Background: Increasing evidence suggests the beneficial effects of probiotics in irritable bowel syndrome (IBS), but little is known about how they can impact the gut microbiota. Our objective was to evaluate the effects of a multistrain probiotic on IBS symptoms, gut permeability and gut microbiota in patients with diarrhoea-predominant IBS (IBS-D). Methods: Adults with IBS-D were enrolled in an open-label trial to receive a multistrain probiotic for 4 weeks. Abdominal pain, stool frequency, quality of life, gut permeability, and the luminal and adherent microbiota from colonic biopsies were evaluated before and after supplementation. Results: Probiotics significantly improved symptoms and quality of life, despite having no impact on permeability in the global population. In the population stratified by the response, the diarrhoea responders displayed reduced colonic permeability after supplementation. The luminal and adherent microbiota were specifically altered depending on the patients’ clinical responses regarding pain and diarrhoea. Interestingly, we identified a microbial signature in IBS-D patients that could predict a response or lack of response to supplementation. Conclusions: The multistrain probiotic improved the symptoms of IBS-D patients and induced distinct effects on the gut microbiota according to the patient’s clinical response and initial microbiota composition. Our study further supports the need to develop individualised probiotic-based approaches regarding IBS. Lactobacillus, Bifidobacterium and Faecalibacterium prausnitzii in IBS patients compared to healthy controls [Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders encountered by primary care physicians and gastroenterologists, with an estimated prevalence of 3–11%, depending on the geographical region and assessment criteria . The patcontrols . These ccontrols ,8,9,10.Lactobacillus and Bifidobacterium species [These findings have encouraged the evaluation of probiotics in the management of IBS as they represent an attractive approach, given their multiple mechanisms of action. These include the production of antibacterial substances, the inhibition of pathogens and antagonism of toxins, anti-inflammatory properties, the beneficial effects on intestinal barrier function, and the inhibitory effects on visceral hypersensitivity ,9,10,11. species ,18,19,20Lactobacillus and Bifidobacterium species in patients with IBS-D, whereas no significant difference was seen between the IBS-C patients and healthy control subjects. Tap et al. identified a microbiota signature associated with IBS severity [A major challenge in treating IBS is the diversity of symptoms and their underlying mechanisms, leading to a search for more personalised therapeutic approaches. In line with this aim, the American Gastroenterological Association (AGA) has just issued recommendations to differentiate pharmacological treatment for IBS according to its subtype, namely diarrhoea-predominant (IBS-D) or constipation-predominant (IBS-C) IBS . Whetherseverity . However®, PiLeJe Laboratoire, Paris, France), comprising a mixture of five lactic acid bacteria, has already been shown to prevent epithelial barrier alteration in various in vitro and in vivo models of IBS [In this context, the first objective of our study was to identify the clinical, functional, and microbial effects of a multistrain probiotic in patients suffering from IBS-D. The multistrain probiotic tested . The study was approved by the local Ethics Committee on 22 January 2016 and was performed in accordance with the ethical standards laid down in the Declaration of Helsinki and the rules of Good Clinical Practice (GCP). It was registered on the ClinicalTrials.gov site on 5 April 2016 (registration number NCT02728063).® , comprises a mixture of five viable lyophilized lactic acid bacteria  at a total concentration of 10 × 109 colony-forming units (CFU) per capsule, with corn starch and magnesium stearate as the excipients. Patients were to take two capsules per day, which were to be swallowed with a large glass of water in the morning on an empty stomach for 4 weeks. At the first study visit (V1), patients were provided with a sufficient supply of capsules for 30 days of supplementation.The tested multistrain probiotic, Lactibiane ToléranceTo be eligible for enrolment, male or female patients had to (i) be between 18 and 75 years of age; (ii) present IBS-D according to the Rome III criteria; (iii) be in a general and mental state of health compatible with participation in the study; (iv) agree to maintain their usual lifestyle throughout the study; and (v) signify their willingness to participate in the study by signing and dating an informed consent form.Patients were not included in the study if they had (i) a history of hypersensitivity to the test product or to fluorescein; (ii) an immunodeficiency or a serious or progressive illness; (iii) a metabolic disorder or an inflammatory bowel disease affecting bowel movements or nutrient absorption, such as diabetes, hyperthyroidism, coeliac disease or Crohn’s disease; (iv) an existing medical history or condition that, in the investigator’s opinion, was likely to interfere with the results of the study or expose the patient to additional risk; (v) a treatment that might interfere with the study. Pregnant or breastfeeding women were also ineligible for inclusion.The study comprised three visits, one for patient screening , one for inclusion (V1) and one at the end of the 4-week supplementation phase ± 2 days (V2).At V0, a medical examination was performed, socio-demographic data, medical and surgical history, and information on lifestyle and concomitant treatments were recorded, and the eligibility criteria were checked. If their eligibility was confirmed, the patients were enrolled and invited to return for V1 and V2 with the following recommendations: (i) not to change their lifestyle  and eating habits; (ii) to stop taking anti-diarrhoeal medication, but not to change their other treatments unless these were specifically prohibited in the study (antispasmodics were accepted); (iii) not to start any new treatment with psychotropic drugs, antihistamines, antibiotics or anti-inflammatory drugs (aspirin or ibuprofen) unless absolutely necessary; (iv) not to consume foods or food supplements enriched with prebiotic fibres, probiotics, omega fatty acids, or other substances, such as vitamins and minerals; (v) not to consume food products containing polyols, such as chocolate, sweets or “sugar-free” chewing gum, during the 48 h preceding V1 and V2; (vi) not to consume alcohol during the 48 h prior to V1 and V2. In addition, on arrival at V1 and V2, patients were to have fasted for at least 8 h.At V1 and V2, the investigator checked that these recommendations had been followed since the previous visit, performed a medical examination and a urine pregnancy test for women of childbearing age, recorded concomitant treatments and adverse events, and verified that the patient still met the eligibility criteria. If he/she was still eligible, the following procedures and tests were performed: withdrawal of a blood sample of ≤30 mL; preparation for rectosigmoidoscopy using a rectal enema solution (if not administered at home before the visit); rectosigmoidoscopy with confocal endomicroscopy and fluorescein injection; colonic biopsies taken during this same rectosigmoidoscopy; and a 5-h dynamic lactulose/mannitol test. During these visits, the patients completed the Gastrointestinal Quality of Life Index (GIQLI ) comprisThe clinical response was defined on the basis of two criteria: abdominal pain intensity and stool frequency. A decrease of ≥30% in the mean weekly abdominal pain score between V1 and V2 was considered a response with regard to the pain criterion . A decreIntestinal permeability was assessed in vivo by the percentage urinary excretion of lactulose 2 to 4 h after oral intake of a lactulose-mannitol solution, reflecting a small intestine transit at V1 and V2. After oral intake of the lactulose and mannitol solution, urines were collected every hour for 5 h in separate jars . The per3. The medium was continuously oxygenated with a gas flow of 95% O2/5% CO2 and maintained at 37 °C. Fluorescein-5.6 sulfonic acid  and Horseradish Peroxidase  were used to determine the intestinal paracellular and transcellular permeability, respectively. The flux of FSA was evaluated by the fluorescence level, measured on a basolateral chamber over 3 h using a spectrofluorometer  . The HRP activity was determined by an enzymatic assay based on tetramethylbenzidine (TMB) substrate , and the optical density was measured using a spectrophotometer microplate reader (λ 450 nm). The ex vivo paracellular and transcellular permeabilities were determined by averaging the SFA and HRP fluxes of the three biopsies.The ex vivo intestinal permeability was measured from three different biopsies per patient in Ussing chambers, as previously described . BrieflyThe rectosigmoidoscopy was performed by a single endoscopist in non-sedated patients after a distal colon cleansing with an enema using a standard colonoscope . The colonic mucosa was examined up to 35 cm from the anal margin. Standard biopsies were then taken for a conventional routine histology and laboratory analysis. A pCLE recording was performed using a dedicated confocal laser endomicroscopy system comprising a portable laser station  and an endoscopic probe . After an intravenous injection of 5 mL of a 10% fluorescein sodium solution, the probe was threaded through the operating channel of the endoscope and positioned on the colonic mucosa, after which the recording was started within 10 min, as previously reported . The cho® 16 instrument) and 16S metabarcoding sequencing were performed by Biofortis . Both 16S rRNA libraries were constructed to target and amplify the V3–V4 regions of the 16S rRNA gene using the S-D-Bact-0341-b-S-17 and S-D-Bact-0785-a-A-21 adapters. The paired-end (2 × 250 cycle mode) sequencing was performed using the Illumina Miseq platform .Human colonic biopsies and stool samples were used to determine the luminal and adherent microbiota, respectively. Microbial genomic DNA extraction , a workflow system based on the Quantitative Insights into Microbial Ecology 2 (Qiime2) toolbox [The luminal and adherent microbiota data analyses were conducted independently. The raw reads were processed using microSysMics  were considered.Three distinct analyses were conducted: an initial analysis to compare the overall samples from V1 to V2 and two stratified analyses according to the patient’s response with regard to abdominal pain and diarrhoea. The α-diversity was estimated according to three metrics: (a) richness (number of distinct ASVs observed); (b) evenness, based on the Pielou index; and (c) the Shannon index of diversity, using the R 4.0.3 package. The statistical analysis was performed using the Kruskal–Wallis test to compare the diversity between the groups. The β–diversity analysis was calculated according to the Bray–Curtis distance and visualised in PCoA by using the Vegan 2.5-7 package with R 4.0.3. The difference in microbial β-diversity was tested using the permutational multivariate analysis of variance (PERMANOVA), computed with the adonis function of the Vegan package with default parameters (999 permutations). Differential abundance analyses were performed at the genus and amplicon sequence variant (ASV) taxonomic levels using the DESeq2 1.26.0 post-count method . Only tht-test or a non-parametric paired t-test (Wilcoxon test) if appropriate. The normal distribution of data was evaluated by the Agostino and Pearson test. A p-value less than 0.05 was considered significant.The analysis of clinical data was performed on the intention-to-treat (ITT) and per-protocol (PP) populations using Prism 7.04. The categorical variables were expressed as numbers and proportions, and the quantitative variables as means (±standard deviation). Quantitative data were compared between V1 and V2 using a paired A total of 37 patients were assessed for eligibility , of whomp = 0.023; p = 0.01), and the mean number of days per week with diarrhoea   and V2  A. Furthep = 0.058, p = 0.024, The analysis of colonic permeability, according to the clinical responses of patients, revealed differences between the pain responders (Pain R) and diarrhoea responders (Diarrhoea R) D–F. The No significant difference between V1 and V2 was seen in terms of the architectural parameters, crypt distribution and vascular parameters overall . No diffWe compared the evolution of the luminal and adherent microbiota composition between V1 and V2 in the PP population .Lactobacillus spp. and Bifidobacterium animalis were identified following supplementation  could predict the response in terms of abdominal pain and diarrhoea.Prevotella NK3B31 was observed between V1 and V2 , Alistipes and R. gauvreauii, and a concomitant reduction of Turibacter and Coprococcus were observed in Pain R at V2 compared to V1.Regarding the luminal microbiota, the α- and β-diversity indices were similar in Pain R and Pain NR (non-responders) at V1 and V2 A–D. Howe1 and V2 F. In addRoseburia and the species Bacteroides intestinalis, respectively, between V1 and V2 in Pain R, whereas no changes were observed in Pain NR  were significantly enriched in Pain NR compared to Pain R at V1. In contrast, two ASVs belonging to B. fragilis and the Catenibacterium genus, respectively, were more abundant in Pain R when compared to Pain NR at V1.A luminal microbiota signature that could be predictive of the absence to response in terms of abdominal pain was identified at V1 A. Comparresponse B. ThirteRoseburia was observed in the adherent microbiota of Diarrhoea NR between these two visits  were also increased in Diarrhoea R compared to NR at V1, while five ASVs (mainly assigned to Bacteroides and Veillonellaceae) were more abundantly represented in Diarrhoea NR than in Diarrhoea R.A luminal microbiota signature predictive of the diarrhoea response was identified at V1. As compared to Diarrhoea NR, Diarrhoea R showed a significant increase in ASVs belonging to the um genus A. ThirteHafnia-Obesumbacteria. Six ASVs assigned to various families, genera and species  were increased in Diarrhoea R, while five ASVs  were enriched in Diarrhoea NR.Similarly, the differential abundance analysis highlighted a putative adherent microbiota signature predictive of the diarrhoea response at V1 B. At theIn the ITT population, the mean compliance was 100.8 ± 5.2% (range: 82.1–111.1). Twenty-nine adverse events in 15 of 30 patients were reported during the study, of which 14 were considered potentially attributable to one of the study procedures or the supplement. Seven of these fourteen adverse events involve the digestive tract. None of the adverse events was serious, and none resulted in treatment withdrawal.This study showed that the evaluated multistrain probiotic exerted clinical, functional and microbial effects in patients with IBS-D. After 4 weeks of supplementation, we observed: (1) a significant reduction in IBS symptoms, including abdominal pain, discomfort and diarrhoea; (2) a significant improvement in quality of life; as well as (3) a differential impact on gut permeability and (4) specific alterations of the luminal and adherent microbiota, depending on the patient’s response in terms of pain and diarrhoea. Interestingly, we also identified microbial signatures that could predict a response or a lack of response to supplementation.Lactobacillus and Bifidobacterium strains of the probiotic as previously described [The clinical results are consistent with those of previous studies evaluating the combinations of several probiotic strains, some specifically in IBS-D patients ,31,32. Tescribed . Howeverescribed ,41,42,43Prevotellaceae NK3B31 group in the luminal microbiota. A previous study in a porcine model showed that supplementation with an L. plantarum strain  induced an increased abundance of the Prevotellaceae NK3B31 group, which was associated with the biosynthesis of secondary metabolites, such as acetate, and intestinal maturation [Clostridia class. Clostridia spp. has been reported to be capable of producing short-chain fatty acids (SCFAs), including acetate and butyrate, which are involved in intestinal barrier function, inflammation and the maturation of the immune system [beneficial phenotype was only observed in Pain R. In Diarrhoea R, no significant changes in the diversity or composition of either the luminal or the adherent microbiota were detected, although major changes in permeability were observed following supplementation. In contrast, we found that the multistrain probiotic induced a decreased prevalence of an ASV belonging to Roseburia in the adherent microbiota of Diarrhoea NR. This suggests that lactic acid bacteria may improve IBS symptoms (pain and diarrhoea) through different mechanisms and that the initial microbiota composition may influence the response to probiotic supplementation [Interestingly, we detected specific changes in the composition of the luminal and adherent microbiota of Pain R and Diarrhoea R following supplementation. In Pain R, the multistrain probiotic induced the enrichment of the turation . Most ofe system . The abientation .Actinobacteriota phylum , as well as the Clostridia (the genera Subdoligranulum and Peptococcus) and the Negativicutes class (Acidaminococcus genus), were found in the luminal microbiota of Pain NR. Additionally, ASVs belonging to the Bacteroidota phylum (Prevotellaceae and Rikenellaceae families) were also more abundant in the luminal microbiota of Pain NR. A similar enrichment was observed in the adherent microbiota of Pain NR. A microbial signature with a higher level of Actinobacteria and lower Alistipes has also been identified in non-responders to the faecal microbiota transplantation (FMT) at baseline [Firmicutes and Actinobacteriota) or strains associated with the production of SCFA [The analysis of the microbiota prior to supplementation revealed microbial signatures that could be predictive of a response or non-response to the tested multistrain probiotic and be specific to the type of response, i.e., abdominal pain versus diarrhoea. We identified a major signature of the non-response in terms of pain in both the adherent and the luminal microbiota of IBS-D patients. Higher levels of bacteria belonging to the baseline ,47. The  of SCFA  suggestsBacteroidota phylum (Prevotellaceae and Bacteroides). Specifically, the Catenibacterium genus and ASVs belonging to Blautia spp. were enriched in the luminal microbiota, while the Obesumbacterium genus was found in the adherent microbiota of Diarrhoea R. These observations are consistent with the higher prevalence of Bacteroides and Blautia reported in IBS patients and are associated, respectively, with low-grade inflammation and bowel symptoms (diarrhoea) [B. fragilis and their ability to produce toxins or bacteriocins [Obesumbacterium has been described as a common pathogen, although the pathogenicity of these bacteria remains unclear [Catenibacterium genus and B. fragilis was identified in IBS-D responders with regard to both pain and diarrhoea. B. fragilis abundance was also found to be increased in the baseline microbiota of responders to FMT in IBS patients [Conversely, the microbial signature identified in the Diarrhoea subgroup indicated several bacteria that could predict a patient’s response to supplementation. At V1, both the luminal and the adherent microbiota of Diarrhoea R were dominated by the ASVs belonging to the arrhoea) ,48. The eriocins ,48. Obes unclear . Interespatients  and may Our study presents several limitations. First, it was an open-label, single-centre study, which implies a limited number of included patients, a lack of randomization, and the absence of a placebo or other control group. The interpretation of its results should therefore consider these limitations. Further evaluation of the multistrain probiotic in larger patient populations, including a control group, as well as a longer follow-up period, will therefore be important.®, may improve IBS symptoms. In addition, analyses of both the adherent and the luminal microbiota of patients stratified by their clinical response not only revealed the distinct effects of the multistrain probiotic on the microbiota according to this response but also showed that the gut microbiota composition at baseline could predict the response or non-response to supplementation. This highlights the need to develop individualised probiotic-based approaches in patients suffering from IBS.This study provides several insights into how the tested multistrain probiotic, Lactibiane Tolérance


IntroductionAdenotonsillectomy is a common surgical procedure in otolaryngology. Over the years, several techniques have been developed and modified in order to reduce mortality and morbidity. Postoperative pain control remains controversial. The aim of this study was to evaluate the efficacy of paracetamol alone in the control of postoperative pain.MethodsA prospective study was conducted between May 2018 and February 2019, including 76 pediatric patients (age < 18 years), who underwent adenotonsillectomy. The surgeries were performed by the lead author with the same surgical technique. Patients were evaluated one week and one month after surgery through the application of the visual analog pain scale and the number of days of pain was assessed by the need for medication.ResultsSeventy-six total adenotonsillectomy were performed, with a total of 152 tonsils removed. The majority of patients were male , with an average age of 6.9 years . The most frequent surgical indication was sleep breathing disorders, present in 86.9% of the cases. The average duration of postoperative pain was 3 days, with no significant difference between groups (p>0.05). The average intensity of postoperative pain was 3.36 and was higher in patients with infectious criteria as surgical indications (p<0.05). Postoperative bleeding occurred in 3.9% (n=3) of the children, self-limited, without the need for readmission or surgical revision.ConclusionPain after adenotonsillectomy was more intense in patients undergoing surgery for infectious criteria. Paracetamol used in monotherapy has shown safety and efficacy in controlling postoperative pain. Adenotonsillectomy is one of the most performed surgical procedures in children worldwide. Most cases are performed in an outpatient setting and, therefore, the management of postoperative pain usually occurs at home with medication given orally . AdenotoThe American Academy of Otolaryngology - Head and Neck Surgery (AAO-HNS) defines tonsillectomy as a surgical procedure by which the palatine tonsil, including its capsule, is completely removed by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. It can be performed alone or associated with other procedures, such as adenoidectomy .There are several factors that influence the success of post-tonsillectomy pain control, from individual factors related to parents/caregivers, surgical technique and medication used . InadequParacetamol is often used to control pain after tonsillectomy in children. However, there is concern about its effectiveness in optimizing pain control. In fact, studies show that pain may not be completely controlled, even with therapeutic combinations . When coThe main advantage of paracetamol is its safety; however, there is potential for liver damage, especially if associated with high doses ,6. IntraHowever, many surgeons remain concerned about post-tonsillectomy bleeding, despite systematic reviews showing no statistically significant difference in bleeding rates between NSAIDs, opioids and placebo, including bleeding requiring hospitalization or surgery ,8,9. AltAnalgesic protocols based on the use of acetaminophen and NSAIDs as an alternative to opioids have been adopted in younger children and children with oSDB in several institutions, with studies demonstrating the achievement of satisfactory pain control with both acetaminophen and ibuprofen in monotherapy ,14.There are several surgical techniques and instruments for performing tonsillectomy, including cold and hot dissection, for total (extracapsular) or partial (intracapsular) removal of the tonsils and, at the instrument level, cold dissection tools, monopolar and bipolar electric scalpel, coblation devices, harmonic scalpel and argon plasma coagulation, among others .Cold dissection is associated with a less painful postoperative period compared to hot dissection techniques. However, its use has been decreasing due to longer operative time and hemorrhagic risk ,15. In pRegarding adjuvant treatments, pre-incisional peritonsillar infiltration with local anesthetic and/or corticosteroid has been shown to provide complementary analgesia . HoweverA prospective study was conducted in Hospital da Senhora da Oliveira - Guimarães, for a period of 10 months, between May 2018 and February 2019, including 76 pediatric patients (age < 18 years), who underwent extracapsular tonsillectomy associated with adenoidectomy with or without myringotomy with placement of a transtympanic ventilation tube, to assess the safety and efficacy profile of paracetamol in monotherapy for the control of postoperative throat pain.All patients were submitted to adenotonsillectomy with cold dissection, extracapsular, and under general anesthesia with orotracheal intubation. All the surgeries were performed by the lead author. Every patient in this study met the criteria for surgical intervention based on the 2019 AAO-HNS guidelines, such as obstructive sleep-disordered breathing or acute recurrent infections .2/air and sevoflurane (1.5-3 vol%), intravenous propofol (2-3 mg/kg), fentanyl (2-3 micrograms/kg), dexamethasone (0 .2 mg/kg), paracetamol 15 to 20 mg/kg, tramadol 1-2 mg/kg, ondansetron 0.1 mg/kg and sugammadex 2 mg/kg. Patients started a cold liquid diet six hours after surgery. In the outpatient regimen, all patients remained under observation for a period of up to 24 hours, with clinical discharge without any recorded complications.During surgery, anesthesia was administered by inhalation of OAfter surgery, each patient/parent/caregiver was given the same recommendations, to administer analgesia at a fixed time, with paracetamol at a dose of 10 to 15 mg/kg/dose every 6 hours (maximum 100 mg/kg/day or 4 g/day if >50 kg). All the orientations were given by the doctor and reinforced by a nurse, in addition to the written instructions given to each family. The recommended diet was a soft and cold diet until the evaluation at the first appointment.Patients were evaluated seven and 30 days after surgery. At the first appointment after surgery, patients/parents/caregivers were asked about throat pain intensity and duration. Children were assessed for their pain intensity, with the help of their parents/caregivers, using the visual analog scale (VAS). Information and explanations on how VAS works were provided to the child at the time of the assessment. The VAS was presented as a 10 cm horizontal line with two ends (0: no pain and 10: worst possible pain) to both parents/caregivers and the child. The children, with the help of their parents/caregivers, were asked by the author to place a mark at the point where they thought it represented the intensity of their pain. Pain duration was evaluated by parents/caregivers as the number of days in which analgesic medication was required. Complications, such as nausea, vomiting, bleeding or fever, were recorded during the follow-up period.This study was conducted in a manner that warrants the confidentiality of all included patients. Data collected had been deidentified prior to being stored. Permission was granted by the institution’s ethical committee before starting the study and the data collection. Written informed consent was obtained from the parents of the patients for participation in this study.Statistical analysis was performed using the Statistical Package for the Social Sciences® (SPSS V.25.0) program, with the application of a t-test for independent variables. The level of statistical significance adopted was p < 0.05.Seventy-six patients were included in the study, 39 (51.3%) male and 37 (48.7%) female, with an average age of 6.9 years . Patients without pathological history and usual medication were included in the study. All of the patients did not have any history of respiratory infections or use of antibiotics for at least two weeks before surgery.The most frequent surgical indication was OSAS, present in 86.9% (n=66) of the cases. The history of recurrent tonsillitis as an isolated surgical criterion was present in 13.1% of the cases (n=10) and in 40.8% of the cases (n=31) when associated with OSAS. The average duration of postoperative pain was three days and 81.6% of patients had pain for two to four days . The average pain intensity was 3.4, with 77.6% (n=59) of patients presenting pain intensity between two and four Figure .Pain intensity was higher in patients with infectious criteria (p<0.05) and there was no statistically significant difference between the gender group (p>0.05). Regarding the presence of complications, bleeding was recorded in 3.9% of the children (n=3), which was self-limited, without the need for new hospitalization or surgical revision.Adenotonsillectomy is the second most performed surgical procedure in the pediatric age. Postoperative recovery is strongly associated with pain intensity and underlying functional limitations . ConsideThe VAS presents itself as a reliable measure for pain assessment (self-assessment) and has been widely used. VAS values were sensitive to changes in pain levels during the postoperative period and after analgesia and showed a significant correlation with parents' ratings of children's pain ,21.In this study, VAS was used to assess the efficacy of paracetamol in the treatment of pain after extracapsular tonsillectomy by cold dissection. Other medications, such as NSAIDs or opioids, were not used in this sample. Pain intensity can also be indirectly assessed by other measures, such as returning to a normal diet, refusing fluids, nausea, or the use of antibiotics .Paracetamol has a central analgesic effect that results from the activation of descending serotoninergic pathways, by inhibition of prostaglandin synthesis or indirect activation of cannabinoid receptors. Paracetamol has a weak anti-inflammatory effect, little or no gastrointestinal side effects, and causes only a small dose-dependent change in platelet function .Ibuprofen has become the main NSAID used for postoperative analgesia, achieving adequate pain control. However, their use remains controversial, since NSAIDs can also cause platelet dysfunction, which can lead to an increased risk of postoperative bleeding .The administration scheme of analgesics remains a controversial topic in the literature. Fixed regimen medication is widely used, as adopted in this study. A fixed administration plan is especially necessary to obtain the optimal analgesic effect of paracetamol in monotherapy .In our sample, the average duration of postoperative pain was 3 days, with 81.6% of the cases having pain for two to four days, with an average intensity of 3.4, which demonstrates that paracetamol can be administered safely and relatively effectively as monotherapy.In our study, no statistically significant association was observed between gender, intensity and duration of postoperative pain, unlike other studies in the literature ,23. HowePostoperative tonsillectomy pain has its own natural course. There are studies that have verified that in children, regardless of the analgesic and dosage regimen used, pain is classified as moderate to severe, with VAS values greater than 5 in the first seven days .After seven days, the rating of pain intensity decreases significantly ,24. RegaThere is still no consensus on the most effective postoperative pain control plan after tonsillectomy. In addition, pain assessment methods in studies are very heterogeneous, especially for the pediatric population. However, our study demonstrated that adequate pain control can be achieved with paracetamol alone, without undesired complications.


U test was applied to compare clinical data according to data distribution. Seventeen hypothesis-driven pain-related brain regions were selected as regions of interest (ROIs). FC values among pain-related brain regions across the three groups were computed by using ROI–ROI functional connectivity analysis. ANCOVA with a post hoc test was applied to compare FC differences among the three groups. p < 0.05 indicated statistical significance. Correlation analysis was conducted to explore the potential relationship between the FC values and clinical characteristics. Except for years of education, no significant differences were revealed among the three groups in age, gender, or neuropsychological assessment. In the CP+ group, FC alterations were mainly concentrated in the dorsal lateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), secondary somatosensory cortex (SII), and amygdala compared to the CP− group. Among these brain regions with statistical differences, FC between the right DLPFC and the right ACC showed a positive correlation with the duration of cancer pain in the CP+ group. In addition, in the CP− group, altered FC was found in the bilateral SII, ACC, and thalamus compared to the HC group. Altered FC in pain-related brain regions may be a brain pattern of bone metastatic pain and may be associated with the long duration of cancer pain.Bone metastatic pain is thought to be a severe type of cancer pain that has refractory characteristics and a long duration. This study is aimed at exploring the brain functional connectivity (FC) pattern in lung cancer patients with bone metastatic pain. In this study, 27 lung cancer patients with bone metastatic pain (CP+), 27 matched lung cancer patients without pain-related complaints (CP−), and 27 matched healthy controls (HC) were recruited. All participants underwent fMRI data acquisition and clinical assessments. One-way ANOVA or a Mann–Whitney  Pain is a common symptom in cancer patients. Approximately 64% of cancer patients with advanced cancer or metastases report cancer pain . Bone meThe pathophysiological mechanisms of bone metastatic pain have begun to be elucidated. Nociceptors are activated by bone metastasis itself or secreted pain-inducing mediators . In addiNeuroimaging studies of patients with pain have suggested that pain is closely related to alterations in brain function and structure , 7. BraiThe prevalence of chronic pain among adult cancer survivors is nearly double that of adults without a cancer diagnosis . PreviouDue to the long duration and the special pathophysiological mechanisms of bone metastatic pain, it is necessary to explore its neuroimaging mechanism. As far as we know, functional connectivity analysis has been reported in a mouse model of metastatic bone cancer, however, not in the human population. This study provides a first attempt to explore the functional connectivity within pain-related brain regions in lung cancer patients with bone metastasis suffering from cancer pain by using region of interest- (ROI-) ROI functional connectivity analyses. We hypothesized that abnormalities in functional connectivity within pain-related brain regions may occur in lung cancer patients with bone metastatic pain and that altered functional connectivity may correlate with pain-related clinical characteristics.Participants were lung cancer patients with bone metastases suffering from cancer pain (CP+), lung cancer patients without pain-related complaints (CP−), and healthy controls (HC). The above three groups were matched by age and gender. All participants were recruited at Chongqing University Cancer Hospital from August 2020 to January 2022. All patients (both CP+ and CP−) were pathologically confirmed to have lung cancer. On the basis of pathologically diagnosed lung cancer, patients with bone metastasis were diagnosed when meeting one of two conditions: (a) the results of bone lesion biopsy showed lung cancer metastasis and (b) typical imaging manifestations of bone metastasis. Pain perception was assessed by the Numeric Rating Scale (NRS) for all participants. The CP+ group should meet NRS ≥ 1, while the CP− and HC group need to meet NRS = 0. All CP+ patients received regular analgesic therapy. Exclusion criteria were as follows: (a) intracranial metastases, encephalatrophy, trauma, or a history of brain surgery; (b) a history of psychiatric disorders; (c) extensive head motion (a maximum rotation greater than 3° or a maximum displacement greater than 3 mm); and (d) claustrophobia. This study was approved by the Research Ethical Committee of Chongqing University Cancer Hospital (IRB: CZLS2021042). Signed informed consent was obtained from all participants.Of the 40 lung cancer patients with bone metastatic pain who were initially recruited for this study, seven patients had brain metastasis, four patients were diagnosed with encephalatrophy, and two patients had head motion displacement greater than 3 mm. Of the 35 recruited lung cancer patients without cancer pain, four patients had brain metastases, one patient had a history of cerebral hemorrhage, and three patients had head motion displacement greater than 3 mm. Of the recruited healthy volunteers, 27 matched volunteers were selected for this study. Therefore, 27 lung cancer patients with bone metastatic pain, 27 lung cancer patients without cancer pain, and 27 healthy volunteers were included in this study.Clinical pain, depression, and anxiety assessments and MRI scans for each participant were acquired on the same day. NRS was adopted to evaluate pain intensity. The NRS includes 11 numbers, and 0 represents “no pain” to 10 represents “the worst pain imaginable.” The participants scored the pain intensity under the guidance of an experienced physician. The duration of cancer pain in the CP+ group was calculated according to the medical record. Anxiety and depression statuses were assessed by the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS), respectively. Demographic information of all participants was obtained by the self-report questionnaire.2, matrix = 256 × 256, slice thickness = 1 mm with no slice gap, and slices = 192. The total scanning time was 4 minutes and 53 seconds. Second, rapid gradient echo-planar pulse imaging (EPI) was used to acquire the resting-state blood oxygenation level-dependent (BOLD) signal: TR = 2000 ms, TE = 30 ms, flip angle = 70°, FOV = 240 × 240 mm2, slices = 36 (interleaved), matrix = 80 × 80, and voxel size = 3 × 3 × 3 mm3. From each participant, 240 volumes were acquired over 8 minutes and 8 seconds. Additionally, routine axial T2-weighted images were obtained to exclude subjects with intracranial metastases or other lesions, as demonstrated by the exclusion criteria above.Acquisition MRI scans were examined on a 3.0 T scanner  equipped with a 64-channel head-neck coil. Participants were instructed to remain motionless, close their eyes, stay awake, and avoid thinking about any topics. Earplugs were used to alleviate the influence of noise, and cushions were used to restrict head motion. Three sequences were collected as follows. First, the structural information was acquired to guide subsequent functional imaging with a T1-weighted three-dimensional magnetization prepared rapid gradient echo (MPRAGE) sequence: repetition time (TR) = 2100 milliseconds (ms), echo time (TE) = 2.26 ms, flip angle = 8°, field of view (FOV) = 256 × 256 mmBased on functional connectivity analysis results from previous pain-related studies, 17 hypothesis-driven pain-related brain regions were selected as ROIs in the current fMRI study. The selected brain regions included the bilateral thalamus, bilateral insula, bilateral amygdala, bilateral ACC, bilateral SI, bilateral SII, bilateral dorsal lateral prefrontal cortex (DLPFC), bilateral medial prefrontal cortex (mPFC), and PAG. Detailed information on these pain-related brain regions is shown in http://rfmri.org/DPARSF) based on MATLAB R2020a. All process followed a standard procedure as described in previous studies [3. To reduce spatial noise, the images were spatially smoothed with a Gaussian kernel of 6 mm full width at half maximum (FWHM). A bandpass filter was set as 0.01 Hz < f < 0.10 Hz to remove the influence of low-frequency physiological drift and high-frequency noise. After these steps, a 4-dimensional residual time series dataset was created in the standard MNI space. Intragroup functional connectivity ROI-ROI analysis was conducted among the 17 pain-related brain regions using RESTplus V1.22 (http://www.restfmri.net). For each ROI, the mean time series was calculated and then correlated with the other ROIs for each subject. By using Fisher's r-to-z transformation, Pearson correlation coefficients were converted to normally distributed scores.The preprocessing of the BOLD data was carried out using the Data Processing Assistant for Resting-State fMRI .For intergroup comparisons of functional connectivity, the normally distributed ups. Age , 26 and ups. Age , 27 wereups. Age . Becausez scores of functional connectivity and clinical characteristics . Age, gender, education in years, and head motion parameters were set as covariates. p < 0.05 was considered as statistically significant.A partial correlation was conducted on the CP+ group to evaluate the association between the transformed The demographic and clinical characteristics of the participants are detailed in p > 0.05/17).Functional connectivity matrices of the three groups are shown in r = 0.451, p = 0.035). No significant correlations were found between the FC values and pain intensity.As shown in We report alterations in functional connectivity in pain-related brain regions in lung cancer patients with bone metastasis suffering from cancer pain compared to the control groups and correlations between altered functional connectivity and the duration of cancer pain. The results showed that the altered functional connectivity was mainly concentrated in the DLPFC, ACC, SII, and amygdala in the CP+ group compared to the CP− group. Among these brain regions that showed statistical differences, functional connectivity between the right DLPFC and the right ACC showed a positive correlation with the duration of cancer pain in the CP+ group. In addition, altered functional connectivity was found in the bilateral SII, ACC, and thalamus between the CP− group and the HC group.We found weaker functional connectivity between the right DLPFC and the right ACC in the CP+ group compared to the CP− group, and this functional connectivity showed a positive correlation with the duration of cancer pain. The DLPFC and ACC are two major cognitive-emotional modulation areas that are known to receive nociceptive input from the periphery and control pain perception by top-down modulation . A previIn addition, we found stronger functional connectivity between the left ACC and the left amygdala in the CP+ group compared to the CP− group. The amygdala is a crucial subcortical region thought to contribute to emotional components of pain . HyperexMoreover, we found stronger functional connectivity between the left SII and the right SII in the CP+ group compared to the CP− group. To our knowledge, SII generally presented stronger functional connectivity with the other pain-related brain regions in patients under pain conditions , 35. SurIn addition, in the CP− group, weaker functional connectivity was found in bilateral SII, ACC, and thalamus compared to the HC group, due to the complexity of lung cancer, brain function susceptible to cancer treatment, psychological factors, and the lung cancer itself . Researcp values may not yield robust findings [The limitations of this study should be mentioned. First, our results could not bear the multiple comparisons correction in this exploratory study. However, a previous study found a high false-positive rate when using a stringent threshold for multiple comparison correction and revealed that small findings . Becausefindings , 18. LasThese data were the first to show altered brain functional connectivity within pain-related brain regions in lung cancer patients with bone metastatic pain and to reveal its correlation with pain duration. This study may provide a better understanding of bone metastatic pain.


Patients undergoing allogeneic hematopoietic cell transplantation  spend many weeks of treatment in an isolated environment with little room for exercise. Feasibility of a daily-performed, unassisted fascia-training program and its effects on back and foot pain, back flexibility, and quality of life were investigated.n = 9; 60.7 ± 9.2 years) or control group  and assessed from 1 week before to 3 weeks after transplantation (t0–t3). CG received standard care physical therapy, IG performed additionally fascia training for the back and feet twice daily. Back and foot pain, back flexibility, muscle tone, and quality of life were assessed for both IG and CG at baseline and three timepoints after alloHCT.Eighteen patients receiving alloHCT were randomized to an intervention (IG: p = .074), whereas CG showed a slight increase in back pain at t3 (p = .257). IG also improved back flexibility  while CG declined . No differences between groups were found for muscle tone and no significant improvements in quality of life were reported at t3.Fascia-training program was well accepted. No increase in hematoma formation was observed. IG reported a trend towards reduction in back pain from pre- to post-intervention (Unassisted fascia training is feasible and safe for patients undergoing alloHCT. This pilot study suggests that fascia training has the potential to improve back flexibility and reduce back pain, and might be a valuable component for physical therapy in patients receiving alloHCT. Allogeneic hematopoietic cell transplantation  is a potentially curative treatment in patients with hematologic malignancies, such as leukemia and lymphoma . Prior tCurrent literature indicates that exercise is generally safe and feasible in patients with cancer and strong evidence for positive effects of exercise in this population was found –9. TheseThe purpose of the present study was to examine feasibility and safety of a daily-performed, unassisted fascia training program in addition to daily physical therapy compared to a standard care procedure in patients receiving alloHCT. In addition, it was examined whether regular fascia training has the potential to reduce back and foot pain, and to improve back flexibility and muscle tone as well as quality of life in alloHCT-patients.This prospective, monocentric pilot study is based on a randomized control group design with an ad hoc sample. The investigation was conducted from 1 week before to 3 weeks after HCT. The study was approved by the ethical review committee of the Technical University of Dresden  and conducted in accordance with the Declaration of Helsinki.A total number of 194 patients underwent alloHCT at the University Hospital of Dresden from May 2019 to January 2021 (21 months). Inclusion criteria were (a) presence of hematological malignancy and receiving an alloHCT, (b) age ≥ 18 years, and (c) ability to provide informed consent and deliver study questionnaires. Exclusion criteria were (a) insufficient hematological capacity (platelets < 10 mmol/l), (b) acute pain, swelling or reddening of muscle tissue, and (c) motoric dysfunction or other comorbidities such as reduced stance and gait performance that impede participation in the exercise program. All patients had to sign informed consent.n = 9) or a control group . Both groups received standard care for alloHCT patients, which included daily physical therapy and comprises 15 to 45 min of supervised endurance and strength training using barbells, bicycle, and rowing machine ergometers, as well as mobilization, respiratory physiotherapy, and pain therapy depending on individual medical conditions. In addition, patients within the IG completed an unassisted daily fascia-training program  and three further points of measure (t1–t3). Back and foot pain were assessed based on the German version of Neuropathic Pain Symptom Inventory , using aIn addition to the standard care physical therapy, participants of the IG performed an unassisted fascia-training program twice daily in 5- to 7-min sessions, followed by 2 min of documentation. Beforehand, the fascia-training exercises were explained and demonstrated by a physical therapist. Exercises were conducted with very low tare weight to minimize the risk for patients with existing bleeding tendency  and Andhera fascia roll and BlackCat Mini fascia roll . The first exercise was performed sitting on the front edge of a chair. A small fascia roll was placed below the patient’s ball of the foot. The foot was then moved forward and backward for 30 to 60 s Fig. . This exContraindications and abort criteria for the fascia-training program were fever, strong pain that impedes physical exercise, nausea and dizziness, insufficient hematological capacity (platelets < 10 mmol/l), or acute bleeding signs.U tests. Nonparametric tests were selected because of the small sample size and missing normal distribution. As this pilot study had exploratory character, a 5% significance threshold for all p-values was defined and data were not adjusted for multiple tests.To evaluate effects of the fascia-training program from pre- (t0) to post- (t3) intervention, Wilcoxon tests were calculated for back and foot pain, back flexibility, muscle tone and the three scales of EORTC-QLQ-C30 global health, physical functioning, and fatigue. Statistical differences between IG and CG concerning changes in back and foot pain were calculated using Mann–Whitney All statistical tests were processed using IBM SPSS Statistics, Version 28.0.1.0 (142) . The low–high bar graph was created using GraphPad Prism, Version 5.01 for Windows . Table data are presented as mean ± standard deviation. The low–high bar graphs depict lines as mean with bars ranging from minimum to maximum.n = 9, mean age: 60.7 ± 9.2 years, 7 male, 2 female) and CG . The study participants underwent alloHCT due to malignant hematological neoplasms  were able to complete the prescribed daily fascia-training program with a mean of 24 (range 14–31) training days . Patients needed to interrupt the fascia-training program occasionally due to pain or discomfort, but all of them continued the intervention. No increases in hematoma formation and other serious events in conjunction with the training program were observed and patients reported acceptance and toleration of the fascia-training intervention.Patients of the IG (p = 0.074). In contrast, CG showed a slight increase in levels of back pain from t0 to t3   concerning the changes of back pain could be verified. Scores for foot pain did not change from t0 to t3 in both IG (p = 0.317) and CG (p = 0.713).A tendency towards a reduction in levels of back pain from t0 to t3 was observed in IG , whereas CG showed a slight decline in back flexibility  (Table p = 0.182).Back flexibility adaptation, measured by finger-floor distance test, was calculated as difference from t0 to t3. Two patients of CG were excluded from evaluation because they were not able to perform the exercises due to impairment by therapy. IG slightly improved back flexibility after daily fascia-training program by reduction of the finger-floor distance  and CG (p = 0.317).In both groups, a muscular hypertension was observed at t0. After fascia-training program (t3), two patients of IG had normal muscle tone and five patients had light muscular hypertension. In CG, one patient had normal muscle tone, five patients had a muscular hypertension, and three patients could not be evaluated because they were not able to sit due to strong pain. Changes in muscle tone from pre (t0) to post (t3) intervention were not significant in both IG (p = 0.041), but the mean score at t3 was still higher than that in CG.Scales for physical functioning, fatigue, and global health status were analyzed from the EORTC-QLQ-C30 . Global The primary aim of this pilot study was to evaluate the feasibility and safety of a daily fascia-training program for patients undergoing alloHCT. Recent studies show that physical therapy and training is safe and effective for patients after alloHCT , 10, 15.The autonomously executed daily fascia-training program was well accepted and tolerated by the patients. Because of alloHCT and concomitant medical therapies, patients are at risk for bleeding and hematoma formation . In the Muscle atrophy caused by medication and prolonged inactivity frequently leads to back pain in patients after alloHCT. Previously published studies could verify positive effects of fascia training on back pain in healthy adults , 18. In Adhesion of fascias and concomitant reduction of flexibility result from immobility as well as inflammations and trauma . InactivIn comparison to a study in healthy adults , patientAcknowledging that muscular hypertension is often associated with subjectively experienced muscle pain , the bacQuality of life plays an important role in patients undergoing HCT. Investigations of 2800 stem cell–transplanted patients  provide reference data for the subscales of EORTC-QLQ-C30 at different points of in- and outpatient treatment , 28. In The present pilot study was conducted as a randomized controlled trial with two arms. Only 18 patients (9 per group) were recruited within 21 months. Due to feasibility reasons, only one patient at a time was able to be included in the study, thus not every patient had the chance to participate. The sample size was small and patients’ age, gender, and the underlying diseases were heterogeneous. Furthermore, other confounding variables cannot be ruled out. No clinically meaningful differences have been defined for the variables foot and back pain, back flexibility, and muscle tone, as well as for quality of life. This should be conducted in a consecutive study. The fascia training in this study was designed as a daily unsupervised program. Other studies show better results in supervised exercise interventions compared to home-based or unsupervised interventions [Fascia-training exercises in addition to standard care physical therapy are feasible and safe for patients undergoing alloHCT. The present pilot study suggests that fascia-training exercises have the potential to improve back flexibility and reduce back pain and might be a valuable component for physical therapy in patients undergoing alloHCT. Low costs, low expenditure of time, and the opportunity of autonomous training also support fascia training to be integrated in alloHCT physical therapy standard care procedure.The effect sizes and confidence intervals determined in this pilot study can be instrumental to plan larger investigations which aim at demonstrating improved flexibility, physical function, quality of life, and pain after fascia training in patients undergoing alloHCT.


The aim of this trial was to collate, analyze, and compare the effectiveness of phonophoresis and ultrasound adjunct to Otago exercise program for pain, knee range of motion, and functional disability in patients with grades I and II of knee osteoarthritis. This is a single-blind randomized control study. A total of 52 patients with pre-diagnosed osteoarthritis on radiological investigation were included in the study. They were then randomly assigned into two groups: group A (n=26) received the experimental treatment, which included phonophoresis, and group B (n=26) subjects were treated with conventional physiotherapy. The interventions were given for six days/week for two weeks. Pain via the visual analog scale, knee range of motion via a goniometer, level of functional disability through the Western Ontario and McMaster Universities Osteoarthritis Index, and balance through the star excursion balance test were evaluated. Measurements of the outcome were taken prior to initiation of intervention and on the day of the last session, succeeding the treatment. Statistically, both the groups showed significant improvement in pain, range, dynamic balance, and functioning. Between the two groups, no clinically significant difference was present for balance, but the intergroup comparison for pain and functions was statistically and therefore clinically significant. Phonophoresis treatment was observed to be effective in treating pain in osteoarthritis. Combined Otago exercises and phonophoresis with modified gel can be used to achieve superior clinical results. Globally, a painful knee in the elderly population is a major disabling condition. Pain in such older individuals is predominantly associated with osteoarthritis (OA) of the knee. A total of 303 million people were affected globally in 2017, with a prevalence of 16.0% and 22.9% in a population aged above 15 and 40 years, respectively [Physical therapy treatment involves the use of electrotherapeutic modalities to work on both reducing pain and gaining strength. Therapeutic ultrasound, a deep heating modality, produces a heating effect via mechanical sound waves, up to a minimum depth of 5 centimeters below the surface of the skin. The coupling medium is a part of the ultrasound unit essential for the transfer of electrical current as it reduced the diversion of the waves away from the tissues by minimizing air between the transducer head and skin. It is in the form of water, oil, and gels having their impedance ,9. NumerStudy designThis study was performed during the years 2021 and 2022, after approval from Institutional Ethics Committee (IEC) with IEC No. 242 and Clinical Trial Registration of India (CTRI) No. Ref No. 2021/04/043216. A research protocol of the study was published in the Journal of Pharmaceutical Research International prior to beginning of the study. Patients were thoroughly evaluated, and those (n = 52) who fulfilled the inclusion criteria were then included in the study for a duration of two weeks. After randomization with a lottery method, they were allocated into two groups: group A (n=26) and group B (n=26).ParticipantsAll participants were educated about the details of the intervention, research, and data confidentiality prior to the start of the study. Patients in the study were referred from either orthopedicians, tertiary health care providers, or self-referred subjects. Subjects were pre-diagnosed cases aged between 40 and 60 years with grade I or II OA on Kellgren and Lawrence scale with unilateral OA of the knees and less than 30 minutes of morning stiffness in the knees. Patients with superficial and deep sensory impairments, those who underwent total hip joint replacement, those with clinically diagnosed neurological disorders such as stroke and parkinsonism, those with current participation in another OA intervention study, those with physical disability , and those who are unable to comprehend were excluded from the study.Treatment procedure and intervention design2 [The medicinal coupling medium was made with the assistance of the Head of Department and Faculty of Ayurveda College. A small sample of 40 mL was made with trial and error method using wet ginger carbapol for achieving gel-like consistency, and a preservative. After evaluating the consistency and safety of the gel, a larger batch of 350 mL was made with the same ratio. Ultrasound is applied to the affected knee for a total of 10 sessions for two weeks, that is, five sessions/week, using a device with a 1-MHz probe for a period of 8 minutes at an intensity of 0.8 W/cm2 . UltrasoStatistical analysis was conducted using descriptive and inferential statistics using the chi-square test and Student’s paired and unpaired t-test, and software used in the analysis were SPSS Version 27  and GraphPad Prism 7.0 version. A p-value of <0.05 was considered as level of significance. There was no significant difference within the two groups with respect to age, gender, and grade of OA. The comparison of means within the group and between two groups is given in the following.Assessment of disease-specific measure of symptomsVisual Analog ScaleTable Western Ontario and McMaster Universities Osteoarthritis IndexTable Range of motionStatistics show that post-treatment a minimum change of 5-8 degrees was seen in after two weeks of intervention in both the groups.Measure of balanceStar excursion balance test: affected extremityFigure In this study, individuals with grades I or II of OA who had appreciable levels of pain during the pre-treatment phase in both groups were present. The causative factor for dependent lifestyle, reduced physical activity, and an increased apprehension in both the groups was pain. These findings are parallel with previous studies that indicate reduced activity levels in affected individuals -22. SimiThe study also includes the Otago exercise program as a part of the intervention given to both the experimental and control group. It also states that overall physical activity is at suboptimal levels regardless of pain severity in OA patients and therefore emphasis should be made to include exercise programs in rehabilitation strategies and daily activities . We haveWe conclude that application of phonophoresis using wet ginger nano gel along with strengthening and balance retraining exercises performed daily are more effective in relieving pain and improving functional status in patients with grades I and II of OA compared to conventional therapeutic ultrasound. It is a cost-effective, safe treatment that can be used routinely for treatment of knee pain and other conditions with pain arising from degenerative changes or pain associated with inflammatory conditions, having benefits of natural products. This method of phonophoresis will also increase the usage of natural products and their properties in treating pain.


The pathophysiology of pain in patients suffering from rotator cuff (RC) tendinopathy or tears has been examined in various ways. Several molecules from tissue samples taken from the subacromial bursa, supraspinatus tendon, glenohumeral joint fluid, and synovium as well as from peripheral blood have been investigated. This article explores these studies, the assessed biomarkers, and groups their results according to the status of tendon integrity (tendinopathy or tear). Through a structured PubMed database search, 9 out of 658 articles were reviewed. Interleukins, mostly IL-1b and its antagonist, IL-1ra, matrix Metalloproteinases (MMPs), the vascular endothelial growth factor (VEGF) and TNF-a are biomarkers directly searched for correlation to pain level. Most studies agree that IL-1b is directly positively correlated to the degree of pain in patients with RC tendinopathy, especially when the examined sample is taken from the subacromial bursa. VEGF, and TNF-a have been related to shoulder pain preoperatively and TNF-a has also been linked with sleep disturbance. Further studies pointing to more biomarkers taken from the subacromial bursa or tendon directly relating to pain degree are warranted. The rotator cuff (RC) of the shoulder consists of the subscapularis tendon, the supraspinatus, the infraspinatus, and the teres minor muscles. Rotator cuff pathology affects a large percentage of the population and in particular the elderly . PatientAlthough the nociception histological and molecular pathway has been described , it is nMany other biomarkers have been also detected in bursa and tendon tissue of patients and cadavers with degenerative or torn rotator cuff and have been reviewed ,7. MatriDue to the plethora of biomolecules and the heterogeneity of investigations performed so far, we conducted a scoping review to search human studies that examined biomolecules found in synovial fluid, bursal, or tendon tissues, in patients suffering from rotator cuff-related pain.We decided to conduct a scoping review versus a systematic review, following Munn et al.’s recommendations . So far,All studies presented were found through a systematic approach via the PubMed website. Only human studies written in English, of any year, were searched. Firstly, we searched for previous relative studies and reviews and identified a list of biomolecules that could be related to our research question. Search in title and abstract began with the keywords “shoulder” AND “biomolecules” retrieving 12 results (1 review) and “shoulder AND “biomarkers” retrieving 557 results (73 reviews). A list of abbreviations of the biomolecules is presented in Then, after finding the related molecules, we conducted a final search in March 2022 by using keywords in the following way: ((Shoulder[Title/Abstract]) AND (pain[Title/Abstract])) AND ((IL[Title/Abstract]) OR (CD45[Title/Abstract]) OR (CD206[Title/Abstract]) OR (KA1[Title/Abstract]) OR (mGluR2[Title/Abstract]) OR (MMP[Title/Abstract]) OR (NMDAR1[Title/Abstract]) OR (PGP9.5[Title/Abstract]) OR (TNF[Title/Abstract]) OR (VEGF[Title/Abstract])). We retrieved 89 results from the last search having a total of 658 results. After removing duplicates and reviews, we screened 550 studies. We excluded 526 studies for not being related to our review or not performed in humans, and assessed 24 studies. Studies were thoroughly analyzed and checked in the discussion and reference section.We finally excluded 15 studies for not having a specific biomolecule directly associated with cuff-related pain, finally leaving 9 studies for analysis in our review. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram is shown in Few studies directly investigated the relationship of biomolecules with pain in patients suffering from RC tendinopathy. The scientific team of Gotoh, Hamada, Yanagisawa, and their colleagues from 1998 to 2002 produced considerable work regarding the search for biomolecules that attributed to the feeling of pain in that subset of patients ,11,12,13Angiogenesis is an important feature in inflammatory diseases. In shoulder tendinopathy, the inflammatory response is mediated by several biomarkers. The vascular endothelial cell growth factor (VEGF) has a powerful angiogenic and mitogenic ability that targets specifically the vascular endothelial cells . YanagisGotoh et al. in 2001, took synovial tissue specimens from 39 patients undergoing shoulder surgery due to subacromial bursitis (10 patients), partial-thickness RC tear (9 patients) and full thickness RC tear (20 patients) . Pain waAn RC tear has been described as perforating when the full thickness of the tendon has been torn and the subacromial space directly communicates with the glenohumeral joint space . Some stSubstance P is a molecule involved in the transmission of pain and its release from small sensory neurons may mediate neurogenic inflammation . Gotoh eSeveral IL biomolecules and mostly IL-1b have been studied in relation to RC pain. Gotoh et al.  who had IL-1b has been also investigated in other clinical studies. Siu et al., in 2013 took subacromial fluid samples from 68 patients with RC tear who were grouped according to diabetic status. Fluid was tested for IL-1b levels with an enzyme-linked immunosorbent assay (ELISA). It was found that IL-1b levels were positively correlated with the degree of pain. Furthermore, diabetic patients had significantly higher IL-1b levels and associated pain when compared to the non-diabetic group.p = 0.069), but was not significant.Along with IL-1b, other interleukins have also been studied. Okamura et al. utilized ELISA to test for IL-1b, IL-6, and IL-8 in the glenohumeral joint fluid of 38 patients undergoing RC surgery. Cuff tears were sub-grouped according to the Cofield classification . Pain waShih et al. studied the glenohumeral joint fluid of 42 patients with a chronic RC tear, defining chronic as a tear that was at least 3 months old . RotatorSleep disturbance related to pain in RC tear cases has also been examined in relation to IL-type biomolecules. Cho et al. made a 3-arm trial of 63 patients, including 21 patients with RC tear and sleep disturbance (SD group), 21 patients with RC tear but with normal sleep (NS group), and 21 asymptomatic patients (control group) . PeripheThe above study also found that TNF-a levels were significantly higher in the SD group when compared to both other groups  and therThe levels of TNF-a along with other biomarkers in association to RC-related pain has also been studied by Dean et al. . SupraspAlthough the role of MMPs, which are a family of 24 zinc-dependent endopeptidases, in tissue remodeling after injury has been documented, their overactivity may cause progressive wear of the tendon matrix . Shih etThis study has identified several biomolecules that are associated with rotator cuff-related pain. Substance P, IL-1a, IL1b, IL-2, IL-6, IL-8, IL-10, TNF-a, and VEGF are involved in the pathophysiologic mechanism of subacromial inflammation. Human studies have narrowed analysis mostly on cytokines IL1-b and TNF-a, which have been positively correlated with nociception ,16,17,18No tissue so far has been recommended as the ideal candidate for retrieving these molecules from humans. The subacromial bursa is a tissue that has a direct topological relation to the rotator cuff and undergoes inflammatory changes in several stages of tendinopathy. Literature has supported the presence of pain-related molecules in that tissue ,11,12. BThis scoping review has several limitations. We have examined only human studies and have not taken into account animal-model studies. However, our goal was to narrow down the biomolecules found in humans and target which tissues would provide these molecules consistently, in order to encourage further human studies and future systematic reviews, focusing on specific biotargets. Also, we only searched one database and we may have missed human studies not published in the PubMed database. We do not know if the included studies are suitably statistically powered for their investigations, as none of them had an a-priori power analysis performed.The subacromial bursa has been demonstrated to produce two major biomarkers of RC-related pain, IL-1b, and VEGF. Biopsies of not fully torn supraspinatus tendons support the increased expression of inflammatory and angiogenic molecules from that tissue.The published results of synovial fluid analyses are mixed, especially when the fluid directly communicates with the subacromial space. Future studies should focus on identifying more biomarkers directly related to pain, taken from the subacromial bursa. Since TNF-a has been shown to be linked with sleep disturbance, its bursa levels and relation to pain should be further clarified. Melatonin levels may be also examined in relation to pain levels during sleep in patients suffering from RC tendinopathy or tear. Antagonists of these biomarkers may be valuable in reducing the pain in this shoulder patient population.


Recently, cryotherapy has become a common practice for postoperative pain management. The current accepted practice in Japan is the use of cryotherapy at 5 °C after arthroscopic shoulder surgery. However, this therapy has been reported to be highly intense because the sustained low temperature causes discomfort for patients. The optimum temperature and duration of cooling required for comfortable and effective cryotherapy after arthroscopic shoulder surgery were investigated.Because pain levels might differ depending on the condition, we selected 52 patients with rotator cuff injuries, which were the most common disorders indicated for arthroscopic shoulder surgery. Patients were treated with cryotherapy at 5 °C or 10 °C for 16 h or 24 h. The pain level was determined using the visual analogue scale, and deep shoulder joint temperatures were recorded at different time points for analysis.Pain after arthroscopic shoulder surgery was found to be related to the presence of a brachial plexus block using the interscalene approach during surgical anesthesia. To obtain effective analgesia with cryotherapy, the cooling temperature and duration of cryotherapy had to be changed based on the presence or absence of the brachial plexus block. Patients who received brachial plexus blocks had the lowest recorded pain scores after receiving cryotherapy at 5 °C for 24 h after surgery. Patients who did not receive the block had the lowest recorded pain scores when receiving cryotherapy at either 5 °C for 16 h or 10 °C for 24 h.Using universal cryotherapy intensity and duration settings regardless of the use of other interventions is likely to unintentionally increase postoperative pain levels. This study revealed that cryotherapy at 5 °C for 24 h was optimal for patients who received an anesthesia block and at 5 °C for 16 h or at 10 °C for 24 h for those who did not receive the anesthesia block. These results can be used as a reference for setting the temperature and duration of cryotherapy after arthroscopic shoulder surgery. Cryotherapy has been popular in the field of sports medicine since the 1950s, and research of its methodology and effectiveness in clinical practice has been conducted since the 1980s. Initially, intermittent cooling was performed using an ice bag, but sustained cooling at a constant temperature was considered more effective. Even though the equipment for icing systems was introduced in the late 1990s, the effective cooling temperature and duration remain unclear.The recovery period after arthroscopic shoulder surgery invariably involves a certain degree of pain for patients –4. PostoCryotherapy is the cornerstone of postoperative management , 27–29 aBecause of the short history of cryotherapy use after arthroscopic shoulder surgery in Japan < 30 years), according to the Japan Shoulder Society, each medical institution using cryotherapy provides different intensities and durations of cooling. The physiological effects of cryotherapy were studied by Knight et al.  years, a, 29, 31.Cryotherapy was performed as part of postoperative management between March 30, 2017, and November 15, 2018, for patients of 16 years or older who underwent arthroscopic shoulder surgery. This was a prospective study. At the beginning of the study, we considered investigating all cases of arthroscopic shoulder surgery at our hospital . Because the cooling temperature and duration of cooling considered most effective for cryotherapy have not yet been clarified, the patients were randomly divided into the following four groups: 5 °C for 24 h; 5 °C for 16 h; 10 °C for 24 h; and 10 °C for 16 h. Due to the shortage of measuring equipment, we were able to collect the data of only one patient at a time. Patients were randomly divided into four groups based on several conditions. If the patient underwent surgery during the morning, then the temperature was set at 5 °C for 24 h. When the number of patients reached approximately 15, the temperature was shifted to 10 °C for 24 h. If the patient underwent surgery during the afternoon, then the temperature was set at 5 °C for 16 h. When the number of patients reached approximately 15, the temperature was shifted to 10 °C for 16 h. The duration was chosen so that cooling would not limit the patient’s activities the next day or affect early ambulation. At the beginning of this study, there were 66 patients. However, complete information was only available for 64 patients: 52 had rotator cuff injuries, nine had repetitive shoulder dislocations, and three had other conditions.Because pain might differ based on the condition, we focused on the 52 patients with rotator cuff injuries, which were the most common disorders in this study. All cases of rotator cuff injuries were included in the study. The cause of injury, such as work-related injuries, car accidents, reoperations, or complications of underlying diseases such as diabetes mellitus were not considered. In this study, there were no cases of reoperation, diabetes, or other underlying complications. Therefore, there were no exclusion criteria for patient selection. After this adjustment, the included patients were 42 years or older. Fifteen patients were subjected to 5 °C for 24 h, 13 patients to 5 °C for 16 h, nine patients to 10 °C for 24 h, and 15 patients to 10 °C for 16 h.Whether a brachial plexus block using the interscalene approach (anesthesia block) comprising ropivacaine hydrochloride hydrate was performed depended on the anesthesiologist on duty at the time of surgery. If an anesthesia block was used, then it was followed by inhalation anesthesia with sevoflurane. If no anesthesia block was used, then sevoflurane inhalation anesthesia was administered.Cryotherapy provided effective and accessible pain relief for patients who underwent arthroscopic shoulder surgery , 29–31 aThe lowest temperature that could be set on the cooling system in the orthopedic surgery ward was 4 °C. However, 5 °C was chosen for the cooling temperature because temperatures below 5 °C can lead to nerve damage . AdditioCryotherapy was performed immediately after returning to the room in the postoperative ward. The Icing system CF-4000 was used after covering the affected area with a cooling pad and immobilizing it so that it would not be compressed, could be observed, and could be removed as needed. To ensure consistency, fixing of the cooling pad was performed for all patients by the same nurse , and placement of the deep temperature probe and fixing of the gauze was performed for all patients by the same physician who performed the surgery (one of the co-authors of this study).The following outcomes were measured and compared: body temperature; deep shoulder joint temperature; objective pain as indicated by the pain level based on the PAINVISION PS-2100 instrument used in clinical practice in Japan; subjective pain as indicated by the visual analogue scale (VAS) score; and C-reactive protein (CRP) level. To determine the deep shoulder joint temperature, the Coretemp CM-210 probe was placed at one location in the acromioclavicular joint region on the affected side by the surgeon at the end of surgery. The healthy side was measured by the nurse and surgeon upon return to the room in the postoperative ward. The temperature-sensitive part of the probe tip, which is bonded to the skin, would generate high heat and cause a burn if the Coretemp was maintained on; therefore, the temperature was read by turning it on at the measurement time and turning it off at the end of the measurement. The deep shoulder joint temperatures were measured immediately after the patient returned to the room in the postoperative ward and at 2, 6, 12, 16, 18, and 24 h postoperatively. The recorded pain level was determined using the average of two measurements obtained with the PAINVISION PS-2100 quantitative pain analysis device. The pain level and VAS score were recorded immediately, 2 h later, and every 6 h until 48 h after returning to the room in the postoperative ward. The CRP level was measured during the immediate postoperative period and 1, 4, and 7 days after surgery.Data analysis was performed using IBM SPSS Statistics version 25. The nonparametric Wilcoxon rank sum test was performed to compare the pain level. Student’s t test was performed for all other comparisons. Pearson’s correlation analysis was also performed to evaluate relationships.The mean age of the patients included in this study was 62.9 years (± 9.2 years), and 41 patients (78.8%) were men and 11 (21.2%) were women. The mean operative time was 131.6 min (± 38.4 min). Seven patients (13.5%) underwent surgery for one tendon, 34 patients (65.4%) underwent surgery for two tendons, and 11 patients (21.2%) underwent surgery for three tendons. Twenty-eight patients (53.8%) underwent tenotomy. Table Regarding the administration of analgesics for postoperative pain relief, 37 patients 71.2%) received intravenous patient-controlled analgesia (IV-PCA) comprising fentanyl citrate or remifentanil hydrochloride . There were significant differences in the pain level immediately, 2 h, and 6 h after returning to the room , and at 24, 30, and 48 h after returning to the room . The pain level was significantly lower (p < 0.05) with anesthesia blocks . The presence or absence of the use of an anesthesia block was associated with the relief of postoperative pain in the affected shoulder joint. Tables At 10 °C, 15 patients received an anesthesia block and nine did not. Significant differences in the relationship between pain and the use of an anesthesia block were observed only for objective pain up to 2 h after returning to the room and for subjective pain immediately after returning to the room  after returning to the room according to the comparisons of the VAS scores at different times.The pain level with an anesthesia block was not significantly different between groups at all measurement times. The pain level of the 16-h group was significantly higher at 30 h and 36 h . In other words, in the 16-h group, the lowest pain levels were recorded at 42 h and 48 h. Additionally, the 16-h group had significantly lower VAS scores at 42 h after returning to the room than the 24-h group (p = 0.023).A significant difference in the pain level of the 16-h group was observed between patients with and without anesthesia block at 42 h and 48 h after returning to the room  only on the postoperative day 1. Similarly, the CRP level at 10 °C was highest in the 24-h group on postoperative day 1 (1.37 ± 0.92 mg/dL) and in the 16-h group on postoperative day 4 (1.46 ± 1.07 mg/dL); however, there was no significant difference between groups , which had a longer operative time, more tendons that underwent surgery, and a higher rate of tenotomy.The CRP level at 5 °C was highest in the 24-h group (2.56 ± 1.91 mg/dL on postoperative day 1) and in the 16-h group (1.84 ± 1.18 mg/dL on postoperative day 4). A comparison based on the cooling time showed that the CRP level was significantly higher in the 24-h group . To obtain effective analgesia with cryotherapy, it is necessary to vary the cooling temperature and duration of cryotherapy based on the presence or absence of the anesthesia block.At 5 °C, with an anesthesia block, the objective pain level was not related to the cooling time. However, there was a significant difference in subjective pain levels. The 16-h group experienced more pain at 1.5 days after surgery. Therefore, it is suggested that continuous cooling at 5 °C for 24 h is better for reducing sensory pain.However, without an anesthesia block, the 16-h group reported less pain overall and at two days postoperatively. The 24-h group reported significantly more objective and subjective pain, suggesting that 16 h is the optimal cooling time without an anesthesia block.The VAS is a universal subjective pain assessment tool used in various fields. However, the PAINVISON was created in Japan to assess objective pain. Although it is currently being introduced into medical practice, its usefulness is still being studied. Therefore, in this study, the VAS was considered essential.At 10 °C, there was no difference in cooling times in terms of both objective and subjective pain with or without an anesthesia block. However, the mean VAS scores were higher in the 16-h group at 18 h after surgery. Additionally, the retrospective VAS scores, which was performed within one or two days after the end of cryotherapy, were not different between the 24-h group with and without block; however, the 16-h group with an anesthesia block felt more pain (approximately 4 cm more according to the VAS) during cryotherapy. Additionally, the 10 °C and 16-h group experienced an increase in deep shoulder joint temperature when continuous cooling was discontinued. Therefore, at 10 °C, objective and sensory pain were not affected by 24 h and 16 h of continuous cooling. However, in the presence of an anesthesia block, it was suggested that, whenever possible, 24 h of cooling at 10 °C was preferable to 16 h of cooling to reduce sensory pain.This study was limited because it was difficult to include the use of analgesics in the analysis. Because the patients were advised not to tolerate pain, they were administered analgesics as soon as they experienced any pain. In addition, different types of analgesics were administered prophylactically before the pain intensified. Furthermore, if the use of analgesics had been included in the analysis, then there would have been more variables. The number of patients would have become statistically insufficient for inter-group comparisons. Therefore, we were unable to examine the effect of analgesics on the studied parameters.Cryotherapy was investigated to determine its benefits in terms of pain relief. Pain after arthroscopic shoulder surgery was related to the presence or absence of a brachial plexus block using the interscalene approach during surgical anesthesia. It was necessary to change the postoperative cooling temperature and time depending on the presence or absence of the brachial plexus block using the interscalene approach. We propose that the cryotherapy cooling temperature range should be 5 °C to 10 °C; however, 5 °C for 24 h appears to be optimal for patients with an anesthesia block. For patients without an anesthesia block, cooling at 5 °C for 16 h and at 10 °C for 24 h provides optimal benefits. The participants of this study were patients with rotator cuff injuries. Hence, in the future, we intend to investigate further applications of cryotherapy and compare its efficacy for treating patients who underwent arthroscopic shoulder surgery because of other disorders.Importantly, our findings support the view that universal cryotherapy intensity and duration settings regardless of the use of other interventions will unintentionally increase postoperative pain levels. Therefore, the results of this study could provide a guide for determining the temperature and duration of cryotherapy after arthroscopic shoulder surgery.


A correlation analysis was conducted to explore the potential relationships between neuroimaging indices and pain intensity. Receiver operating characteristic curve analysis was applied to assess the classification performance of neuroimaging indices in discriminating individual subjects between the BMP patients and HCs. No significant intergroup differences in demographic and neuropsychological data were noted. BMP patients showed reduced ALFF and ReHo largely in the prefrontal cortex and increased ReHo in the bilateral thalamus and left fusiform gyrus. The lower FC was found within the prefrontal cortex. No significant correlation between the neuroimaging indices and pain intensity was observed. The neuroimaging indices showed satisfactory classification performance between the BMP patients and HCs, and the combined ALFF and ReHo showed a better accuracy rate (93.7%) than individual indices. In conclusion, altered brain functional activity and connectivity in the prefrontal cortex, fusiform gyrus, and thalamus may be associated with the neuropathology of BMP and may represent a potential biomarker for classifying BMP patients and healthy controls.Bone metastasis pain (BMP) is one of the most prevalent symptoms among cancer survivors. The present study aims to explore the brain functional activity and connectivity patterns in BMP of lung cancer patients preliminarily. Thirty BMP patients and 33 healthy controls (HCs) matched for age and sex were recruited from inpatients and communities, respectively. All participants underwent fMRI data acquisition and pain assessment. Low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were applied to evaluate brain functional activity. Then, functional connectivity (FC) was calculated for the ALFF- and ReHo-identified seed brain regions. A two-sample  Pain is the most frequent symptom of cancer survivors, and this symptom has increased in prevalence . A previThe brain is necessary for the multidimensional pain experience, and activity in multiple brain regions has been found to be associated with noxious stimuli. Therefore, brain imaging, such as functional magnetic resonance imaging (fMRI), provides valuable information. Among the fMRI indices, the amplitude of low-frequency fluctuations (ALFF) is used to evaluate brain functional activity , and regvia the dorsal horn of the spinal cord. Thus, the sensory, cognitive, and affective aspects of pain experience will be processed within the brain. For instance, the primary somatosensory cortex and thalamus receive nociceptive input from the spinal cord and encode the intensity of pain. In addition, nociceptive signals are sent to the brainstem, midbrain, and medullary areas, where they might modulate the perception and sensation of a noxious stimulus  matched for age and sex were recruited from communities. Inclusion criteria: (1) lung cancer patients suffering from bone metastasis pain, (2) the BMP patients can tolerate the MRI scan and (3) right-handed. BMP patients were diagnosed with lung cancer according to pathology and bone metastasis according to medical imaging and/or pathology. Subjects with brain structural abnormalities, neurological or psychiatric diseases, disability, left-handedness, and contraindications to MRI examination were excluded prior to enrollment. The experiment was approved by the Medical Research Ethics Committee of Chongqing University Cancer Hospital . All participants provided written informed consent before the experiment. All procedures were performed in accordance with the approved study protocol.According to the head motion profile derived from subsequent MRI data processing, six BMP and three HCs with head motion >2 mm in any direction or 2° at any angle were excluded. Therefore, 30 BMP patients and 33 HCs were involved in the study. Demographic information, including age and sex, was obtained across the two groups. The intensity of real-time pain was obtained according to patients' feelings on a visual analog scale (VAS). All subjects underwent evaluation of anxiety and depression using the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). Details are shown in Soon after the pain evaluation, structural and functional MRI scanning were performed with a 3.0 T scanner  using a 64-channel head-neck coil. Earplugs were used to alleviate the influence of noise and cushions to restrict head motion. Subjects stayed awake with their eyes closed and were instructed to not think about any topics during the scanning.2, slices = 192, thickness = 1 mm, matrix = 256 × 256 and voxel size = 1 × 1 × 1 mm3, for a total of 4 min and 53 s. Resting-state functional images were acquired transversely using an echo planar imaging (EPI) sequence: repetition time/echo time = 2,000 ms/30 ms, flip angle = 70°, field of view = 240 × 240 mm2, slices = 36, thickness = 3 mm, matrix = 80 × 80, voxel size = 3 × 3 × 3 mm3, and 240 volumes with a total of 8 min and 8 s.Conventional T2-weighted images and fluid-attenuated inversion recovery (FLAIR) images were acquired for radiological evaluation of brain structural abnormalities. Then, sagittal T1-weighted structural images were acquired using volumetric 3D magnetization prepared by a rapid-acquisition gradient-echo (MP-RAGE) sequence: repetition time/echo time = 2,100 ms/2.26 ms, flip angle = 8°, field of view = 256 × 256 mmhttp://rfmri.org/)  . (1) DatPearson correlation coefficient values for the remainder of the whole-brain voxels. Fisher's r-to-z transformation was applied to normalize the distribution correlation coefficient to obtain FC.Then, ALFF and ReHo were calculated and standardized with the mean division to reduce the impact of many sources of nuisance variation and increase the test–retest reliability . Specifit-tests or Mann–Whitney U-tests were applied to compare the data between two groups according to the distribution checked with the Kolmogorov–Smirnov test. The chi-square test was applied to intergroup comparisons of sex. Values of p < 0.05 were considered statistically significant.Demographic and neuropsychological data were analyzed with SPSS software . Two-sample t-test, Jarque-Bera goodness-of-fit test was conducted to confirm the normal distribution of ALFF, ReHo, and FC maps . Subsequently, neuroimaging indices were analyzed using DPABI software. First, a one-sample t-test was performed to examine the functional activity and connectivity patterns in each group. Then, the t-statistics of group effect was analyzed after adjusting for covariates  with multiple linear regression. The test results were corrected for multiple comparisons with Gaussian random-field theory .Before the one or two-sample z scores in significantly altered brain regions were extracted for Spearman correlation analysis with pain intensity and neuropsychological data in BMP patients. We also explored the relationship of pain intensity with neuroimaging indices of each voxel . The extracted values of both groups were used for receiver operating characteristic (ROC) curve analysis to evaluate their performance in discriminating individual subjects between the two groups. Leave-one-out cross-validation was performed to prevent possible inflated estimates of discriminant power and the validated AUC was obtained. Collinearity among neuroimaging indices was checked by using linear regression to avoid the loss in statistical power. And the probabilities of combined neuroimaging indices were obtained by using logistic regression in SPSS software and were used for the ROC curve analyses. The Delong test was applied to compare areas under ROC curves (AUCs)  .p > 0.05). The duration of pain in patients ranged from 20 to 2,095 days, and the pain score ranged from 1 to 7. Details are shown in The BMP patients did not differ from the HCs in terms of age, sex, SAS, and SDS score . FC z scores were not involved in the combination due to their collinearity. The combined AUC of ALFF and ReHo showed no significant difference from the AUC of FC values  have been repeatedly reported to be associated with chronic pain . As the A few studies have reported the possible role of the fusiform gyrus in pain processing. The fusiform gyrus anatomically connects the ventral visual network and is associated with facial recognition or face selection . HeighteNeuroimaging indices have been used as biomarkers to discriminate between pain patients and controls. ALFF maps were used to classify chronic low back pain patients and controls with a moderate discriminate performance (accuracy rate >70%) . In addiOf note, no correlation between brain activity or connectivity was found with pain intensity in the present study. The dissociation between the magnitude of the response in the brain and the persistence of pain may be due to the habituation of repetitive noxious stimuli . For insSome limitations should be acknowledged. First, the sample size is relatively small. The findings should be further validated in other datasets with larger sample sizes. Second, patients suffering from severe intensities of pain are impractical to be involved with potential evident head movement and only those with mild and moderate intensities were included. Therefore, bias is not avoidable. Third, we cannot exclude the confounding effects of analgesics, lung cancer, and its treatment. Fourth, the MRI data processing should be taken into consideration since there is no definite standard procedure. For instance, though the effects of variables of interest have remained largely after standardization , we mustIn conclusion, it is necessary to better understand cancer pain. Our findings suggested a decrease in brain functional activity mainly in the frontal cortex and an increase in the thalamus and fusiform gyrus in BMP. Moreover, a decrease in functional connectivity within the frontal cortex was observed. These abnormalities may be associated with the neuropathology of BMP and hold the potential to classify BMP patients and HCs. However, we should note that the present preliminary findings should be verified in future elaborate study designs.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical Research Ethics Committee of Chongqing University Cancer Hospital. The patients/participants provided their written informed consent to participate in this study.DL contributed to the experiments, statistical analysis, and the writing of the manuscript. XZ contributed to the MRI data analysis. YT, HY, YC, LT, LY, SW, SL, JC, JL, and CW contributed to MRI and clinical data collection. HYQ and JZ are the guarantors of this study and had complete access to all the data in the study. All authors contributed to the article and approved the submitted version.The study was supported by the National Natural Science Foundation of China (82071883), Chongqing Medical Research Project of Combination of Science and Medicine (2021MSXM035), Graduate Research and Innovation Foundation of Chongqing, China (CYS21071), 2020 SKY Imaging Research Fund of the Chinese International Medical Foundation (Z-2014-07-2003-24), and Chongqing Natural Science Foundation (cstc2021jcyj-msxmX0319 and cstc2021jcyj-msxmX0313).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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