scale , and there was no statistically significant difference in RP , BP , and GH  between trial groups and the controls. These results indicated that Pilates could positively improve SF-36-PF but not RP, BP, and GH in CLBP patients. The results of the meta-analysis are presented in p = 0.13], SF , RE , and MH  between trial groups and control groups, which suggested that Pilates had no positive effect on SF-36-VT, SF, RE, and MH in CLBP patients. The results of the meta-analysis are presented in Four of the included RCTs ,46,48,53p = 0.56] and the sit-and-reach test  in CLBP patients were conducted. The results showed that there was a significant difference in the sit-and-reach test, but not QBPDS, between trial groups and control groups, which indicated that Pilates had a positive effect on the sit-and-reach test but not QBPDS in CLBP patients. The results of the meta-analysis are presented in Finally, meta-analyses for the efficacy of Pilates on QBPDS . In two RCTs [p = 0.03]. Furthermore, there were three RCTs [p = 0.01]. For RCTs with follow-ups on SF-36, we included a total of two [To determine the long-term effects of Pilates on chronic low back pain, we performed a meta-analysis for Pain Scale, ODI, RMDQ, and SF-36 in follow-ups. A total of six RCTs followed the Pain Scale ,48,50,54two RCTs ,50, the ree RCTs ,48,54 whl of two ,48. A fip = 0.008, p < 0.05), and there was no publication bias for ODI  and RMDQ . The details are presented in Begg’s test was conducted to analyze publication bias for the outcome indicators which were involved in five or more RCTs. The results showed that there was a publication bias risk for Pain Scale , concentration , control , precision , breathing , and flow  ,15,64. PIn view of the results of this meta-analysis, Pilates seems to have positive efficacy for pain relief and the improvement of functional disorders in patients with chronic low back pain, and the effects of treatment may be maintained for a period. However, there appears to be no positive effect on quality of life in CLBP patients. Furthermore, the safety of Pilates could not be determined.It is suggested that a more uniform and standardized study design and treatment protocol should be established in future studies, while the doses of Pilates should also be intensively studied. Furthermore, measurements of objective instruments, such as electromyography and nuclear magnetic resonance, should also be added, in order to explore changes in neuromuscular regulation and imaging, and further verify the authenticity of the efficacy.In this meta-analysis, the study languages of the included RCTs were only Chinese and English, and the study sample sizes were relatively small, which may have biased the results.In the included RCTs, the exercise methods of Pilates were not all consistent, and the treatment methods of the controls were not all consistent.There was high heterogeneity among small parts of the literature, which may have caused some influences on the reliability of the meta-analysis.The bias risk in Pain Scale, according to the publication bias analysis, may be due to the difference in the pain assessment methods among studies, which may lead to an effect on the reliability of study results.


Endometriosis has a large impact on the lives of patients, affecting nearly 90% of women with chronic pelvic pain and infertility. Unfortunately, diagnosis for this condition is often delayed by an average of 7 years, with adolescent patients experiencing disproportionate delays. This is in part due to the use of an invasive procedure for primary diagnosis and limited access to subspecialty care. While laparoscopy serves an important purpose in the diagnosis and management of endometriosis, it has been found to be less cost-effective than empiric medical therapy and puts an emphasis on the lesion as opposed to the patient and the disease process as a whole. As studies emerge, we gain a deeper understanding of the complex nature of this disease. Laparoscopy has been shown to have variable results, with high recurrence rates and varying improvement in symptoms over time. Additionally, studies have shown a poor correlation between patients’ pain and the stage and location of lesions, with laparoscopy showing greater benefit for later-stage disease and deep infiltrating endometriosis. This article seeks to evaluate the current standards for the management of endometriosis, discuss the place for diagnostic laparoscopy, and review future directions and alternatives.Endometriosis is an inflammatory disorder that occurs when uterine tissue is found outside the uterus. This condition affects women of reproductive age and can have serious impacts on their lives, causing pain and difficulty getting pregnant. The primary method of diagnosis is surgical, which has associated risks and can delay care to patients. As further studies emerge, our understanding of this condition improves, and it is important to evaluate current practices. This article focuses on the pros and cons of using surgical methods to diagnose endometriosis and alternative options that may be safer and provide more timely care to patients. Endometriosis affects 10% of women of reproductive age and nearly 90% of women with chronic pelvic pain and infertility , combined hormonal contraceptives, progestins, and gonadotropin-releasing hormone (GnRH) agonists with or without add-back therapy  practice bulletin on endometriosis management recommends trialing oral contraceptive pills, non-steroidal anti-inflammatory drugs, and a 3-month course of a GnRH agonist prior to considering diagnostic surgery . SurgeryWhile the risks of diagnostic laparoscopy are low, often less than 1%, the patient is still at risk of surgical and anesthetic complications for a diagnostic test. Complications can include bleeding, infection, injury to surrounding organs including bowel, bladder, ureters, and vasculature, as well as conversion to laparotomy. Greater than 50% of injuries occur from the first entry. Given the high rate of pain and recurrent symptoms after surgery, it is understandable that clinicians and patients would want to delay surgery to avoid these risks when the benefit is limited.The 2008 US health care costs for endometriosis were estimated to be $4000 per affected woman . ImagingEvidence shows that the pain associated with endometriosis can be effectively treated with several medications including hormonal options, NSAIDs, GnRH analogues, and medications for central sensitization. Continuous oral contraceptive pills were found to provide significant pain reduction for patients with both dysmenorrhea and endometriosis . In two Many proposed mechanisms have been described as to how endometriosis causes infertility and subfertility, though all of these remain controversial . For morIn stages I and II endometriosis, laparoscopic treatment of endometrial implants has been associated with a small improvement in live birth rate. Aggregating the data of two randomized controlled trials found that 40 asymptomatic patients with unexplained infertility would need to have surgery for one additional pregnancy . Distortin vitro fertilization likely maximizes cycle fecundity over any surgical intervention. Conflicting observational data does not show a clear benefit of surgery with assisted reproductive technologies, particularly in asymptomatic patients with unexplained fertility. The ASRM does not recommend diagnostic laparoscopy solely to increase the likelihood of pregnancy  findings such as site-specific tenderness, fixed ovaries, negative ‘sliding sign’, and evidence of DIE nodules in the anterior and posterior compartment can be indicative of endometriosis. Additional techniques, including bladder site tenderness-guided TVS (97.4% sensitivity and specificity) and rectal endoscopy-sonography and rectal water contrast TVS (>92% sensitivities and specificities), have been shown to be effective for diagnosing site-specific diseases (Similarly, advances in MRI technique and identification of specific MR-acquisition protocols and imaging findings suspicious for endometriosis can potentially improve diagnosis, although current studies show similar diagnostic performance of TVS and MRI in detecting DIE (Endometriosis has a significant impact on the lives of the patients it affects. Self-esteem, sexual health, emotional wellbeing, and functional status can all be affected. Additionally, as a chronic pain condition, improper management with opioids and anxiolytics can lead to addiction. Given the complex nature of this condition, a multidisciplinary approach to treatment is thought to be crucial with the involvement of gynecologists, psychotherapists, psychiatrists, pain specialists, and sexologists. There is limited data assessing the benefits of multidisciplinary care for endometriosis; however, large healthcare centers have started implementing these approaches given successes observed for other chronic pain conditions, including low back pain. An earlier diagnosis without requiring surgery may allow for better treatment of pain, preventing chronic pain syndromes and resulting in a healthier and more productive population.Deep infiltrating endometriosis has been most frequently associated with pelvic pain, while minimal to mild disease has had variable symptomatology. Symptom-based questionnaires have been shown to accurately predict advanced disease and DIE lesions. These clinical symptoms, augmented by ultrasound and MRI findings, can increase the ability for clinicians to identify deep infiltrating endometriosis, which is most likely to be responsive to surgical management. Initial empiric treatment with medical therapies has been shown to be equally effective and more cost-effective than diagnostic laparoscopy. Focusing on the entire clinical picture as opposed to the endometriotic lesion can provide earlier diagnosis and access to treatment, promote an emphasis on multidisciplinary care, and decrease unnecessary costs and risks associated with surgical procedures.S S declares no conflicts. K N W is a consultant for Aqua Therapeutics, Hologic and Karl Storz.This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.Both authors met criteria for authorship. Both S S and K N W performed a literature search and wrote the paper.


Successfully surgically treating degenerative disc diseases can be challenging to the spine surgeons, the long-term outcome relies on both the physical and mental status of the patient before and after treatment. Numerous studies underlined the role of inflammatory cytokines – like interleukin 1B and 6 – in the development of chronic diseases such as failed back surgery syndrome (FBSS) and major depressive disorder (MDD) which alter the outcome after spinal surgery. Our aim was to evaluate the associations of IL6 and IL1B gene polymorphisms with the long-term outcome of degenerative lumbar spine surgeries.An international genetical database (GENODISC) was combined with our institute’s clinical database to create a large pool with long term follow up data. Altogether 431 patient’s data were analysed. Patient reported outcome measures and surgical outcome was investigated in association with IL1B and IL6 SNPs with the help of ‘SNPassoc’ R genome wide association package.Interleukin 1B variants analysis confirmed association with improvement of pain after surgery on individual SNP level and on haplotype level, moreover relationship with patient reported outcome and preoperative level of depression was found on individual SNP level. IL6 variants were associated with preoperative depression, somatization and with subsequent surgery.Understanding the complexity of spinal surgery patients’ long-term well-being is crucial in effectively treating chronic debilitating somatic diseases and the associated mental illnesses. Further studies should investigate more comprehensively the linkage of chronic physical and mental illnesses focusing on their simultaneous treatment.The online version contains supplementary material available at 10.1186/s12891-022-05711-0. Degenerative disc disease (DDD) is a chronic and debilitating condition, which leads to loss of workdays in an active adult’s life . ConservPain processing is a complex multifactorial pathway with different regulatory molecules. It has a biomedical component defined by tissue damage, an evaluative component which is influenced by coping mechanisms and an affective component which is altered by psychological disorders like depression and anxiety . CytokinSingle nucleotide polymorphisms (SNPs), the most common genetic variants have been identified in the genetic background of the development and outcome of several multifactorial diseases –14. DDD The current study focuses on evaluating the relationship between IL1B and IL6 gene polymorphisms and the long-term outcome of degenerative lumbar spine surgeries.Data were collected prospectively from adults (above the age of 18) who underwent routine, elective surgery for lumbar disc degeneration at one or two levels at a tertiary spine center. Prospective clinical data were linked with the subjects’ genetic data derived from the GENODISC multicenter international collaboration. Patients with minimum 2-year follow-up data were included into the final study cohort to explore the long-term outcome of the surgical procedures. Patients reoperated within 2 years due to a surgical site infection, proximal junctional kyphosis (PJK) or adjacent segment degeneration (ASD) as well as subjects undergoing either acute intervention because of neurological emergency or tumour surgery were excluded from the study. Surgeries were performed by board-certified orthopaedic surgeons or neurosurgeons specified in spinal surgery. Applied procedures included microdiscectomy, decompression and instrumented fusion . All procedures were carried out using the standard median-sagittal posterior approach. All subjects signed a written consent form describing the scientific purpose of the systematic collection of their clinical and genetic data. The study was approved by the Scientific and Research Ethics Committee of the Medical Research Council Hungary (431/PI/2007).Patients completed standard and validated PROMs to assess their clinical status before the surgery and during the follow-up period , 30. PaiDNA was extracted from venous blood or saliva samples using commercial. Five SNPs in IL1B and four SNPs in IL6 genes were selected for genotyping based on previous literature data , 33–37. P-value less than 0.05 was considered significant.Allelic and genotype distributions, Hardy-Weinberg equilibrium, minor allele frequency (MAF) as well as associations between genetic variants and outcomes were determined and analysed using the 'SNPassoc' and 'haplo.stats' R software packages . GeneticA total of 431 subjects  met the study inclusion criteria. Mean age were 52.7 (SD:13.9y) years (from 20 to 88 years) and male/female ratio was 0.6 . As the index surgery 171 patients had microdiscectomy, 22 patients had decompression, 142 patients had one level fusion and 96 patients had 2-level fusion. In the final study cohort, 44 patients required a subsequent lumbar surgery at the index level during the follow-up. Eight patients had re-discectomy or decompression, 35 required fusion and in 1 case the implants had to be removed.(‘rs1143634-rs1143633’and ‘rs1143627-rs16944’) and no haploblock was identified on the IL6 gene as seen on Fig. Table rs1143627 IL1B SNP was associated with higher level of depression . IL1B rs16944 ‘G’ allele carriers also showed higher level of depression . rs1143634 IL1B was associated with ZDS in an overdominant model . The ‘C’ allele of IL6 SNP rs2069835 was linked to increased level of depression .In the overall population the mean±SD values of preoperative ODI score was 47.4±18.4 and the mean VAS score was 7.2±1.9, the mean ZDS was 39.6±8.1, MSPQ was 8.3±5.7. No individual SNP was associated with preoperative ODI and pain  .rs1143633 was strongly associated with the change in the reported pain at follow-up, where the ‘A’ allele carriers had the largest improvement in pain intensity (mean change±SD (%) in pain intensity was -3.7±3.3 (50%) in ‘A/G’+’A/A’ group vs -2.9 ±3.2 (40%) in ‘G/G’ genotype, p=0.00085 in dominant model) (Table rs1143634) was associated with sciatica in the disc herniation subgroup. In this cohort, the level of preoperative pain was significantly higher in the ‘CC’ genotype   in the study cohort. IL1B rs1143627 was related with better GTO  (Table In the study cohort 350 patients (82%) reported good outcome while 75 patients (17%) reported poor outcome (6 patients’ data were missing). The ‘C’ allele of IL1B rs1800796 , ‘G/A’ genotype of rs2069852  and ‘C’ allele of rs2069835  were associated with worse outcome. rs2069861 was associated with surgical outcome in an overdominant model (p=0.014) . All 4 IL6 SNPs were associated with the risk of reoperation within 2 years, even after adjusting to type of index surgery. ‘G/G’ genotype of rs1143634-rs1143633) which was associated with change in pain. ‘C-A’ haplotype was associated with the greater improvement in pain compared to the most common ‘C-G’ haplotype (p= 0.001)  is also not uncommon in this population. Understanding the pathophysiology of chronic pain conditions - such as FBSS - can lead clinicians to develop and apply new therapeutic methods in order to alleviate pain and improve the quality of life in this large patient group. The well-being of a patient is determined by multiple musculoskeletal, functional, and psychosocial factors . Geneticrs1143633 as well as ‘C-A’ haplotype of rs1143634-rs1143633 haploblock were associated with greater improvement in pain. No other gene variant was associated with pain relieve however when we analysed the microdiscectomy subgroup we found that patients with ‘C/C’ genotype of rs1143634 had significantly higher preoperative pain compared to the other genotypes. Other IL1B variant (rs1143627) was associated with patient reported global treatment outcome, while majority of the studied IL1B variants were related to the preoperative level of depression. Interestingly IL6 variants were significantly associated with the need for a subsequent surgery during the follow-up period. The ‘C’ allele of rs2069835 IL6 SNP was associated with a higher risk for reoperation and also with increased level of preoperative depression and somatization. None of the studied gene variants were associated with preoperative spinal pain and disability level.IL1B variants were significantly related to the improvement in pain after the spine surgery, ‘A’ allele of rs1143627 IL1B SNP and treatment outcome, however they did not publish the genetic effect of single SNPs but their combinations on a mixed  patient groups. The same SNP (rs1143627) was found to be associated with symptomatic disc herniation [Number of studies supported the relationship between intervertebral disc degeneration and IL1, IL6 gene variants , 39–42. rniation  and withrniation  by otherrniation , 40. IL6rniation , 39, 42.The association between IL1B, IL6 genetic variants and the therapeutic outcome after lumbar spinal surgeries can be explained by different mechanisms:rs1143633 in IL1B was associated with improvement of pain after surgery in our study while this SNP was found to be associated previously with the higher occurrence of disc degeneration (HIZ) [1) Progressive degeneration process can lead to persistent spinal pain and a potential indication of a subsequent surgery. IL1B is involved in multiple pathological process of disc degeneration. It stimulates extracellular matrix degradation, accelerates cellular senescence and induces apoptosis . rs11436on (HIZ)  what canon (HIZ) , 12, 42.rs1800796 IL6 SNP (what we found to be strongly associated with FBSS) is associated with increased promoter activity boosting the local secretion of IL6 [2) Tissue damage is often mediated through local inflammation. Inflammatory mediators such as IL6 and IL1B carry an important role in regulating and sustaining inflammation and pain. Different studies showed their potential role in disc degeneration related inflammatory process –51. IL6 n of IL6 , 42. Then of IL6 , 51, [56n of IL6 , 57–62.rs1143627 IL1B polymorphisms and MDD [rs1143634 had a tendency of suffering from less severe depressive symptoms than ‘T/C’ homozygotes [rs1143627 is reported to have a strong connection with major recurrent depression [rs16944 and rs1143627 are located in the promoter region of the gene. These polymorphisms lead to altered expression of IL1B which results in local inflammation and promotes the production of MMPs [rs16944 gene polymorphism hinder the pharmacological response in the treatment of MDD by increasing the risk of non-remission over 6 weeks of antidepressant treatment [rs1143633) was strongly associated with postoperative pain in our study while rs1143634 was strongly associated with the preoperative pain intensity but only in the disc herniation subgroup. Previously, association of intensity of back pain and this SNP have been published in war veterans with posttraumatic stress disorder [rs1143633 and pain have not been published yet, however there are a few studies investigating its relationship in paediatric MDD and schizophrenia [rs2069861 in IL6 was associated with both depression and somatization in our cohort. Somatization is also an important factor in the development of symptomatic DDD [3) Psychological issues are also important in pain response and in the development of chronic pain. Depression and anxiety have been previously described as risk factors of DDD and poor surgical outcome after spine surgeries , 63, 64. and MDD . In accoozygotes . ‘T/T’ gpression , in the  of MMPs . A studyreatment . Anotherdisorder . Associaophrenia , 77. rs2atic DDD –82.Recently published data showed the possible role of interleukin agonist drugs in the treatment of pathological pain  , therefoIn genetic association studies the sample size is highly important, as it can significantly alter the results. However, the sample size varies in the published studies, hence inconsistent genome wide association study results with non-reproducible results exist . Thus, iIn conclusion we can state that IL1B and IL6 gene variants are associated with the psychological status and the long-term outcome of surgically treated lumbar DDD patients and these associations can be related to each other. The most plausible explanation to these findings could be linked to the major role of these cytokines in local and systemic chronic inflammation. Based on our findings and the corresponding literature advanced treatment methods could be established targeting interleukin 1B, interleukin 6 and its genes to successfully prevent/treat FBSS or even primary lumbar degenerative pathologies. On the other hand, the consideration of patient-specific genetic difference can be important to maximize the therapeutic outcome.Additional file 1.


This study aimed to assess clinical outcomes following intradiscal injections of higher-concentration (> 10 ×) platelet-rich plasma (PRP) in patients with chronic lumbar discogenic pain and to compare outcomes with a historical cohort.This retrospective study included 37 patients who received intradiscal injections of higher-concentration (> 10 ×) PRP and had post-procedure outcomes data . Outcomes were compared to a historical cohort of 29 patients who received intradiscal injections of < 5X PRP.Pain and FRI scores significantly improved by 3.4 ± 2.5 and 46.4 ± 27.6, respectively, at 18.3 ± 13.3 months following intradiscal injections of > 10 × PRP (p < 0.001). These improvements were greater than those reported by the historical cohort . Additionally, the satisfaction rate was higher in patients receiving > 10 × PRP compared to those receiving < 5 × PRP .Findings from this study suggest that clinical outcomes can be optimized by using PRP preparations that contain a higher concentration of platelets. Further research is needed to continue to optimize the composition of PRP used to treat patients with lumbar disc disease. Low back pain (LBP) is the leading cause of disability worldwide , affectiThe pathophysiology of LBP—while multifactorial—is often associated with damage to the intervertebral disc (IVD). Up to 42% of chronic LBP cases are discogenic in nature . The injImproved understanding of the pathophysiological basis of CLDP has led to the ongoing development of targeted intradiscal biologic therapies that aim to facilitate healing by delivering autologous growth factors directly to the site of injury. In particular, platelet-rich plasma (PRP) can be beneficial in regions in which vascularity is minimal, such as the IVD , 9, due Although data supporting the use of intradiscal PRP therapy for a subset of patients with CLDP is promising, certain questions remain. Determining the optimal PRP preparation is one such area of clinical interest. Jain et al. demonstrated a positive correlation between higher platelet concentrations and improvements in outcomes in patients receiving intradiscal PRP therapy for discogenic LBP . The majThe objectives of this study were to (1) determine whether intradiscal injections of PRP with higher platelet concentrations would improve clinical outcomes in patients with CLDP, and (2) compare clinical outcomes to historical data from a previous study utilizing intradiscal injections of PRP with lower platelet concentrations. It was hypothesized that intradiscal injections of PRP with higher platelet concentrations would significantly improve pain and functional outcomes in patients with CLDP, and that these improvements would be greater than those observed in a historical cohort of patients receiving intradiscal injections of PRP with lower platelet concentrations.This retrospective cohort study was approved by the Institutional Review Board. Written informed consent was waived, as all data were retrospectively collected from patients’ charts. Patients with CLDP who received intradiscal PRP injections between January 2017 and January 2019 were retrospectively assessed for eligibility at a single outpatient interventional orthopaedic clinic. The inclusion criteria were: (1) chronic refractory low back pain greater than leg pain for > three months; (2) failure of conservative treatments; (3) maintained disc height of at least 50%; (4) lumbar protrusion < 4 mm; (5) higher concentration (> 10 ×) intradiscal PRP procedure; (6) absence of any contraindications ; and (7) available post-injection outcome data. The exclusion criteria were: (1) previous spinal fusion surgery; (2) spondylolysis; (3) disc extrusion or sequestered fragment; (4) severe disc degeneration; (5) missing contact information preventing follow-up; and (6) intradiscal PRP combined with another orthobiologic agent. Patients who had degenerative grade I spondylolisthesis or a previous history of microdiscectomy were permitted to be included in the study.PRP was prepared as previously described . BrieflyDemographic information, duration of pain, and patient-reported outcomes were collected. Baseline patient-reported outcomes included the numerical rating scale (NRS) pain score and Functional Rating Index (FRI). Follow-up patient-reported outcomes included the NRS pain score, FRI, and the North American Spine Society (NASS) Patient Satisfaction Index. The minimum clinically important differences (MCIDs) for NRS pain and the FRI are 2 points and 9 points, respectively , 17. PatFor the descriptive analysis, continuous data are reported as means, standard deviations, and/or ranges, and discrete data are reported as counts and percentages. Patient-reported outcomes data from the 37 patients in the current study were subsequently compared with one year historical outcomes data from 29 patients from a 2016 double-blind randomized controlled trial , where pEighty-one patients were retrospectively assessed for eligibility at a single outpatient interventional orthopaedic clinic. Forty-four patients did not meet inclusion criteria. The remaining 37 patients were included in the study (> 10 × PRP 2021 cohort).The mean age was 42.7 ± 18.2 years (range: 14–72); 12 patients were between 14 and 29 years of age, 15 patients were between 30 and 55 years, and ten patients were between 50 and 72 years. There were 23 males and 14 females. The mean follow-up time from the date of procedure was 18.3 ± 13.3 months . All but three patients reported a pain duration for seven months or more prior to the procedure, and 15 patients reported a pain duration for greater than 24 months.Pain and FRI scores are reported in Table The majority of patients reported that they started noticing improvements in the first 12 weeks  and were satisfied with their PRP injection . Five (13.5%) patients noted that they were the same or worse than before the procedure and did not experience any improvements. The procedure was defined as successful if patients reported all of the following: (1) ≥ 2-point change in NRS pain score; (2) ≥ 9-point change in the FRI; and (3) satisfaction with the procedure. Twenty-six patients met the criteria, for a success rate of 70%. Seven patients (19%) did not meet any of the criteria for success and failed to improve at all. One patient had a complication of spondylodiscitis . No pati2 = 4.9; p = 0.027). Of note, age and gender distributions were similar between the > 10 × PRP 2021 cohort and the historical cohort .For the historical (< 5 × PRP 2016) cohort, the mean change in pain score from baseline was 1.7 ± 1.6 (p = 0.063), and the mean change in FRI score from baseline was 33.7 ± 12.3 (p = 0.001). Compared to the historical cohort, the > 10 × PRP 2021 cohort started with worse pain and function scores and experienced significantly greater degrees of improvement in both pain and function   failed to improve at all. Future studies involving further characterization of the PRP injectate, including cell differentials and bioactive protein levels, and assessment of MRI criteria are needed to better elucidate why some patients do not experience any improvements following these injections.There are several limitations to consider for this study. First, the follow-up time points were variable, due to the retrospective nature of the study. Second, baseline NRS pain and FRI scores in the current > 10 × PRP cohort were worse than those in the historical < 5 × PRP cohort; however, age and gender distributions were similar between cohorts. Lastly, shorter-term effects were not assessed in the study and should be investigated in the future.Overall, there is a need for evidence-based, interventional treatments that address the underlying pathology of CLDP. Intradiscal PRP therapy has shown promising results in the CLDP literature, but there are wide variabilities in PRP type and processing. Results from this study suggest that clinical outcomes following intradiscal PRP injections in patients with CLDP can be optimized by using a PRP preparation with a higher concentration of platelets (> 10 ×). Future studies exploring PRP with higher concentrations of platelets in larger sample sizes and with longer follow-ups are warranted, as well as a more detailed analysis of the cellular composition of PRP  to assess other variables.


Background and Objectives: Quality of life (QoL) and chronic pain are important outcomes following hernia surgery. The long-term effects of Transcutaneous Electric Nerve Stimulation (TENS) on postoperative recovery are not well known. In this trial we investigated the role of TENS on QoL and on the incidence of chronic pain following inguinal hernia repair with mesh. Materials and Methods: A total of 80 male patients with elective primary unilateral hernia Lichtenstein repair were randomly allocated to receive TENS or a placebo-TENS procedure. The TENS group received conventional TENS twice a day on the first and second postoperative days. The intensity was set at 0–0.5 mA in the placebo-TENS group. General and hernia-specific QoL, as well as the incidence of chronic pain were assessed using SF-36v2 and the Carolinas comfort scale. Results: Less sensation of mesh was reported by the TENS group patients one week after surgery. At this time point, the mean sensation score was 6.07 ± 8.88 in the TENS group and 14.08 ± 16.67 in the placebo-TENS group (p = 0.029). Although at two days and one week postoperatively, TENS group patients tended to have less pain, less movement restrictions and better overall hernia-specific QoL, the differences were not statistically significant. At 6 months postoperatively, no incidence of chronic pain was found in either the placebo-TENS or TENS group. Conclusions: Conventional TENS applied in the early postoperative period following inguinal hernia repair with mesh was found to reduce mesh-related foreign body sensation one week after surgery. Promising results were also found for other QoL domains. Inguinal hernia repair is one of the most common surgical procedures performed today. The lifetime occurrence of inguinal hernia is 27–43% in men and 3–6% in women . Open, tPain is the most common complaint reported by patients following inguinal hernia surgery . One of Transcutaneous electrical nerve stimulation (TENS) is a noninvasive, inexpensive and easy to learn technique that is used to manage acute and chronic pain of nociceptive and neuropathic origin ,23. TENSWe present here the follow-up results of a randomized, double blind and placebo-controlled trial in which TENS was incorporated into the multimodal treatment of acute postoperative pain following open inguinal hernia repair with mesh. We evaluated the impact of TENS on early and late QoL and on the development of chronic pain.Details regarding the study design, sample size calculation, randomization and blinding, surgery, postoperative treatment, TENS and placebo-TENS application were described in our previous open access report . BrieflyInclusion criteria for the trial were: male gender; primary hernia; no prior TENS procedure; American Society of Anesthesiologists physical status I to III; no cognitive, language, hearing or visual disorders; no movement disorders. Exclusion criteria were: surgical complications; nerves in the inguinal region could not be identified or were damaged; known allergy to a patch glue; chronic use of non-steroidal anti-inflammatory drugs or opioids; neuropathic disease; general contraindication for TENS procedure (such as skin disorder at site of electrode application or pacemaker); non-Lichtenstein modification for hernia repair.The final sample size was calculated using data on pain ratings when walking at the interim analysis, a two-group design, α = 0.05, and power = 0.80. The sample size for QoL analysis was not calculated separately because this was planned as a secondary outcome of the trial.On the first postoperative day, participants were randomized to receive active TENS procedures (TENS-group) or inactive TENS procedures (placebo-TENS group) according to a computer-generated random assignment list. Participants and the investigators responsible for outcome measurements and data collection were blinded to the group assignment. Group affiliation was revealed after discharge of the participant and when the investigators could not impact the participant’s future responses. During the first two postoperative days, participants received regular pharmacological analgesia to treat their pain and reach a comfortable level. They could ask for additional doses in case of insufficient analgesia. On the first and second postoperative days, the TENS group received conventional TENS using a constant stimulation frequency of 100 Hz and pulse duration of 200 μs. Segmental and local stimulation was used. Two adhesive electrodes (10 × 5 cm) were placed on the skin at the inguinal region on both sides of the surgical incision. Two adhesive electrodes (5 × 5 cm) were also placed on the skin and parallel to the spine 2 cm from the adjacent spinal processes of the 12th thoracic to 3rd lumbar vertebrae on the surgical side, according to segmental innervation of the inguinal region. The intensity was increased until the participant was able to feel a maximal tolerable tingling sensation without causing discomfort, pain, or muscle contraction. In the placebo-TENS group the whole procedure was the same as in TENS group, but intensity was set at 0–0.5 mA, and participants could not feel any sensations. TENS and placebo-TENS procedures were applied twice a day on the first and second postoperative days, giving a total of 4 procedures for each participant. On the day of discharge from hospital, Ketorolac was prescribed as 10 mg pills and participants were instructed to keep the pain at a comfortable level during daily activities and during rest. The study design is shown in The outcome measures were general and specific hernia-related QoL in the early and late postoperative period, as well as the incidence of chronic pain and the proportion of symptomatic patients in the TENS and placebo-TENS groups.General QoL was evaluated using the well-known QoL questionnaire SF-36 v2 short form. This is a reliable and validated measuring instrument that has already been used in the Lithuanian population for different clinical conditions ,40. SF-3Specific (hernia-related) QoL was evaluated using the Lithuanian version of the Carolinas Comfort Scale (CCS) . This haGeneral QoL and specific QoL were assessed before surgery on the admission day, then on the second postoperative day and 1-week, 4-weeks and 6-months postoperatively. At each time point the participants were asked to complete SF-36 and CCS questionnaires. Participants were briefly instructed on how to complete the questionnaires. On the second postoperative day, participants completed the questionnaires before discharge from the hospital. The questionnaires for other time points were mailed to participants, together with stamped, self-addressed envelopes. Participants completed the questionnaires and mailed them back to investigators. This method has been validated against in-person responses or replies obtained by telephone and used successfully in previous trials ,43.The incidence of chronic pain was determined from the CCS questionnaire completed 6 months after surgery. The criteria for chronic pain were: question b, any activity rated > 2; and question c, any activity rated > 0. Symptomatic patients were identified from the CCS questionnaire completed 6 months after surgery and according to the scoring algorithm. Cases with late postoperative complications were recorded in the follow-up period.p < 0.05. Continuous variables were represented as the mean ± Standard Deviation (SD), while categorical variables were represented as percentages.SPSS version 22 software  was used for statistical analysis. Categorical variables were analyzed using Pearson’s chi-square test. The Mann–Whitney test for independent samples was used to compare QoL subscales and total scores between the placebo-TENS and TENS groups at different time points. CCS scores were expressed as percentages of the maximum possible score. Pearson’s chi-square test was used to compare the incidence of chronic pain between the groups. Results for all tests were considered significant at n = 40) group and the placebo-TENS (n = 40) group. At the end of the 6-month follow-up period, QoL was analyzed for 33 and 31 participants in the placebo-TENS and TENS groups, respectively. The flow chart for this study is shown in A total of 80 patients were enrolled in the trial and divided equally into the TENS (p > 0.05)  .p = 0.029)  . At the = 0.029) , howeverFewer responders in the TENS group scored ≥ 1 in the sensation scale compared to the placebo-TENS group (35.5% vs. 54.5%), but the difference was not significant .There were no differences in total SF-36 scores or scores for the different SF-36 domains between the placebo-TENS and TENS groups for general QoL at any of the time points. Results for the SF-36 total score, pain and physical functioning scores are shown in No incidence of chronic pain was found in any of the placebo-TENS (0/33) or TENS (0/31) patients at 6-months postoperatively.A seroma occurred one-week postoperatively in one case from the TENS group and was treated using several punctions. No other surgery or TENS-related complication was registered.p = 0.125).More participants were symptomatic 6 months after surgery in the placebo-TENS group  than in the TENS group , but this did not reach statistical significance  one week after open unilateral inguinal hernia repair surgery. However, the impact of an early postoperative TENS course on late general and hernia-specific QoL at different time points remains to be determined, as does the role of TENS in reducing chronic pain following open inguinal hernia repair.Earlier results from this trial showed that TENS reduces acute postoperative pain and analgesic use after open inguinal hernia repair with mesh . HoweverTo date, the TENS procedure is known to produce a short-term analgesic effect . TENS haMany patients report a feeling of stiffness or foreign body after implantation of a mesh in the inguinal region following hernia surgery . The patIn a meta-analysis of open pre-peritoneal versus Lichtenstein repair, chronic postoperative pain of greater than 6 months duration was found in 7.1% and 12.3% of patients, respectively. In another meta-analysis of totally extra peritoneal (TEP) hernia repair versus Lichtenstein, chronic postoperative pain of greater than 3 months duration was reported in 12.5% and 16.8% of patients, respectively . In our Another reason for the development of chronic pain is the presence and poor control of risk factors , such asWe believe that good postoperative pain control and the absence of other risk factors can reduce the incidence of chronic pain.We also evaluated the impact of TENS on specific hernia-related QoL following open hernia surgery with mesh. Total CCS scores and results for other domains at the two-day and 1-week postoperative time points were promising. The TENS group had a lower total CCS score than the placebo-TENS group, but this did not reach statistical significance. After one month and 6 months postoperatively, no differences were apparent between the two groups for all CCS domains and for the CCS total score. At 6-months postoperatively, fewer patients in the TENS group tended to respond positively to the mesh perception question compared to the placebo-TENS group, with less symptomatic patients identified in the TENS group. A statistically significant difference was not apparent between the two groups. The main reason for this was likely to be the smaller number of patients analyzed at these time points. Indeed, this was a major limitation of the follow-up part of this trial.Another reason why TENS did not impact the long term QoL may have been the short course of TENS therapy. Extending the course is likely to result in a greater benefit from TENS. Observational studies on the efficacy of long-term TENS for the treatment of chronic pain from various causes have shown that it reduces pain interference with work, home and social activities. Long-term TENS also increased activity levels and pain management, decreased the use of other therapies , and decreased the use of narcotics, tranquilizers, muscle relaxants, nonsteroidal anti-inflammatory drugs and steroids ,61. In mThe main limitation of the study was that sample size calculation was based on acute pain outcomes in specific on pain ratings when walking. Therefore, secondary outcome analysis was not enough powered. Perhaps this is the reason why the difference in general and specific hernia-related quality of life outcomes were not found. Other limitations of this study were the selection of participants according to narrow criteria  and a single-center study site.In conclusion, conventional TENS applied in the postoperative period following inguinal hernia repair with mesh has an analgesic effect. It also reduces mesh-related foreign body sensation one week after surgery and shows promising results for other QoL domains. We suggest that physicians involved in hernia surgery should consider integrating conventional TENS into multimodal postoperative pain treatment. Additional good quality trials with a larger sample size are needed to confirm the potential benefit of TENS for reducing the incidence of chronic pain and for improving late postoperative QoL following hernia repair.Conventional TENS applied in the postoperative period following inguinal hernia re-pair with mesh has not only analgesic effect but also reduces mesh-related foreign body sensation one week after surgery.


The aging population and increasing chronic diseases make a tremendous burden on the health care system. The study evaluated the relationship between comorbidity indices and common geriatric syndromes.A total of 366 patients who were hospitalized in a university geriatric inpatient service were included in the study. Sociodemographic characteristics, laboratory findings, and comprehensive geriatric assessment(CGA) parameters were recorded. Malnutrition, urinary incontinence, frailty, polypharmacy, falls, orthostatic hypotension, depression, and cognitive performance were evaluated. Comorbidities were ranked using the Charlson Comorbidity Index(CCI), Elixhauser Comorbidity Index(ECM), Geriatric Index of Comorbidity(GIC), and Medicine Comorbidity Index(MCI). Because, the CCI is a valid and reliable tool used in different clinical settings and diseases, patients with CCI score higher than four was accepted as multimorbid. Additionally, the relationship between geriatric syndromes and comorbidity indices was assessed with regression analysis.p < 0.05). CCI and ECM scores were related to dementia, polypharmacy, and frailty. Moreover, CCI was also associated with separately slow walking speed and low muscle strength. On the other hand, unlike CCI, ECM was associated with malnutrition.Patients’ mean age was 76.2 ± 7.25 years. The age and sex of multimorbid patients according to the CCI were not different compared to others. The multimorbid group had a higher rate of dementia and polypharmacy among geriatric syndromes. All four indices were associated with frailty and polypharmacy(In the study comparing the four comorbidity indices, it is revealed that none of the indices is sufficient to use alone in geriatric practice. New indices should be developed considering the complexity of the geriatric cases and the limitations of the existing indices. The world's population is getting older, and one of every ten people is over 65 years of age in 2021 . In liteDue to multiple comorbidities, overlapped signs and symptoms may cause difficulty in diagnosis . MoreoveThe functional, cognitive, psychosocial, and nutritional status of older adults should guide the treatment decision. CGA, which allows multidimensional holistic assessment of older adults, should predict the benefits and side effects of treatment and outcomes of the interventions on older people . FurtherTherefore, this study aims to determine an appropriate comorbidity index for geriatric patients and compare four comorbidity indices, which are most frequently used in older adults, to predict geriatric syndromes.This study was designed as retrospective and cross-sectional. A total of 2935 patients admitted and hospitalized in a university hospital geriatrics inpatient clinic between January 2015 and February 2019 were screened retrospectively. Three hundred sixty-six patients whose hospital records were suitable were included in the study.All patients over 60 years without exclusion criteria were included in the study. Patients were excluded if they transferred to another clinic, died during the follow-up, refused to complete the treatment, and were hospitalized for only intravenous drug infusion or transfusion. Patients who needed acute care, including acute coronary syndrome, gastrointestinal bleeding, acute cerebrovascular event, sepsis, respiratory distress, and unable to complete CGA parameters  were also excluded. The flowchart of the study is shown in Fig. Sociodemographic features , length of stay (LOS), and medications were reviewed. As a part of CGA, Montreal Cognitive Assessment Scale (MOCA)(for patients with nine years or more education) , Mini-MeDepression and Dementia were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria.Orthostatic Hypotension: Postural blood pressure changes were evaluated via the Head-Up Tilt Table Test (HUT). Orthostatic hypotension is considered of fall in systolic blood pressure > 20 mmHg and/or diastolic blood pressure > 10 mmHg within the first 3 min after standing up from the supine position. Frailty: Frailty was defined using the Fried Physical Frailty Scale.  Walking Polypharmacy was defined as the concurrent use of 5 and more drugs [Urinary incontinence was diagnosed if the patient experienced involuntary urinary loss in the past three months except for urinary tract infection .Fall was defined as an event that resulted in a person coming to rest inadvertently on the ground or floor or other lower level in the last year. Malnutrition: MNA-SF classified Nutritional status as malnourished when the score ≤ 7. Comorbidities are assessed with four different indices; Charlson Comorbidity Index (CCI), Elixhauser Comorbidity Measure (ECM), Geriatric Index of Comorbidity (GIC), and Medicine Comorbidity Index (MCI). CCI score was calculated based on the International Classification of Diseases (ICD) diagnosis codes with 19 categories weights from 1 to 6. Metastatic solid tumor and HIV has the highest points (6 points). ECM categorizes patients according to the burden of 30 comorbidities. GIC classifies patients for 15 chronic conditions considering the presence and severity of the diseases. Each condition is grouped into four classes . MCI was designed to evaluate 20 chronic diseases and the drugs used concerning these diseases. Patients were scored with CCI between 0 and 37 , ECM betFrequency and percentages were used for categorical variables, and mean ± standard deviation was used for continuous variables in Table Of the 366 patients, 249 (67.8%) were female, and the mean age was 76.2 ± 7.25 years. The most common comorbidities were hypertension (74.3%), diabetes mellitus (34.7%), and dementia 25.1%). When patients were divided into two subgroups according to their CCI score, there 55 (15.1%) patients were in the high CCI group. No significant differences between the two groups were revealed in terms of age, gender, and education level. Patients in the high CCI group were using more drugs, and their length of stay in hospital was more extended than low CCI group (p < 0.05). The rates of dementia and polypharmacy were significantly higher in the multimorbid group (p < 0.001), while the rate of other common geriatric syndromes was similar between groups. As expected, the frequency of chronic diseases was higher in the multimorbid group, except for congestive heart failure and hyperlipidemia. When the comorbidity scores were calculated, the mean CCI score, ECM score, GIC score, and MCI score were higher in the high CCI group (p < 0.01). BADL scores were worse in the high CCI groups, while other CGA parameters showed no significant difference. Patients in the low CCI group have higher levels of hemoglobin, glomerular filtration rate (eGFR), LDL, albumin (p < 0.05). Demographic characteristics, laboratory results, and CGA parameters of patients are shown in Table %. When pWhen the association of indices with common geriatric syndromes was reviewed, all four indices were linked with frailty and polypharmacy(p < 0.05). Only ECM was associated with malnutrition and depression (p < 0.05). However, there was an inverse relationship between ECM score and depression. Low muscle strength and low walking speed, which are also the components of sarcopenia, were related to CCI score, while falls were only associated with GIC (p: 0.04). When age and sex were adjusted, all relationships were preserved except frailty with GIC score Table .Table 2AAccording to the reference scores, multinomial regression analyses with CCI, ECM, and GIC subgroups showed no linear relationship between indices and MMSE, YGDS, POMA, MNA ADLs, Fried frailty score, number of drugs, LOS. Also, the Group 4 of ECM subgroups was associated with MMSE, MNA, ADLs, frailty scores, and total drug number as well as the LOS, and the Group 4 of CCI subgroups was associated with Basic ADLs, frailty score, the number of drugs, and LOS, the Group 4 of GIC was related to the only number of drugs compared to the reference groups when age and gender-adjusted Table .Table 3MThis cross-sectional study suggests that none of these four comorbidity indices, which are expected to represent the older adults as a whole, fully complied with CGA or geriatric syndromes. However, it was also demonstrated that CCI and ECM were related to frailty, dementia, polypharmacy, whereas ECM was also associated with malnutrition. Moreover, although the ECM subgroup 4 seems to be closely associated with ADL, MMSE, nutritional assessment scores, and LOS, there was no linear relationship between the subgroups.Considering that 92% of older adults have at least one chronic disease or geriatric syndrome, and at least 30% use five or more medications, it is better to understand how heterogeneous these patients are. , 31 ComoThis study found that CCI was correlated with LOS and most CGA parameters, such as physical fitness, nutritional status, functionality, frailty, and number of drugs, in older patients. Consistent with our results, many studies have shown that CCI is associated with ADLs and functionality. –46 In coPrevious studies reported that ECM predicted LOS better than CCI in the general population, , 48, 49 Given the importance and complexity of pharmacotherapy in geriatric cases and polypharmacy, a geriatric syndrome,  it wouldThe GIC, the last scale we evaluated, was developed especially for geriatric cases; however, we found that it was not associated with nutritional status, cognitive status, and depressive mood. Moreover, GIC was inversely related to dementia. Accordingly, Rozzini et al. also reported that GIC was correlated with ADL, not IADL, using the Katz index as in our study.  This mayFrailty and polypharmacy were both related to the four indices. GIC had higher odds for both geriatric syndromes. The relationship may be explained index characteristics for assessing the severity of the diseases. Besides, ECM and CCI had a closer relationship with CGA parameters. In clinical practice, patients with higher scores of GIC, ECM, or CCI should be part of a further evaluation to provide a comprehensive management plan.On the other hand, no linear relationship was observed when the CCI, GIC, and ECM groups were categorized according to increasing comorbidity scores. The low number of patients may explain it in the subgroups and the heterogeneity of patients. Moreover, considering depression is a common geriatric syndrome, it is remarkable that it was not associated with the depressive mood at four indices. Furthermore, ECM was inversely related to depression. Therefore, it is essential to evaluate depressive mood in studies to increase the compatibility of these scales with CGA and develop new comorbidity scales for older adults. Our study's strengths are an adequate sample size, such as 366 geriatric cases, and performing CGA to each patient. In addition, this study is one of the first studies evaluating the relationship between four comorbidity scales and geriatric syndromes. The limitations of our research are retrospective and cross-sectional design and the inability to assess mortality.The present comorbidity scales are insufficient to reflect geriatric syndromes simultaneously. New indices should be developed considering the complexity of the older geriatric patients and the limitations of the existing ones.


T, and arrival by ambulance). 29,291 patients  with dyspnea  or chest pain  were included. Dyspnea patients were older than patients with chest pain  and had more comorbidity and higher average blood troponin T and c-reactive protein levels. Dyspnea patients also had higher hospitalization rates  2.1–2.3), including the intensive care unit , and more ED revisits  in 30 days. Dyspnea patients had five-fold increased mortality compared to those with chest pain; hazard ratio (HR) 5.1 (4.8–5.4), adjusted for markers of disease severity, the mortality was two-fold higher, HR 2.2 (2.0–2.4). Compared with chest pain patients, ED dyspnea patients are older, have more comorbidity, and have worse outcomes in terms of hospitalization, morbidity, and mortality.Dyspnea and chest pain are major and important causes of contact at the emergency department (ED). Dyspnea is associated with high morbidity and mortality, but data on characteristics and outcomes compared with chest pain in the ED are limited. This was a retrospective cohort study of consecutive patients with contact causes of dyspnea or chest pain at two Swedish EDs from 2010 to 2014. Hospital admittance, ED revisits, and mortality were analyzed using multivariable regression models, adjusted for ED and markers of disease severity (age, sex, centre, Charlson comorbidity index, c-reactive protein, troponin  Dyspnea and chest pain are major and important causes of contact at the emergency department (ED), with dyspnea comprising 5–9% and chest pain 11–13% of total ED admissions , 5, and Management of chest pain, with coronary artery disease as the major underlying pathology , 10, is ED patients with dyspnea have been reported to have higher in-hospital mortality than those with chest pain , 10, andThe aim of this study was to evaluate characteristics and outcomes in patients presenting to the ED with dyspnea compared to chest pain.This was a retrospective consecutive cohort study using the Evaluation of Unknown Predictors of Electrocardiographic Changes (EXPECT) database , 16. TheThe present study was approved by the Regional Ethics Review Board at Lund . Active patient consent was waived by the ethics review board, but individuals were informed about the study and had the opportunity to decline participation.The present study included data from the EDs of Lund University Hospital  and Helsingborg General Hospital  during 2010–2014. Both EDs used the Rapid Emergency Triage and Treatment System (RETTS)  for triaT (hs-cTnT), c-reactive protein (CRP), and hemoglobin (Hb), as well as ED revisits and mortality within 7, 30, and 365 days. The variable “arrival by ambulance” was only available at Lund. Sensitivity analyses without adjusting for “arrival by ambulance” yielded similar findings.From the EXPECT database, we extracted the following data: patient's age, sex, previous diagnoses, Charlson comorbidity index (CCI) , ED arriThe contact causes were defined according to RETTS  and wereThe date of death was obtained from the Swedish National Population Registry longitudinally up to 31 December 2015. Data on previous medical conditions were retrieved as all the International Classification of Diseases 10th Revision (ICD-10) diagnoses made within the region (region Skåne) in the five years preceding the ED presentation.t-tests for continuous variables and chi-square tests for categorical variables. Differences in outcomes were analyzed using linear regression for continuous outcomes and logistic regression for categorical outcomes. Time of death was analyzed using Cox regression. Associations were expressed with 95% confidence intervals (CI) and were estimated unadjusted and adjusted for potential confounders: age, sex, centre, CCI, CRP, hs-cTnT, and arrival by ambulance. Statistical significance was defined as a two-sided p value <0.05. Non-normally distributed continuous variables were analyzed using Wilcoxson's rank sum test and were reported as median (IQR). Statistical analyses were conducted using the software packages Stata, version 14.2  and SAS, version 9.3 .Patient characteristics, comorbidities, and outcomes were compared between the dyspnea and chest pain groups using n = 8,812) or chest pain . Characteristics for the groups are shown in We included a total of 29,291 patients  who presented to the ED of Helsingborg (51%) or Lund (49%) with a primary or secondary complaint of dyspnea , including to the ICU (1.4% vs. 0.1%), and had longer hospital stays and more ED revisits. Mortality was assessed during a median of 3.5 years (range 0–6.0 years), yielding a total of 97,812 person-years of follow-up. Mortality was clearly higher in dyspnea patients at all points of follow-up. As shown in p < 0.001).Outcomes are shown in In this large consecutive cohort of ED patients, the main findings were that dyspnea patients had a markedly higher rate of hospitalization, an almost ten-fold higher ICU admittance, more ED revisits, and a five to ten times higher crude mortality compared with ED patients with chest pain. The excess risks in dyspnea patients decreased after adjusting for differences in disease severity , indicating that the worse outcomes were largely attributed to more severe underlying illness.Our study adds novel and important data on morbidity in unselected ED patients with a contact cause of dyspnea or chest pain. Dyspnea patients commonly had previous diagnoses of COPD, heart failure, asthma, and pneumonia, while angina pectoris and previous AMI were more common in chest pain patients. Diabetes and hypertension were common in both groups. Previous COPD, heart failure, asthma, and pneumonia are common in ED patients with dyspnea and have previously been reported in Europe , SoutheaDyspnea as a cause of contact was more common in the winter months compared to chest pain. A previous study suggests that ED dyspnea patients in the winter months are typically older and often have a lower respiratory tract infection, COPD, and/or heart failure .Dyspnea patients had markedly worse outcomes than chest pain patients, with e.g. a 10-fold higher 7-day crude mortality, which is well in-line with previous findings of 10 times higher in-hospital mortality for dyspnea compared to chest pain patients . The lonThe novel finding that the HR for mortality decreased from 5.1 to 2.2 when adjusted for age, sex, centre, CCI, CRP, Hs-cTnT, and arrival by ambulance supports that the worse outcomes in the dyspnea group is partly related to more severe underlying illness. The remaining two-fold increased mortality suggests that dyspnea in itself is an independent risk factor, but other factors such as other underlying conditions, lung function and smoking , hypercaA strength of this study was the large consecutive ED patient cohort with a complete follow-up of outcomes using cross-linked registry data. Several clinically relevant variables could be analyzed to evaluate the difference in outcomes between the groups. Another strength was the possibility to rinse for overlap between the two causes of contact. Overlap between the groups of dyspnea and chest pain was present in about 5% of patients, which is in line with previous studies comparing symptoms as causes of contact , 26. HowThe increased morbidity and mortality of dyspnea patients in this study strengthen the evidence that a chief complaint of dyspnea in itself is an early marker of severe disease, indicating a need for prioritized care. The finding that morbidity and mortality to a large part were explained by underlying factors indicates that it should be possible to create risk-stratification tools for ED dyspnea patients, quickly identifying those who will benefit from specific and/or aggressive care, ICU admission, close follow-up at discharge, or perhaps a more palliative approach.This large consecutive cohort study indicates that compared with chest pain patients, ED dyspnea patients are older and have more comorbidity and that they fare markedly worse in terms of hospitalization and mortality. Our findings support that a contact cause of dyspnea is a marker of severe illness and should warrant fast diagnostics and treatment to lower the risk of a bad outcome.


Using these network measures at multiple spatial scales, both at the level of single nodes (brain regions) and communities (clusters of nodes), we found that PC at the community level was generally higher in RA patients compared to HC during and after painful pressure over the inflamed joint and corresponding site in HC. This shows that all brain communities integrate more in RA patients than in HC for time points following painful stimulation to a disease-relevant body site. However, the elevated community-related integration seen in patients appeared to not pertain uniquely to painful stimulation at the inflamed joint, but also at the neutral thumbnail, as integration and segregation at the community level did not differ across body sites in patients. Moreover, there was no specific nodal contribution to brain network integration or segregation. Altogether, our findings indicate widespread and persistent changes in network interaction in RA patients compared to HC in response to painful stimulation.Functional brain networks and the perception of pain can fluctuate over time. However, how the time-dependent reconfiguration of functional brain networks contributes to chronic pain remains largely unexplained. Here, we explored time-varying changes in brain network integration and segregation during pain over a disease-affected area (joint) compared to a neutral site (thumbnail) in 28 patients with rheumatoid arthritis (RA) in comparison with 22 healthy controls (HC). During functional magnetic resonance imaging, all subjects received individually calibrated pain pressures corresponding to visual analog scale 50 mm at joint and thumbnail. We implemented a novel approach to track changes of task-based network connectivity over time. Within this framework, we quantified measures of integration  and segregation (within-module degree  Alterations in the functional connectivity between brain regions have been reported in patients with chronic pain , bringinWithin this framework, recent advances have been made in the identification of an objective biomarker of chronic pain. Notably, a recent study provided evidence for a neuroimaging marker for tonic experimental pain predicting sustained clinical pain . An inteVariables obtained from modeling functional magnetic resonance imaging (fMRI) data in the context of time-varying brain networks may act as more sensitive markers of acute and chronic pain, given the dynamic nature of pain and the brain itself. Specifically, there is evidence to suggest that the organization of brain networks fluctuates between states of integration and segregation  and, witHowever, the application of integration and segregation measures to the investigation of pain-related patterns of network reconfiguration is still in its infancy. Recent work from our group assessed TVC changes in network integration/segregation in HC during thermal pain, showing increased brain network integration with increased pain . To add Based on these premises, the objective of the present work was to determine whether and how the degree of change in integration and segregation between network communities and nodes varies over time and is putatively influenced by pressure pain stimuli across groups and stimulation sites in patients. This might add more specificity to the understanding of cerebral pain processing mechanisms in patients with RA.The dataset used in the current study has previously been described in https://www.clinicaltrials.gov; ). Previously, we have reported differences in spontaneous brain activation patterns  of the left hand and to the non-affected, left thumbnail via an automated, pneumatic, computer-controlled stimulator with a 1 cm2-hard rubber probe . Each participant first received a series of stimuli with a step-wise increase in pressure, then followed by a series of stimuli that had a randomized order of different pressure. The pressure stimuli, in both series, were delivered for a duration of 2.5 s and with 30 s inter-stimulus intervals. After each stimulus, participants were prompted to rate pain intensity on a 0–100 mm visual analog scale (VAS), ranging from “no pain” to “worst imaginable pain.” Stimuli in the ascending series were presented in increasing pressure steps of 50 kPa, which led to the identification of each participant’s pressure pain threshold  and stimulation maximum . It is within this subjectively calibrated range of PPT and SM that five pressure pain intensities were obtained and delivered, each three times, in a randomized series. A polynomial regression was applied to the 15 VAS ratings from the randomized series and, consequently, used to determine each subjective representation of VAS 50 mm (referred to as P50). Please refer to One day prior to fMRI scanning, the degree of pain pressures to be used during scanning was subjectively calibrated. Pain sensitivity was assessed by applying pressure to the patient’s clinically most affected proximal interphalangeal (PIP) joint  obtained from day 1 and a standard non-painful pressure (50 kPA) were presented during four pseudo-randomized fMRI runs. Two of the four fMRI runs contained stimuli that were delivered to the most affected joint in patients , while the remaining two fMRI runs included stimuli applied to the thumbnail. Each run consisted of a total of 30 pressure stimuli events (15 painful and 15 non-painful) presented in a pseudo-randomized fashion. The duration of each stimulus was 2.5 s and all stimuli onsets were jittered over time with a mean interval of 15 s (range 10–20 s) to ensure a fine-grained sampling of the events. The total duration for all runs was 8 min and 15 s. All participants were instructed, prior to scanning, to concentrate on the pressures delivered to joint and thumbnail and to refrain from invoking coping strategies. No pain ratings were collected during the course of the fMRI runs.MRI data were acquired on a 3T General Electric 750 MR scanner installed at the MR Research Center at Karolinska Institutet (Stockholm) using a 32-channel head coil. Four task-based fMRI scans, each consisting of 160 volumes, were acquired for each subject using a T2*-weighted single-shot gradient echo planar sequence . Anatomical MRI data were obtained using a high-resolution T1-weighted image sequence . Additionally, T2-weighted images were acquired and assessed for clinical abnormalities by a neuroradiologist.The pre-processing of anatomical and functional data was performed using fMRIPrep  were carried out using teneto (version 0.5.3), a Python package for temporal network analysis 1. PleaseThe BOLD signal time-series from the pre-processed fMRI data were extracted from brain areas defined using the 7-network (community), 400-node Schaefer parcellation scheme . Subsequx and y over all the individual time points, excluding data at time point t, and then multiplies the resulting correlation value by –1  method . When apue by –1 .This application of the JC method to compute time-varying functional connectivity was first introduced by qualia , a network metrics that quantifies the degree to which specific nodes communicate across communities . As desci = node, s = index of community (NM), isk = degree of links within each community, ik = total degree of i. In the computation of PC values, only positive edges were included in the analysis. Next, we computed the within-module degree z-score (z), a network metrics that measures the extent to which specific nodes communicate within their own communities  of nodes in the whole network.For all analyses, we used the same static parcellation for all time points . Taken tz for all nodes, integration and segregation were assessed both at community level  and nodal level . The idea was to probe brain network organization at multiple spatial scales , whereas a community with high median z has more within-community edges for nodes in the community (segregation on the community level).On the community level, the median PC or 2) the brain activation map produced by entering the text query “chronic pain” into NeuroQuery, a recently developed tool for comprehensive meta-analysis of the neuroimaging literature , whereas a node with high z has more within-community edges for the community .On the nodal level, node selection was informed by overlapping , the 160 time point data series were broken down into 6 event-related bins, with bins representing the onset TR when the stimulation was being delivered and until –2 TR pre- and + 3 TR after-stimulus onset, each averaged across participants. This binning partition served as an indicator for the time-varying changes in functional connectivity occurring before, during, and after participants received the painful stimulation.p < 0.05, false discovery rate (FDR) corrected for multiple comparisons.All analyses were carried out using Python version 3.7.2 and were performed: (1) separately for each community and nodal level, (2) only for painful stimuli, (3) by averaging together the two joint or the two thumb runs, respectively, and (4) by focusing only on onset and after-onset time points, each treated separately. Pre-onset time points were not included in the analyses, as the pain pressure task used in the study had not been designed to capture the cerebral processing involved in anticipating pain. However, these pre-onset time points were nonetheless plotted in the graphs, for completeness. Statistical significance was set, conventionally, at ols function in the Python statsmodels library (z) was used as dependent variable, the group variable was treated as independent variable with two levels , and age was used as a covariate. Despite the unbalanced design, Type II Sum of Squares was used, as proposed by A one-way analysis of covariance (ANCOVA) test was performed using the  library  to test  library . In the statsmodels implementation (MixedLM). The variable “site”  was entered into the model as fixed effect while controlling for age. A random intercept for each subject and, by default, for each site  were also introduced to account for the variability of subjects and sites  at baseline. The model was adjusted, also by default, by the Restricted Maximum Likelihood Estimation and the Powell optimization method was used for model fitting.Differences in the degree of change in integration and segregation over time at the community and nodal level in response to painful stimulation of the affected joint compared to the neutral thumb in patients .Brain plots were generated using lotbrain 3.z-score, z) at the community level across groups when pain was delivered to the diseased joint and corresponding site in HC (Contrasts 1 and 3 in z) change over time  and segregation  at the nodal level across groups when pain was delivered to the diseased joint and corresponding site in HC  and segregation  at the community and nodal level in patients when pain was delivered to the diseased joint compared to the neutral thumb . None of the analyses showed any significant degree of change  and segregation (within-module degree f change –8.The present study capitalized on previously analyzed fMRI data in order to detail the temporal profile of cerebral pain processing in patients with RA, with the final objective to track pain-related patterns of network reconfiguration at the resolution of single data time points.A major finding of this work is that the participation coefficient was generally higher in RA patients compared to HC during and following pressure pain over the inflamed joint compared to the corresponding site in HC. This result shows that all brain communities integrate to a relatively higher degree in patients than in HC during some, but not all, time points when painful stimulation is delivered to the disease-relevant body site . InteresWhen exploring whether this maladaptive brain network configuration in patients was specific to when pain was delivered to the inflamed joint or also to the non-clinically relevant thumb, our results pointed to the latter. Indeed, there was no difference in community-related integration over time across body sites , which mrobustness of the measures applied at the nodal level might have been more easily affected by the high number of multiple comparisons. While for PC and z at the community level, we computed the median of all nodes within each community, for PC and z at the nodal level, we considered single nodes among the 400 nodes generated by the Schaefer 400 node x 7 network parcellation. Further, we note that, as also discussed by Shifting focus from the organization of communities to the role of single nodes in the whole network, all our results indicate that there is no contribution from the six selected network nodes to brain network integration or segregation, neither during pain to joint across groups, nor during pain to joint compared to thumb within patients only , 3. ThisThe balance between integration and segregation is crucial for the brain . WhereasWith the present study, we were able to track the temporal profile of pain-related network changes in RA patients and HC. From a clinical perspective, this is of great importance for the understanding of the mechanisms involved in the perception of pain and could possibly contribute to the identification of a brain-based biomarker for chronic pain.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by the regional ethical committee of Stockholm. The patients/participants provided their written informed consent to participate in this study.SF: conceptualization, methodology, formal analysis, visualization, and writing – original draft and review and editing. RA: data curation, investigation, and writing – review and editing. IE: contribution to formal analysis and writing – review and editing. JL: data curation, funding acquisition, investigation, project administration, resources, and writing – review and editing. EK: conceptualization, data curation, funding acquisition, investigation, project administration, resources, supervision, and writing – review and editing. PF: supervision and writing – review and editing. WT: conceptualization, methodology, supervision, contribution to formal analysis, contribution to visualization, and writing – review and editing. All authors contributed to the article and approved the submitted version.