Background and aim: Radial shortening after distal radius fracture causes ulnar impaction, and a mild reduction loss of radial height occurs even after volar locking plate fixation. This study aimed to determine whether preoperative ulnar-sided sclerosis affects clinical outcomes after volar locking plate fixation for distal radius fracture (DRF). Method: Among 369 patients who underwent volar locking plate fixation for DRF, 18 with preoperative ulnar-sided sclerosis of the lunate were included in Group A and compared to a 1:4 age-, sex- and fracture-pattern-matched cohort without sclerosis . The visual analog scale (VAS), Disabilities of the Arm, Shoulder, and Hand (DASH) score, and grip strength were assessed as clinical outcomes. Ulnar variance (UV), radial inclination, radial length, and volar tilt at two weeks after surgery and the final follow-up were measured as radiographic outcomes. Results: The mean VAS and DASH scores and grip strength did not differ between the two groups. The mean UV at two weeks after surgery and the last follow-up was significantly higher in Group A. The mean changes in UV were +0.62 mm in Group A and +0.48 mm in Group B. There were no significant intergroup differences. Neither UV nor its changes showed any association with DASH and VAS scores. Conclusions: Preoperative ulnar-sided sclerosis of the lunate did not affect clinical outcomes after volar locking plate fixation, even if UV increased postoperatively. Distal radius fracture (DRF) is quite common, accounting for approximately 3% of all upper-extremity fractures . The recUIS is a painful degenerative condition that results from the abutment of the distal end of the ulna against the ulnar carpus. This syndrome may occur in wrists with positive ulnar variance (UV), which can be caused by malunion after DRF, such as radial shortening and loss of volar tilting ,9,10. ThThis study primarily aimed to determine whether preoperative ulnar-sided sclerosis of the lunate increases the risk of ulnar-sided wrist pain and affects clinical outcomes after VLPF for DRF. The secondary aim of this study is to determine whether a joint-leveling procedure would be required during surgery in patients with ulnar-sided sclerosis of the lunate in whom symptoms of UIS may manifest or worsen after VLPF for DRF. The authors hypothesized that patients with preoperative ulnar-sided sclerosis are vulnerable to a shortening of the radius of a few millimeters after VLPF. Furthermore, they hypothesized that postoperative symptoms of UIS, such as ulnar-sided wrist pain, may manifest or worsen according to positive changes in UV after VLPF for DRF.n = 6), Kienböck’s disease (n = 1), or inflammatory arthritis (n = 6); presence of ipsilateral upper-extremity fractures including distal ulnar and shaft fractures, except ulnar styloid process fractures (n = 12), or presence of open fractures (n = 2); and inadequate radiographs for obtaining a true measurement (n = 20). Patients who were not monitored for more than 12 months were also excluded (n = 16). Finally, 369 patients were included in this study. Of them, 18 with subchondral sclerosis with or without cystic changes in the proximal ulnar portion of the lunate identified on preoperative plain radiographs and CT scans were included in Group A . Pain levels were measured using a visual analog scale (VAS) ranging from 0 to 10 points. Among patients complaining of wrist pain, patients who had ulnar-sided wrist pain were asked whether the same pain had preceded a fracture and whether UIS had been diagnosed. Ulnar-sided wrist pain was defined as pain exacerbated by a forceful grip, pronation, and ulnar deviation. For patients who had ulnar-sided wrist pain, positive ulnocarpal stress test findings and tenderness were performed to determine whether the pain was caused by UIS at 6 and 12 months after surgery. The patients were asked to complete the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire to assess patient-reported outcomes at 6 and 12 months after surgery. Grip strength was measured in both hands using a Jamar hydraulic hand dynamometer and calculated as a percentage of the unaffected side at 6 and 12 months after surgery. The right hand was assumed to be 15% stronger than the left hand in right-handed patients.Fractures were classified according to the AO Foundation and Orthopaedic Trauma Association classification system . The radStatistically significant intergroup differences were determined using independent t-tests after the Kolmogorov–Smirnov and Shapiro–Wilk tests, as appropriate, for normally distributed continuous variables. The last non-normally distributed UV and DASH scores were analyzed using the non-parametric Mann–Whitney U test. Fisher’s exact test was used to analyze categorical variables. The association between the UV and DASH scores was confirmed for each group. Spearman’s correlation was used to analyze the UV scores at the last follow-up, which were non-normally distributed. Immediate postoperative changes in UV that satisfied normality were analyzed using Pearson’s correlation coefficient. The relationship between the UV and VAS scores was assessed using Spearman’s correlation coefficient. A posteriori power analyses of the study and effect size were performed using the postoperative DASH scores of the two groups. The effect sizes (Cohen’s d) were calculated for clinical and radiologic outcomes. Statistical analyses were performed using the R software package (R version 3.5.1) and SPSS software .The number of patients with ulnar-sided wrist pain was two (11.1%) in Group A and three (4.1%) in Group B. All patients were diagnosed with UIS before the fracture. None of the patients had newly diagnosed UIS or an exacerbation of ulnar-sided wrist pain. The mean VAS and DASH scores did not differ between the two groups at 6 and 12 months after surgery. The mean grip strength in Group A was slightly lower than that in Group B at 6 and 12 months after surgery. However, there were no significant intergroup differences .p < 0.05).The mean UV at 2 weeks after surgery and at the last follow-up was higher in Group A than in Group B . Howeverp > 0.05, >0.05, and >0.05, respectively). In addition, the UV and VAS scores showed no significant association .The mean UV at 2 weeks after surgery and at the last follow-up and the change in UV showed no significant association with the DASH score (This study aimed to determine whether preoperative subchondral sclerosis with or without cystic changes in the proximal ulnar portion of the lunate is associated with an increased risk of ulnar-sided wrist pain or affects the clinical outcomes after VLPF for DRF. In our study, patients with ulnar-sided sclerosis of the lunate had a significantly larger UV value than those without. However, we could not confirm the clinical effects of preoperative ulnar-sided sclerosis of the lunate after VLPF for DRF and even increased postoperative UV values. Moreover, there were no correlations between UV and clinical outcomes, including VAS and DASH scores. Taken together, although ulnar-side sclerosis of the lunate occurred frequently in patients with positive UV findings, it did not manifest or worsen symptoms of UIS, even if UV increased slightly after VLPF for DRF.A positive UV is a known risk factor for UIS because it increases the load on the ulnocarpal joint ,21,22. PAlthough ulnar-sided sclerosis of the lunate may result from UIS, it has also been observed in asymptomatic patients. Rhee et al.  comparedThe prevalence of lunate subchondral cysts in the normal population is unknown because most patients with carpal bone cysts are asymptomatic . A previThis study had several limitations. First, it was limited by its retrospective design, and the sample sizes of the experimental and control groups were too small to enable us to draw any significant conclusions. This was partially due to the low incidence of ulnar-sided sclerosis of the lunate: approximately 4.8–10%. However, the authors attempted to overcome this limitation by using a matched case-control study design. Second, in this study, the presence of ulnar-sided sclerosis was confirmed by plain radiography, and CT and radiographic parameters were measured in posteroanterior and lateral views of the distal radius, which could have led to bias among the observers. To overcome this bias, two independent experienced orthopedic surgeons repetitively confirmed ulnar-sided sclerosis of the lunate and performed radiographic measurements at 2-week intervals. Finally, because preoperative ulnar-sided wrist pain was documented based on patient recall, it is unclear whether ulnar-sided wrist pain before trauma was caused by UIS.The presence of subchondral sclerosis with or without cystic changes in the proximal ulnar portion of the lunate, as evidenced on plain radiographs prior to VLPF for DRF, did not increase ulnar-sided wrist pain or affect the postoperative clinical outcomes if anatomical reduction and stable fixation of the fracture were achieved, even if the postoperative UV was slightly increased during follow-up after VLPF.


The prevalence of post-surgical lumbar neuropathic radiculopathy is approximately 30%. Poor response to the recommended treatments for neuropathic pain, namely antidepressants and/or gabapentinoids, requires the development of new techniques to prevent chronic pain. One such well-tolerated technique is the administration of autologous plasma enriched in platelets and fibrin (PRF). This approach is largely used in regenerative medicine owing to the anti-inflammatory and analgesic properties of PRF. It could also be an interesting adjuvant to surgery, as it reduces neurogenic inflammation and promotes nerve recovery, thereby reducing the incidence of residual postoperative chronic pain. The aim of the present study is to evaluate the benefit of periradicular intraoperative application of PRF on the residual postsurgical neuropathic pain after disc herniation surgery.A randomized, prospective, interventional, controlled, single-blind study with evaluation by a blind outcome assessor will be performed in Strasbourg University Hospital. We will compare a control group undergoing conventional surgery to an experimental group undergoing surgery and periradicular administration of PRF (30 patients in each arm). The primary outcome is the intensity of postoperative neuropathic radicular pain, measured by a visual analog scale (VAS) at 6 months post-surgery. The secondary outcomes are the characteristics of neuropathic pain (NPSI), the quality of life (SF-12 and PGIC), the presence of anxiety/depression symptoms (HAD), and the consumption of analgesics. We will also carry out transcriptomic analysis of a panel of pro- and anti-inflammatory cytokines in blood samples, before surgery and at 6 months follow-up. These gene expression results will be correlated with clinical data, in particular, with the apparition of postoperative neuropathic pain.This study is the first randomized controlled trial to assess the efficacy of PRF in the prevention of neuropathic pain following surgery for herniated disc. This study addresses not only a clinical question but will also provide information on the physiopathological mechanisms of neuropathic pain.NCT05196503, February 24, 2022.This study is registered at ClinicalTrials.gov: The online version contains supplementary material available at 10.1186/s13063-023-07420-y. Neuropathic pain is defined by the International Association for the Study of Pain (IASP) as “pain resulting from an injury or disease affecting the somatosensory system” . From anAcute lower back pain is one of the most commonly observed acute pains in clinical practice. Its natural history is most often favorable, with healing usually occurring within a few weeks. The problem appears when nerve root pain occurring in the lower back as a result of discoradicular conflict persists. Among these patients, some will benefit from spinal surgery. However, after spinal surgery, some patients will develop residual chronic pain, which has been shown to occur in 10–50% of cases . For appFrom a pathophysiological point of view, disc compression on the root quickly induces intraneural edema, leading to nerve fiber degeneration complications a few months later . SimilarThe development of numerous animal models of neuropathic pain has made it possible to clarify some of the pathophysiological mechanisms. Communication between the nervous system and the immune system, in particular via cytokines at the peripheral or central level, contributes to the development and maintenance of neuropathic pain . This neGrowth factors such as platelet-derived growth factor (PDGF) have been shown to decrease pro-inflammatory cytokine synthesis , 20. PlaOther studies go even further by adjusting centrifugation speeds to successfully produce plasma rich in platelets and fibrin (PRF) . Thanks In light of these properties, PRF would be interesting to use in the prevention of neuropathic pain, in particular within the context of spinal surgery. In the current protocol, we have chosen to focus on the prevention of residual neuropathic pain following surgery for herniated disc. Although this study population does not represent the majority of postoperative pain following spinal surgery, a selective population is required in order to assess the effectiveness of PRF in preventing neuropathic pain. To date, this study is the only randomized controlled trial designed to address this question.The present NeuroPRF trial is designed as a superiority, prospective, single-center, randomized, parallel group study, conducted in a single-blind manner, with evaluation by a blind outcome assessor. Eligible patients will be randomized into one of two treatment groups: experimental group (surgery and periradicular administration of PRF) or control group . Patients will be followed for a total of 6 months. This manuscript used the SPIRIT reporting guidelines.Patients and the public were not involved in the design of this study.The aim of the NeuroPRF trial is to determine whether the intraoperative periradicular application of PRF can prevent residual post-surgical neuropathic pain after disc herniation surgery.The primary objective is to evaluate the effect of an intraoperative periradicular application of PRF on the intensity of postoperative residual leg neuropathic pain 6 months after primary surgery for a herniated disc.The incidence and characteristics of residual neuropathic pain;Quality of life;Anxious and depressive symptoms;The correlation between neuropathic pain and gene expression of a panel of cytokines in the blood (specific search for a panel of pro- and anti-inflammatory cytokines);The use of analgesics;Safety.Secondary objectives evaluate:Study outcomes are assessed by a designated, blinded study investigator, and the patient (self-assessment), who is also blind to their treatment arm. All outcomes will be assessed at baseline (preoperatively) and at 2 weeks and 6 months after the surgery.The primary outcome is the intensity of postoperative neuropathic radicular pain, measured by a visual analog scale (VAS). The neuropathic radicular pain will be confirmed by a clinical examination and a “Douleur Neuropathique 4” (DN4) score ≥ 4. Thus, VAS for leg pain will be measured during all follow-up visits: baseline (preoperative), 2 weeks and 6 months postoperative. VAS leg pain will be scored on a 0 to 10 points scale with increments of 1 point (0 being zero pain and 10 being the maximum pain possible).The incidence and characteristics of residual neuropathic pain, measured by the DN4 and the Neuropathic Pain Symptom Inventory (NPSI) questionnaires, respectively;The evolution of quality of life with the 12-item Short Form Survey (SF-12) and Patients’ Global Impression of Change (PGIC) questionnaires;Anxiety and depressive symptoms with the Hospital Anxiety and Depression (HAD) questionnaire;The level of gene expression of a panel of pro- and anti-inflammatory cytokines in the blood Table  using muThe use of analgesics;Incidence of adverse events (AE) and serious adverse events (SAE).In order to assess the presence and the neuropathic pain characteristics, the quality of life and the anxiety/depression syndromes, secondary outcomes will be measured at baseline (preoperative), 2 weeks and 6 months postoperative:The study will take place at the Pain Center and the Department of Neurosurgery of Strasbourg University Hospital, in collaboration with researchers from the Institute of Cellular and Integrative Neuroscience (INCI) at the University of Strasbourg. Coordination and monitoring of the study will be carried out by the investigating team.Patients will be recruited by the consulting neurosurgeon in the Department of Neurosurgery at Strasbourg University Hospital. Patients consulting for leg pain due to a disc herniation, for whom surgical intervention is indicated, will be referred for participation in this clinical study. During this routine consultation, a screening interview will be conducted for each potential participant using a questionnaire verifying eligibility criteria.After verification of eligibility criteria, written information about the study will be provided to the patients, who will then be able to reflect on their decision to participate or not for approximately one week. Patients will be re-contacted by the study investigator, and, if they consent to participate, will attend an enrolment visit. After a final verification of eligibility, the patient will provide written informed consent.In the consent form, participants will be asked if they agree to the use of their data, should they choose to withdraw from the trial. Participants will also be asked for permission for the research team to share relevant data with the Universities taking part in the research, or with regulatory authorities, where applicable. This trial does not involve collecting biological specimens for storage.To improve adherence to intervention protocols, the neurosurgeon during the selection visit and the investigating physician during the inclusion visit will explain to the patient the expected benefits, in particular the reduction of neurogenic inflammation of the nerve root, the improvement of nerve healing and thus the potential prevention of chronic postoperative pain. To improve monitoring adherence, such as blood draws, they are taken with the patient's consent as part of the standard of care process. There are no additional visits related to the protocol.Patient > 18 years old;Patient with a diagnosis of radiculopathy on lumbar disc herniation and for whom surgery has been scheduled in the Department of Neurosurgery;Patient affiliated to a social security health insurance scheme;Patient able to understand the objectives and risks of research and to give informed, dated and signed consent;Negative blood pregnancy test for female participants of reproductive age recorded at the inclusion visit and effective contraception used throughout the study.The inclusion criteria are:Patient with a history of lumbar spinal surgery ;Patient with HIV, active cancer, HBV, HCV;Patient receiving long-term systemic corticosteroid therapy;Patient with an American Society of Anesthesiology (ASA) score > 3 during the routine pre-surgery consultation with the anesthetist;Inability to give the patient informed information ;Patient in exclusion period (determined by a previous or ongoing study);Subject under safeguard of justice;Subject under curatorship;Patient actively breastfeeding.The exclusion criteria are:An initial selection of patients will be carried out during a routine consultation with the practicing neurosurgeon, 30 days (± 20 days) prior to surgery. During this visit, the patient will be provided with the necessary study information, the eligibility criteria will be verified, and a clinical examination will be carried out. If the patient is eligible and decides to participate, an enrolment visit will be carried out 1 week (± 6 days) prior to surgery. At this visit, which takes place at the pain center , written informed consent is provided obtained from the participant, who will then complete baseline questionnaires and undergo a clinical examination. Randomization is also carried out at this visit, by using web-based randomization software . The details of randomization will remain unavailable to the medical examinator and the participant during the study. Randomization will be carried out using an allocation ratio of 1:1, which will determine the treatment arm of the patient: the interventional group (surgery and PRF application) or the control group . The allocation sequence is generated by the statistician of the study, using computer-generated random numbers. There will be no special criteria for discontinuing or modifying allocated interventions. To reduce predictability of a random sequence, the randomization will be carried out with two randomly distributed block sizes. Randomization will be carried out without factors of stratification. A specified investigator will carry out the enrolment visits and randomization process. This investigator and the surgeons carrying out the intervention will be the only investigators not blind to participants’ treatment arm. Blinding of the evaluating investigators will remain in place until statistical analysis of the study results has been finalized. Equally, participants are blinded to the intervention that they have received .The day of surgery is designated as V0. At V0, a blood sample will also be collected for RNA extraction and genes of interest expression analysis, just before the surgery. This will be considered as the basal condition. The participant will be examined at two further visits: 2 weeks (± 5 days) post-surgery V1) and 6 months (± 15 days) post-surgery (V2). These visits will consist of a clinical examination, a blood sample collection for gene expression analysis, and completion of questionnaires. Figure  and 6 moThe baseline clinical examination carried out at the enrolment visit includes questions about pain descriptors and history. Medical history, comorbidities, and medications will also be documented. The clinical examinations carried out at V1 and V2 consist of a physical neurological examination including myotomal strength, reflex, and sensory testing .DN4 ;NPSI ;HAD ;SF-12 ;VAS for current leg pain ;PGIC scale .Participants will be asked to complete the following questionnaires:All are self-questionnaires, except for DN4, which will be carried out by the examining clinician. All questionnaires will be completed pre-operatively, at 2 weeks, and at 6 months post-operatively, with the exception of the PGIC scale, which will be completed only after the surgery . Data from these examinations will be entered into the CleanWEB® e-CRF by the examining investigator.Surgery will be carried out under general anesthesia for both groups. Surgical treatment of lumbar disc herniation relies on relieving the compression of the nerve root by the herniated disc. Prior to surgical incision, a blood sample of 5 mL will be taken for gene expression analysis. This must be carried out prior to surgery in order to avoid any systemic inflammatory phenomena caused by surgery itself.- Control group : The patient is placed in the knee-pectoral decubitus position under general anesthesia. The concerned intervertebral space is identified by radioscopy. The most common procedure implies a median posterior cutaneous incision, with subsequent detachment of the paravertebral muscles from the underlying vertebra. The interlaminar space is then approached through removal of the ligamentum flavum. Once the vertebral canal is accessed, epidural fat is retracted in order to visualize the dural sac and emerging spinal roots. Gentle traction on the dural sac and spinal roots allows exposure of the bulging disc at the compression point. The posterior longitudinal ligament is then incised and herniated disc removed with additional discectomy if necessary. Closure is finally performed with respect to each anatomical layer.- Interventional group (surgery and periradicular administration of PRF): The same surgical steps are carried out as those in the control group, with an additional periradicular administration of autologous PRF. Preparation of the PRF will be carried out during the surgery, in the operating theater. Twenty milliliters of venous blood will be collected from the perfusion device, in 2 sterile tubes without anticoagulant (Becton Dickinson‚ Vacutainer‚ 10 mL each), and immediately centrifuged at room temperature for 14 min at 1300 rpm in a suitable centrifuge , according to the A-PRF protocol described by the manufacturer. Under the effect of coagulation activation and centrifugal forces, three layers will appear in the tube: a pellet of red blood cells at the bottom, an acellular plasma supernatant on the surface, and a PRF fibrin clot loaded with platelets in the middle. PRF in gel form is then recovered under sterile conditions by the neurosurgeon, who will shape it using tweezers so that it can be applied to the root lesion before layer-by-layer closing.During the immediate postoperative period, all analgesics are permitted as per standard of care: paracetamol, NSAIDs, nefopam, tramadol, lidocaine, ketamine, morphine. For residual postoperative pain, level 1, 2, or 3 analgesics are permitted.To study the mechanisms of initiation and maintenance of neuropathic pain, and in particular the involvement of the cytokinergic system , we willA 5 mL sample of blood will be taken from participants at V0, V1, and V2 in a pseudonymized EDTA-anticoagulation LeucoSep vials . Briefly, samples will be subjected to density gradient centrifugation  to isolate PBMC. Collected PBMC will be washed  in Hank’s buffer , and red blood cells will be lyzed . After another wash , two identical aliquots of highly-purified PBMCs will be collected; the first one will be resuspended in 600 μL of RNAlater Stabilization Solution  and stored at – 20 °C for back-up. The second will be resuspended in 200 μL of 1-thiogycerol solution , vortexed and stored at – 20 °C for RNA extraction. Total RNA extraction will be performed on a Maxwell RSC device  according to the manufacturer’s instructions. Quality control will be performed on microfluidic chips prepared using the 6000 Nano Kit (Agilent) and loaded on the 2100 Bioanalyzer system (Agilent) according to the manufacturer’s instructions. RNA samples will be quantified on a Nanodrop 2000 spectrophotometer (Thermo Scientific). These high-quality, DNA-free RNA samples will then be stored at – 80 °C.Four hundred nanograms of each RNA sample will be reverse-transcribed with the iScript gDNA Clear cDNA Synthesis Kit (Bio-Rad), which integrates an effective DNase digestion step to remove any trace contamination of genomic DNA.Quantitative PCR will be performed using SYBR Green Supermix (Bio-Rad), on the iQ5 Real Time PCR System (Bio-Rad). Amplifications will be carried out in 42 cycles . Primer sets for all genes of interest and housekeeping genes have been designed using Oligo6.0 and M-fold software. To ensure a high primer specificity and an optimal amplification efficacy for all primer sets in the given PCR conditions, we will use control samples to verify that amplification efficacy given by standard curves will be close to 100% (± 2%) and that amplification specificity, assessed by a melting curve study, will generate a single peak at the melting temperature expected by sequence analysis. Samples will be accurately dispensed in 96-well plates using a robotic workstation, for a final volume of 15 μL per well . Targets will be amplified in triplicate, and threshold cycle (Ct) values will be determined. Fold changes in gene expression among groups will be calculated using the delta-delta Ct method. Gene expression data will be normalized to the arithmetic mean of housekeeping gene expression .Adverse events are defined as any undesirable experience occurring to a subject during the study. All adverse events reported directly by the subject or observed by an investigator will be recorded. In the case of a suspected unexpected serious adverse reaction (SUSAR), the pharmacovigilance officer, in collaboration with the sponsor and investigators, will carry out the unblinding of the participant in question, via the CleanWEB® interface. There is no criterion or formal stopping rules. Indeed, the treatment is unique and, intraoperatively, there is no criterion for definitive discontinuation of the use of the experimental product as such. There is a very small risk that the treatment cannot be administered during surgery for logistical, medical or other reasons. Thus, the patient would then be withdrawn from the study.No data monitoring committee was envisioned because the study was a low-risk intervention. However, the investigators agree to comply with the requirements of the sponsor and the competent authority for an audit or inspection of the study  and dispersion parameters  will be given. The parameters will be estimated firstly on raw data, and secondly within the Bayesian paradigm, on the posterior distribution, for each variable.Secondly, to compare the difference of the means of the VAS, a Bayesian linear regression will be performed. The regression will be simple linear or generalized depending on the distribution of the data. To meet the secondary objectives, Bayesian linear regressions will be performed for continuous variables, and Bayesian logistic regressions for categorical variables.The regressions will be firstly carried out without adjustment and secondly with an adjustment on sex and age. Subgroup analyses are not planned.The priors will be on the one hand very uninformative and on the other hand informative in the context of a sensitivity analysis.For each analysis, the posterior distribution of the parameter of interest  will be estimated using Markov chain Monte Carlo (MCMC) draws. The default number of iteration is 200,000 with a burning of 10,000 and a thinning of 2. Algorithm convergence will be assessed graphically and with the Gelman and Rubin’s convergence diagnostic. Autocorrelation will be assessed graphically and, if required, the number of iterations and thinning will be increased to reduce as much as possible the autocorrelation.Credibility intervals will be calculated at 95% using the quantile method. A particular factor will be considered to exert an effect on the variable in question if the probability that the effect is greater than the reference value is greater than 0.975 or less than 0.025.The proportion of missing data will be given for each variable. Missing data will be treated by simple deletion of cases if these values are very few or by multiple imputation in the opposite case.The intention-to-treat (ITT) data set, which contains all subjects who give their consent for the study and who undergo randomization, whether they follow or not the protocol properly (for instance if they do not follow the treatment or the visits planning).The per-protocol (PP) data set, which contains all subjects who, after randomization, undergo the treatment and who follow the protocol as planned.Two different data sets will be defined:The datasets analyzed during the current study and statistical code are available from the corresponding author on reasonable request, as is the full protocol.The platelet-rich plasma was historically used in dentistry for its osteo-regenerative properties. This technique has been rapidly extended to other fields, such as rheumatology or sports medicine. In the field of pain, some studies have reported its analgesic properties on neuropathic pain of peripheral origin, while perineural injection of PRP has been shown to improve pain in patients with various etiologies, such as postherpetic neuralgia, chronic post-surgical pain, or traumatic peripheral nerve injury –32.Furthermore, it could be an interesting adjuvant to surgery. In a case report, the use of intraoperative PRP during nerve decompression surgery following digital trauma was shown to significantly reduce neuropathic pain and improve functional recovery . PRP couWe elaborated the first randomized controlled trial to assess the efficacy of PRF in the prevention of neuropathic pain following surgery for herniated disc. This study not only addresses a clinical question but will also provide information on the physiopathological mechanisms of neuropathic pain. However, this trial has some limitations. This study is limited by its single-center design. The selected study population  can be considered a limitation in that this population does not represent the majority of patients who experience chronic pain following spinal surgery.Thus, the interest of this therapy is that PRF could also be an interesting adjuvant to surgery and may thus block the initiation of neuropathic pain mechanisms .This trial was registered at ClinicalTrials.gov and this article is based on the 2nd version of the protocol published in February 2022. It was not submitted earlier to be published due to changes in the study status. Recruitment of participants is intended to start in March 2022 and is expected to be completed no later than January 2025. The total duration of the study will be 3 years.Any significant modification of the protocol  will be the subject of a protocol amendment and will be transmitted to the concerned parties . If applicable, the protocol will be updated in the clinical trial registry.Additional file 1. The right of access to source data and documents.


Although palliation of psycho-spiritual distress is of great importance in terminally ill cancer patients, there is a little information about screening patients who benefit from palliative care and identifying the cancer care targets. This study explored the relationship of pain management and positive expectations with depression, anxiety and spiritual well-being (SWB) in terminal cancer patients admitted to a palliative care unit.Eighty-four terminal cancer inpatients were recruited from the Hospice Ward, Shengjing Hospital of China Medical University. Optimism and general self-efficacy (GSE) were evaluated at admission. Patients completed self-report questionnaires on SWB, depression, anxiety and pain both on admission and one week later. The repeated designed analysis of variance was used to explore the correlates of depression, anxiety and SWB .p = 0.041) and faith (p = 0.013), there was a significant pain group (relieved vs. not relieved) × time interaction effect, such that those with satisfied pain control experienced the improved psycho-spiritual outcomes at 1 week. The relationship between positive expectations, peace and faith was also statistically significant, indicating that the improvement of peace or faith was significant in the low group of optimism and GSE.In our sample, only cancer pain diminished significantly one week later. For depression (Our findings indicated that pain management lied at the center of depression and SWB, meaning that effective pain management may reduce depression, and improve SWB among terminal cancer patients. Moreover, positive expectations, especially for optimism, may be the new target for SWB-related intervention research. Palliative care nurse should require the identification of terminal cancer patients who may more benefit from short-term palliative care, and target them with effective cancer care. Terminal cancer patients are confronted with a limited life expectancy, suffer severe refractory symptoms, and face the fear of disability and helplessness , 2, in wSWB has been viewed as a multidimensional construct composed of 3 components: meaning, peace, and faith . MeaningTerminal cancer patients often experience suffering of the whole person. According to the Biopsychosocial-Spiritual Model , it is cThe ability of health care providers to reduce sufferings requires the identification of patients who may more benefit from PC, and target them with effective interventions. Our cross-sectional studies indicated the beneficial effects of positive expectations  in cancer patients , 22, whiGiven the importance of multi-factorial QoL in cancer and the dearth of research on longitudinal outcomes associated with PM and positive expectations, a greater understanding of psychological distress and SWB is warranted to help tailor the intervention of short-term PC. Given shifting trends of medical model in China, psycho-spiritual issues have attracted more and more attention in the field of palliative medicine. The current study adopted a prospective design to explore the relationship of PM and positive expectations with depression, anxiety and SWB in terminally ill cancer patients during the first week of admission to a PC unit. The 1-week period was chosen because the length of stay normally cannot exceed 2 weeks in the Chinese 3-Grade A hospitals.The prospective study was conducted of consecutive inpatients admitted to Shengjing Hospital of China Medical University between July 2019 and October 2020. Patients were recruited at the Hospice Ward as part of a larger study on transitional PC in terminal cancer patients. Eligible patients were at least 18 years of age and had a confirmed diagnosis of solid cancer. Other eligibility criteria were that patients had a life expectancy < 6 months at the time of admission and provided responses to study instruments with clear consciousness. Exclusion criteria were that patients had (1) concomitant psychiatric disorders, (2) psychotropic drug usage within 7 days before admission, (3) drug or alcohol dependence, and (4) HIV-positive. Eligible patients were identified through chart review and discussion with physicians.All patients provided informed written consent prior to participation. Demographic information and medical history were obtained by research assistant through medical record review. Participants were asked to complete the psychometric instruments  both on admission and one week after admission. About the interview schedule in detail, given the declining health and functions, patients decided themselves when they were available for interview, and thus our sample in stable condition finished the questionnaires. Because optimism and GSE are dispositional traits, participants completed the related scales at the time of admission. Based on each collection of valid questionnaires, enteral nutritional powder  was given to patients as material incentives. The study was approved by the Committee on Human Experimentation of China Medical University  and complied with the 1964 Helsinki Declaration and its later amendments.Patients were mainly referred to the Hospice Ward by their medical, surgical, or radiation oncologists. They were under active care focused on physical symptoms, provided by a medical team of physicians and nurses. PM mainly included pharmacological strategies , which were endorsed and promoted by WHO in the now-famous ‘analgesic ladder’ for managing cancer pain properly. Patients in this ward are usually seen over an average of one to two visits per day by a board-certified physician with a focus on pain and non-pain symptom management and nutrition support. PC nurses mainly provide routine cancer care. Due to staffing issues, fewer social workers and psychologists consult with patients as needed.Demographic variables including age, gender, marital status, and education were collected at admission. Cancer type, diagnosis disclose, first or subsequent visit, Karnofsky Performance Scale (KPS) and Barthel Index were determined by medical chart review.The Functional Assessment of Chronic Illness Therapy-Spiritual Well-being (FACIT-Sp) consists of 12 items measuring SWB with 3 empirically validated subscales of 4 items: meaning, peace, and faith . ParticiThe HADS is a 14-item measure of depressive and anxiety symptoms . HADS coCancer pain was assessed by the Numerical Rating Scales (NRS), which is one of the frequently used tools for assessing pain severity , 17. PatThe Life Orientation Scale-Revised (LOT-R) is a 10-item measure of dispositional optimism, which comprises 6 items (3 positively worded and 3 negatively worded items) and 4 filler items . Each itThe General Self-Efficacy Scale (GSES) was employed to assess GSE , 22, whit-test evaluated difference in pain, depression, anxiety and FACIT-Sp subscales between the two groups of dichotomized variables at each assessment time point. Paired samples t-test assessed changes in pain, depression, anxiety and FACIT-Sp subscales between the two assessment time points for each group. The repeated designed analysis of variance (ANOVA) with one between-subject factor “group” and one within-subject factor “time” were used to explore the association of PM and positive expectations with depression, anxiety and SWB. Unstandardized simple slopes were probed and plotted to visualize the interaction term of group and time. The Statistical Package for the Social Sciences  was used to perform the statistical analyses, with two-tailed probability value of < 0.05 considered to be statistically significant.Descriptive statistics were used to summarize participants characteristics and study variables. To dichotomize our sample due to degrees of optimism and GSE, we used the median scores of the distributions as the cut-off criteria . Based oAs shown in Fig. p < 0.001) at admission. One week after admission, NRS scores were significantly lower in the relieved group (p = 0.032). Depression, anxiety and pain were significantly higher in the low optimism group, and the three subscales of FACIT-Sp were significantly higher in the high optimism group at admission. Similar results were observed one week later, except for peace (p = 0.112) and pain (p = 0.063). Additionally, the three subscales of FACIT-Sp were significantly higher in the high GSE group at admission. One week after admission, only meaning scores were significantly higher in the high GSE group (p = 0.036).Table p < 0.05), but the linear trend was not significant in the not relieved group. A significant decline in meaning and peace was observed in the high optimism group, and a significant improvement was reported by the low optimism group one week later. In addition, a significant increase in faith was reported by the low GSE group one week after admission (p = 0.022).Table p < 0.05). For faith domain, there was a significant group × time interaction effect detected, indicating that the group effect of PM (p = 0.013), optimism (p = 0.003) and GSE (p = 0.018) on faith was dependent on time. Interaction of pain/optimism and time was significantly associated with depression  or peace .We used a repeated designed ANOVA to evaluate the association of PM and positive expectations with depression, anxiety and SWB. Table p = 0.174) and GSE (p = 0.295) , while patients reported a significant decline in peace in the high group (p = 0.01).In the pain relieved group, depression was significantly reduced one week after admission, while the change of depression was not significant in the not relieved group see Fig. . Figure Our findings should be interpreted with caution given the restrictions during COVID-19. Several studies found that the limited interaction between patients and family members is one of major challenges in Chinese PC units during COVID-19 , 29. Becp = 0.024), but depression, anxiety and SWB did not change significantly during 1-week period (results of t test not shown). Our previous meta-analysis found that PC was largely effective to relieve pain in Chinese adults with cancer [Cancer pain diminished significantly in our sample receiving PC for one week (t = 2.303, h cancer . Research cancer , 30. MorFor depression scores, there was a statistically significant PM group × time interaction effect. Lee et al. found the similar relationship between depression and PM in advanced cancer patients . Recent The most important findings were that the group effect of PM, optimism and GSE on faith was dependent on time, and the different linear trend of faith was indicated in the Fig. For each group of positive expectations, similar linear trend was observed in the faith see Fig. B C. PossWe also found the relationship of optimism with peace. Peace can be experienced when an individual has reached acceptance of a particular life challenge and pursues meaningful goals . ConsideA better understanding of depression and SWB may be very important for effective cancer care in the palliative settings. Psycho-spiritual care should be an essential element of short-term PC for terminally ill cancer patients. For instance, in addition to pain relief, PC nurses should recognize the improvement in depression and SWB underlying effective PM. Additionally, amelioration in cancer pain may also be associated with improved SWB in the low group of positive expectations. On the other hand, optimism may be the new target for spirituality-related intervention research. PC professionals should pay more attention to providing targeted cancer care for patients with low optimism, which may be beneficial in increasing peace during short-term PC.The present findings should be contemplated within the context of the study’s limitations. First, observational design precluded drawing conclusions regarding causality. For instance, PM was associated with over-time changes in depression, but the opposite conclusion that depression predicted subsequent effect of pain control may be also true. The reciprocal pain-depression relationship is evidenced by their clinical presentations and anatomic regions in the brain . Second,The present study furthered the understanding of depression and SWB in terminally ill cancer patients receiving short-term PC. PM was associated with an improvement of depression and faith. There was a significant relationship between positive expectations and faith. Moreover, interaction of optimism × time was significantly associated with peace. More effective PM may improve depression and SWB among terminal cancer patients. For peace domain of SWB, our findings have implications for screening patients with low optimism who may get more benefit from the short-term PC.


There were two patients who had recurrence of ONP and seven patients who had adverse events. According to our study, repeated GONB can reduce symptom severity in patients with ONP. Therefore, it appears that GONB can be considered a multimodal management method for ONP.Ocular neuropathic pain (ONP) has various etiologies, and patients have various symptoms. The clinical management of patients with ONP has been debated. We aimed to evaluate the effect of repeated greater occipital nerve block (GONB) on ONP based on convergence in the trigeminocervical complex. In this single-center retrospective study, the medical records of 204 patients who were referred to the pain clinic by the ophthalmology department of our hospital and subsequently underwent repeated GONB for chronic ONP between January 2008 and February 2022 were analyzed. They received GONB every two weeks, up to 10 times. Symptoms of ONP were divided into five categories: eye pain, dysesthesias/allodynia, non-eye pain, visual disturbance, and tearing. The primary outcome of this study was the pain relief scale (PRS) score after repeated injections. The differences and magnitude of decrease in the overall pain relief scale score were statistically significant (estimate = −0.55,  Some have defined ocular neuropathic pain (ONP) as ocular pain caused by a primary lesion or dysfunction of the somatosensory system . ONP is The pathophysiology of ONP is related to the complex interplay between the central and peripheral nervous systems but remains unclear . Ocular Patient symptoms and objective findings are often difficult to reconcile. To treat ONP, a multimodal approach may be beneficial, including the use of ocular surface protection, anti-inflammatory agents, and systemic pharmacotherapy, including tricyclic antidepressants and anticonvulsants ,13. HoweGiven the neuroanatomical and functional structure of the TCC and taking into account that GONB is effective in the treatment of several headache disorders ,15,16,17This study is a single-center retrospective observational study. In this study, we analyzed the medical records of 204 patients who were referred to the pain clinic and subsequently underwent repeated GONB for chronic ONP (>3 months) between January 2008 and February 2022. Approval from the Dong-A University Hospital Institutional Review Board and Research Ethics Committee of Hospital was obtained on 4 May 2022. We registered this study in the Clinical Research Information Service of the Republic of Korea on 26 October 2022. All methods were implemented in accordance with relevant guidelines and regulations in the Declaration of Helsinki.In this single center retrospective study, the data of 204 patients who had received GONB for ONP included sex, age, history of ONP (months), surgical history and trauma, and underlying disease. The underlying cause of ocular pain was first identified through sufficient evaluation, including slit-lamp examination, and then existing ocular surface diseases and nociceptive pain were managed. Ocular surface nociceptive pain management includes lifestyle changes, medications, and adjuvant therapies. Patients were treated with warm compresses and received instruction on eyelid hygiene, nutrition, stress management, and lifestyle changes. Medications for ocular surface pain included artificial tears and lubrication, topical nonsteroidal anti-inflammatory drugs and steroids, autologous serum, and topical cyclosporine A. Adjuvant therapies such as taping eyelids while sleeping, scleral contact lenses, bandage contact lenses, and punctal plugging were applied if needed. Patients whose symptoms persisted even after the underlying causes were conservatively treated for at least 3 months consulted our pain medical center and underwent repeated GONB. The exclusion criteria were as follows: contraindications to occipital nerve block .Before injection, the patient was placed in a prone position, and a pillow was placed on the chest for neck flexion. A scrub hair cap was used to secure the hair, and the patient’s clothes were taped to expose the neck and occipital area. If no infection or skin lesion was found after the scalp was checked, the hair and scalp were cleaned and prepared using standard skin cleaning and preparation protocols. The hair was not shaved. After preparation of 5 mL of 0.4% lidocaine solution , the needle was changed to a 6 cm 23 gauge needle . Using Trescot’s approach for GONB, the practitioner identified the injection site by placing the thumb at the foramen magnum and the index finger at the conjoined tendon attachment, and identified the injection site at the base of the skull using the middle finger . The neePatients were asked to visit the pain clinic once every two weeks and received GONB up to 10 times. GONB was discontinued if there was no improvement following 3 or more continuous treatments or if the patient refused to continue. Patients continued their previous ophthalmologic treatments while receiving GONB.ONP can be expressed as various subjective symptoms. In this study, symptoms of ONP were divided into 5 categories: eye pain, dysesthesias/allodynia, non-eye pain, visual disturbance, and tearing. Eye pain was described as stinging, dullness, sharpness, burning, soreness, and irritation. Dysesthesias/allodynia was described as dryness, grittiness, itching, and vague sensation of pressure. Non-eye pain included pain located in the periorbital, frontal, temporal, and occipital areas and cheeks. Visual disturbance and tearing were also included in this study. They occur when some axons from the trigeminal nucleus travel to regions in the brain to adjust lacrimation  and blinking  .The primary outcome of this study was the overall pain relief scale (PRS) score after repeated injections. The secondary outcomes were the PRS scores for eye pain, dysesthesias/allodynia, non-eye pain, visual disturbance and tearing, and adverse events. The severity of initial clinical symptoms was measured by the numerical rating scale (NRS), where 0 points indicated no pain and 10 indicated the worst pain imaginable. The post-treatment outcomes were measured using the PRS at the next visit every 2 weeks. For the PRS assessment, the patients were instructed to consider the pain of the first visit as the baseline (10) and then indicate whether pain was alleviated by reporting a lower score . All patIn addition, the baseline patient characteristics, clinical symptoms, and adverse events were compared and analyzed.The data are presented as frequencies with percentages for categorical variables and means ± standard deviations and medians  for continuous variables. Considering the unbalanced nature of the repeated measured data, a linear mixed model (LMM) with random intercepts was used to fit a model. The LMM model included repeated measures of numeric variables as dependent variables; group, time, and group × time interaction as fixed effects; and subject as a random effect. To avoid making any assumptions about the covariance structure, we used an unstructured covariance matrix that was allowed to differ across groups for the LMM analysis, and the Bonferroni procedure was applied in post hoc analyses. For graphical visualization, an error bar chart and spaghetti plot with an estimated line according to an LMM are displayed.© 2022 The R Foundation for Statistical Computing). p values less than 0.05 were considered statistically significant.All statistical analyses were carried out using SPSS 26.0  and R version 4.1.3 (Copyrightp < 0.001). The estimate represents the expected change per unit of treatment. The PRS score for eye pain also significantly decreased during the assessment time points . In addition, we found significant decreases, such as −0.52 in the PRS score for dysesthesia/allodynia (p < 0.001), −0.39 for non-eye pain (p < 0.001), −0.38 for visual disturbance (p < 0.001), and −0.52 for tearing (p < 0.001). Adverse events, including the recurrence of ONP, are presented in The patients’ demographics and clinical characteristics are presented in p < 0.001)  . This suIn this study, patients had ONP for more than three months. Chronic pain usually has a neuropathic component and requires multimodal pain treatment. Several treatments, including alpha-2 adrenergic agonists, opioids, serotonergic drugs, and gabapentin, modulate neuropathic pain by affecting the trigeminal nucleus to diminish excitation or increase inhibition pathways . NonpharThis report summarizes the authors’ more than 14 years of experience in treating ONP with greater occipital nerve blocks. This study describes the clinical features of ONP, injection composition, and injection technique. The authors previously treated a patient with occipital pain with GONB, and the patient said that existing chronic eye pain had disappeared. Some headaches that originated from trigeminal activation were relieved in severity after GONB, and this response could be explained only by convergence between the trigeminal nerve and upper cervical nerve . ElectroWe only administered a relatively low concentration of lidocaine to affect pain modulation in the TCC. According to previous studies, 0.5% lidocaine can produce sensory blockade, and 0.25% lidocaine can be used for sympathetic blockade . TherefoAdditionally, as secondary sensory neurons in the TNC can receive ipsilateral and contralateral inputs from the GON, we performed GONB on both sides even if the patient reported pain on only one side because a blockade on one side could affect the contralateral side .The present study has several limitations. First, since no widely accepted quantitative assessment of ONP exists in the literature, we had no choice but to rely on the subjective evaluation of patients, the NRS and the PRS. However, according to the Assessment Committee of the Neuropathic Pain Special Interest Group guidelines on neuropathic pain assessment, the intensity of pain should be assessed with the NRS, and the PRS is one of the tools recommended for assessing the effect of treatment for neuropathic pain . Second,This study supports the hypothesis that a series of GONBs may reduce the PRS score and may have therapeutic value in the treatment of patients with ONP. Repeated GONB can be considered a multimodal ONP management method. A multicenter study with a control group will be needed for further evaluation of GONB’s effect for ONP.


The purpose of this study was to describe the diagnostic performance of the Neuropathic Pain Subscale of McGill [NP-MPQ (SF-2)] and the Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaire in differentiating people with neuropathic chronic pain post total joint arthroplasty (TJA).This study was a survey of a cohort of individuals who had undergone primary, unilateral total knee, or hip joint arthroplasty. The questionnaires were administered by mail. The time interval from operation to the completion of the postal survey varied from 1.5 to 3.5 years post-surgery. Receiver Operating Characteristic (ROC) analysis was used to assess the overall diagnostic power and determine the optimal threshold value of the NP-MPQ (SF-2) in identification of neuropathic pain.S-LANSS identified 19 subjects (28%) as having neuropathic pain (NP), while NP-MPQ (SF-2) subscale identified 29 (43%). When using the S-LANSS as the reference standard, a Receiver Operating Characteristic (ROC) analysis for NP-MPQ (SF-2) had an area under the curve of 0.89 ; a cut off score of 0.91 NP-MPQ (SF-2) maximized sensitivity (89.5%) and specificity (75.0%). Correlation between the measures was moderate .These finding suggest some conceptual overlap but some variability in diagnosis of NP which may relate to scale-tapping into different dimensions of the pain experience, or the different scoring metrics.The online version contains supplementary material available at 10.1186/s40945-023-00164-7. Total joint arthroplasty (TJA) procedures are a safe and cost-effective treatment for those with end stage osteoarthritis (OA) , 2. EffeDetection of NP is challenging, in part due to the lack of indication of causality  and goodTo assist with classification, screening tools, such as the Self-Administered Leeds.Assessment of Neuropathic Signs and Symptoms (S–LANSS) scale, have been designed to differentiate between NP and non-NP . DiagnosThe latest reports indicate that a considerable number of patients with chronic pain experience a combination of nociceptive and neuropathic pain features , 13, 14.The purpose of this study was to evaluate the ability of the NP Subscale of McGill of the Short Form Version 2 (NP-MPQ (SF-2)) questionnaire to identify NP in individuals with chronic pain post TJA.Our main objective was to evaluate the discriminatory power and diagnostic accuracy of the NP-MPQ (SF-2) subscale in classification of NP in individuals with chronic pain post TJA by examining rates of classification of NP, and by comparing the NP-MPQ (SF-2) to the S-LANSS as the reference standard. In addition, the association between the raw scores from the two measures [S-LANSS and NP-MPQ (SF-2)] was described.This study was a survey of a cohort of individuals who had undergone primary, unilateral total knee, or hip joint arthroplasty. The project received approval from the human research ethics boards from the institution and the University.The subjects for the study were selected from the total joint arthroplasty (TJA) registry database acquired between 2007 and 2009 as part of an ongoing study. This registry, which includes demographics and outcome measure scores (self-reported pain and function  is a tool designed to provide information about the overall intensity as well as the quality of pain (sensory and affective). It consists of 22 experiences and descriptors of pain (18 sensory and 4 affective). The pain scores are derived from the sum of the intensity rating on a 10-point intensity scale . Both subscales and total scores are calculated by taking a mean of all the item ratings . This top < 0.001) with Harris Hip Scores [The Oxford Questionnaires are joint specific twelve-item numeric rating scales (1–5) developed for assessment of patient’s perception of pain and disability in those undergoing total hip [Oxford Hip Score (OHS)] or knee [Oxford Knee Score (OKS)] replacement , 20. Scop Scores . Similarp Scores . Good rep Scores .The collected data from the postal survey were analyzed using the Statistical Package for the Social Sciences (SPSS) software version 19 . Double data entries were performed by random inspection of the paper surveys against the database entry in SPSS . To summarize the demographics of the sample population, univariate descriptive statistics were performed for all the analyzed variables.n = 148) minus the number returned with an incorrect address (n = 4), minus the number returned with a statement that the addressee was unable to complete it because of death or incapacity (n = 9) and minus the ineligible participants (n = 6) p < 0.05.Differences between the groups of TJA with NP vs. Non-NP were deemed to be significant at Seventy-five patients completed the survey (58%)  scored ≥ 12 and were classified as having neuropathic pain. When the NP-MPQ (SF-2) questionnaire was used, 29 subjects (43%) scored ≥ 0.91 and were classified as having NP. Mean (SD) score on the S-LANSS was 8.18 (7.69) and 1.39 (1.81) on the NP-MPQ (SF-2) subscale.The Area under the curve (AUC) for the ROC curve comparing different cutoffs of the NP-MPQ SF-2) yielded a good AUC = 0.89 . The optimal NP-MPQ (SF-2) subscale cut-off score , indicating a moderate association between scores on the two measures.This study found that the NP-MPQ (SF-2) subscale demonstrated good diagnostic accuracy (AUC = 0.89) in classification of NP vs. non-NP in patients with chronic pain patients post-total joint arthroplasty when the S-LANNS was regarded as the “reference standard”. In the absence of gold standard, an imperfect but accepted reference standard is typically used when validating newer measures . Given tScreening tools such as S-LANSS have been recommended for identification of NP especially for clinicians . HoweverWe chose a ROC analysis to evaluate the sensitivity and specificity of the NP-MPQ (SF-2) because it is considered a robust analysis, with the ability to evaluate accuracy across a range of different scores . This meEven though our primary interest in this study was the extent to which the NP-MPQ (SF-2) subscale classified patients in a similar way to the S-LANSS; the association between the two scales was explored. We found a moderate correlation between these two measures, which may reflect the difference in items and scoring. Moderate association between the tool scores supports a shared construct, but the differences in classification should be expected.The findings of this study should consider some limitations. One of our main limitations is that there is no gold standard, and that we used an accepted but imperfect reference standard, the S-LANSS .n = 1143), we focused on the smaller subset of patients who had worsening pain following arthroplasty (n = 148); and then conducted a follow-up survey that had a 53% response rate. A larger sample would have provided a more precise and stable ROC analysis. Finally, these data were acquired via mail in survey and were dependent on the accuracy of the responses provided, and we did not have a clinician examination as a reference standard.Although we started with a large pool of data  scales respectively] in the group of chronic pain sufferers. Therefore, better tracking and early diagnosis is an important issue for people with OA.Although this study focused on the classification of postoperative patients, a useful extension of this work would be to test the ability of the questionnaire to classify patients as having (or not) neuropathic features prior to surgery. In summary, our study suggests that the NP-MPQ (SF-2) may be useful in monitoring patients with OA and detecting the subgroup with NP.Additional file 1.


Methods: Nuclear magnetic resonance spectroscopy was used for analysis of the CSF metabolome. Multivariate data analysis by projection discriminant analysis (OPLS-DA) was used to separate information from noise and minimize the multiple testing problem. Results: The significant OPLS-DA model identified 26 features out of 215 as important for group separation . Twenty-one out of twenty-six features were statistically significant when comparing the two groups by univariate statistics and remained significant at a false discovery rate of 10%. For six out of the top ten metabolite features, the features were absent in all healthy controls. However, these features were related to medication, mainly acetaminophen (=paracetamol), and not to pathophysiological processes. Conclusion: CSF metabolomics was a sensitive method to detect ongoing analgesic medication, especially acetaminophen.Background: Cerebrospinal fluid (CSF) can reasonably be hypothesized to mirror central nervous system pathophysiology in chronic pain conditions. Metabolites are small organic molecules with a low molecular weight. They are the downstream products of genes, transcripts and enzyme functions, and their levels can mirror diseased metabolic pathways. The aim of this metabolomic study was to compare the CSF of patients with chronic neuropathic pain ( To better understand the pathophysiology of chronic pain and bridge the translational gap between animals and humans ,2,3, cerNeuropathic pain is caused by a lesion or disease of the somatosensory nervous system . AdvanceUntargeted omics methods, such as proteomics  or metabNuclear magnetic resonance (NMR) spectroscopy is a useful technique for the metabolomic study of different diseases including chronic pain conditions, such as neuropathic pain or fibromyalgia. NMR enables the detection of several hundred small molecules in body fluids such as CSF, blood or urine ,17,18,19The aim of this explorative, observational, cross-sectional study was to investigate the CNS pathophysiology of neuropathic pain by comparing the CSF metabolome of patients with healthy controls, using multivariate data analysis by projection (MVDA) to analyze the correlation structure of the material, thereby separating information from noise and minimizing the multiple testing problem ,21. We an = 16) were included in the study. All patients were recruited by convenience sampling from an open-label clinical trial evaluating the effect of bolus injections of ziconotide [Twelve healthy individuals were recruited as healthy controls, as described previously . Chronicconotide . ImmediaInclusion criteria were as follows: patient at least 18 years of age; chronic peripheral neuropathic pain (6 months or more) caused by trauma or surgery for whom conventional pharmacological treatment had failed; average visual analogue scale (VAS) pain intensity last week of 40 mm or more; patient capable of judgement, meaning the patient was able to comprehend information about the drug, its administration and evaluation of efficacy and side effects; signed informed consent. Exclusion criteria were: intrathecal chemotherapy; pregnant or lactating women; limited life expectancy; intracranial hypertension; known liver or kidney disease characterized by serum transaminases, total bilirubin, alkaline phosphatase or creatinine > 1.2 times above the upper normal limit; advanced cardiopulmonary disease, ongoing infection in the lumbar area , coagulopathy; history of psychiatric disorder; allergy to ziconotide or any of the excipients in the ziconotide vial; participation in another clinical trial during the last 30 days. n = 4), polymyalgia rheumatica (n = 1), psoriasis (n = 2), fibromyalgia (n = 1), diabetes (n = 1), mild angina (n = 2), panic disorder (n = 1), mild obstructive lung disease (n = 1), vertebral compressions (n = 1), orthostatism (n = 1), peptic ulcer (n = 1), dyspepsia (n = 1) and anemia (n = 1). The use of concomitant medication including analgesics was also reported. Four of the patients no longer used any pain medication at inclusion, while three patients had a single analgesic and nine patients used two analgesics or more. The distribution of the usage of the different medications were paracetamol (n = 7), non-steroidal anti-inflammatory drugs (NSAID) (n = 2), opioids (n = 9), gabapentinoids (n = 7) and antidepressants (n = 6). As reported in previously published papers ,16,22,23Participants answered questionnaires about pain and their state of health. We registered basic background information such as sex, age, weight, length, pain duration (measured in months), average pain intensity (VAS), location of pain, characterization of pain , impact of physical activity on pain, concomitant diseases and ongoing medication.® laboratory, Linköping University Hospital, centrifuged, divided in aliquots and stored at −70 °C. A lumbar puncture was performed by an experienced anesthesiologist (EB) with a 27 GA pencil-point Whitacre needle , and a 10 mL sample of CSF was drawn in five numbered syringes of 2 mL each. Each sample was immediately cooled on ice, transported to the Painomics2PO4, 580 µM TSP-d4, NaN3, D2O, pH 7.4 and transferred to 3 mm NMR tubes. The samples were analyzed at the Swedish Nuclear Magnetic Resonance (NMR) Centre in Gothenburg using an Oxford 800 Mhz magnet equipped with a Bruker Avance III HD console, 3 mm TCI cryoprobe and a cooled Sample Jet auto sampler , as described previously [CSF samples was mixed (5:1) with phosphate buffer solution containing 1.5 M KHeviously . Generateviously  were usep-value ≤ 0.05 was considered significant. To handle the multiple testing problem, a false discovery rate (FDR) at the 10% level was applied using the Benjamini–Hochberg procedure [IBM SPSS Statistics  was used for bivariate analyses. Unless stated otherwise, data are presented as median (25th–75th percentile). Mann–Whitney U test and Chi square test were used as appropriate for group comparisons. Spearman’s rho was calculated for bivariate correlations. A 2 (goodness of fit), Q2 (goodness of prediction) and cross validated analysis of variance (CV-ANOVA) which provides a familiar metric for the model as a whole . The differences between R2 and Q2 should not be greater than 0.3, otherwise suggesting overfitting. The variable influence on projection (VIP) indicates the relevance of the group of X-variables that best explain Y. A backward variable elimination strategy was applied [2 stopped increasing, indicating an optimal model. We also used p(corr) which is the loading of each variable scaled as a correlation coefficient (range from −1 to +1). VIP ≥ 1.0, absolute p(corr) ≥ 0.6 and CV-ANOVA ≤ 0.05 were considered as significant. The analysis and the presented parameters are in accordance with the guidelines presented by Wheelock and Wheelock [Multivariate data analysis (MVDA) by projection was performed on metabolomics data with SIMCA-P+ . First, principal component analysis (PCA) was used for quality control and to check for multivariate outliers (strong outliers defined as Hotelling’s T2 >> T2Crit (95%) and moderate outliers as DModX > 2 *DCrit). Then, we effectuated orthogonal partial least squares—discriminant analysis (OPLS-DA)—whereby group belonging was used as the outcome variable (Y-variable) and the metabolic features as predictors (X-variables). OPLS was used instead of OPLS-DA when non-categorical variables were used as Y-variables ). The parameters used for evaluation of the OPLS-DA and OPLS models were R applied , wherebyWheelock . The regional ethics committee in Linköping approved the study (Dnr M136-06 and Dnr 2012/94-32). The study was conducted in accordance with the Helsinki Declaration. After verbal and written information, written informed consent was obtained from all the participants. p = 0.249). Patients were older than controls (57.5 (52.0–69.0) vs. 51.0 (27.5–54.5) years, p = 0.005). Patients also had a tendency towards higher BMI (26.5 (23.3–29.7) vs. 23.9 (22.0–25.4) kg/m2, p = 0.072). VAS pain intensity in patients was 72 (59–82) mm and pain duration 59 (36–120) months. The patient group consisted of 36% females and the healthy control group of 58% females; the difference between groups was not statistically significant . Two patients were identified as strong outliers and were therefore excluded from further analyses. As shown in the First, an unsupervised PCA model was computed for overview and quality control of the data using 444 metabolomic features as X-variables , 444 X-variables, R2 = 0.74, Q2 = 0.30 and p = 0.101 by CV-ANOVA, a backward variable elimination strategy was applied, resulting in a final OPLS-DA model with n = 26, 2 components , 215 X-variables, R2 = 0.70, Q2 = 0.42, p = 0.017 by CV-ANOVA. The score plot of the model is depicted in all healthy controls. The six features only identified in patients were 26_C, 41_C, 40_C, 29_C, 30_C and 36_C. After an initial OPLS-DA model with n = 14). A bivariate correlation matrix for the top 10 features is presented in The top 10 features of n = 26, 1 component, 197 X-variables, R2 = 0.29, Q2 = 0.18, p = 0.10 by CV-ANOVA).Then, the features tabulated in n = 14), it was not possible to regress VAS by OPLS using the 444 features as in the OPLS-DA model above as X-variables. Likewise, a non-significant model resulted when regressing pain duration by OPLS  with the same 444 features. In patients  values for the 12 features listed in Additionally, to investigate a potential confounding effect of age (which different significantly between groups) on the main OPLS-DA results as per the above, an OPLS model with age as outcome variable (Y-variable) was computed using the 215 features of the final OPLS-DA model as X-variables. The initial model had n = 14, R2 = 0.37, Q2 = 0.20 and p = 0.29 by CV-ANOVA. Notwithstanding the fact that the model was statistically non-significant, we still scrutinized the absolute p(corr) values for the eight features listed in p = 0.125, see Finally, in a manner similar to age, we also investigated a potential confounding effect of sex on the main OPLS-DA results. After the backward elimination procedure, the final model with sex as Y variable had 175 X-variables, Unexpectedly, the main finding of the study was that CSF metabolomics was a sensitive method to detect ongoing analgesic medication, especially acetaminophen , in chronic pain patients. We wish to highlight three aspects of this “negative” result. First, our findings are a reminder of the importance of collecting information about concomitant medication when conducting pain biomarker studies in general, and perhaps in particular when studying CSF. In correlative studies such as this one, several confounding factors may be at work simultaneously. Ideally, controls should be age-, BMI- and sex-matched. However, this is especially difficult in CSF studies, given the difficulty in obtaining CSF in contrast to blood or saliva. Other possible confounders could be concomitant diseases or concomitant medication—and the latter seems to be the case in the present study. k, where k is the number of comparisons [Second, although in a sense disappointing, our results clearly demonstrate the power of CSF metabolomics combined with MVDA in identifying real and relevant group differences for central nervous system processes. Given that modern omics studies can generate a vast amount of data (meaning that the number of variables can by far exceed the number of participants), the omics field actualizes the multiple testing problem—hence, the potential accusation of being on a fishing expedition, also known as data dredging or p-hacking. Indeed, the phenomenon of alpha inflation means that if two groups are compared two times, the risk of getting at least one significant result due to chance is not 5%, but almost 10%. If instead 20 comparisons are made, the probability increases to 64%; this phenomenon is captured by the formula 1 − 0.95parisons ,28. If 1parisons . MVDA isperipherally acting analgesic [Third, our results are in line with the view that acetaminophen acts in the CNS. Until quite recently, at least in Sweden, the standard textbook teaching was that acetaminophen is a nalgesic . After mnalgesic . In the nalgesic . Alternanalgesic . Even ifThere are few NMR metabolomics studies on neuropathic pain in general, and on CSF in particular. We have previously reported interesting NMR metabolomic findings in blood from the same patients with chronic neuropathic pain . In thatclinical biomarker candidates. If that had been our purpose, dozens or perhaps hundreds of samples would have been necessary. Instead, using the terminology proposed by Pavlou et al., this was an early discovery phase, pre-clinical exploratory study [The low number of participants in this observational study is an obvious limitation. However, it is important to understand that studies such as the present one are not intended to generate ry study . For sucry study . AnotherWe have shown that the combination of CSF metabolomics and MVDA is a powerful tool to detect ongoing molecular events in the central nervous system. We were unable to detect a disease signal in patients with chronic neuropathic pain vs. healthy controls, centrally acting medication overshadowing the putative pathophysiologically interesting findings. These negative results notwithstanding, CSF metabolomics still have a role to play when investigating the mechanisms of chronic pain; however, our study shows that the power of an investigative method can also be its problem.


To obtain data about the evaluation of thyroid nodules (TNs) in the northeastern of the State of São Paulo, compared by health care type, and measure the performance of cytology as a screening test for thyroid cancer (TC).We collected data of 597 patients treated in the Brazilian public health care system (SUS), supplementary health (SH) and in private health system (PHS) in 2014. A total of 803 TNs were aspirated, and 125 patients underwent surgery.The distribution of all cytologic results according to the Bethesda system was: I, 135 (16.8%); II, 475 (59.2%); III, 107 (13.3%); IV, 32 (4.0%); V, 20 (2.5%); VI, 34 (4.2%). The time between cytologic analysis and surgery was longer in the SUS than in the SH for TNs in general (p < 0.001) and for TNs with Bethesda V and VI cytology (p = 0.01). The sizes of the TNs and resected malignant TNs was larger in the SUS than in the SH . The number of PHS surgeries was too small and was not compared. The prevalence of TC was 9.2% and 23.6% of them were treated in the SUS. Cytology showed a 93.6% sensitivity, 95.8% specificity, and 94.7% accuracy when Bethesda III and IV were excluded.Cytology was a good screening test for TC categories Bethesda II, V, and VI. The differences between the SUS and SH indicate a need for improved access to consultations and specialized tests in the SUS. Thyroid nodules (TNs) represent a common clinical scenario and are detected in approximately 5% of women and 1% of men on cervical palpation .The evaluation of patients with TNs begins with clinical assessment followed by laboratory tests including serum TSH measurement, cervical US, cytologic analysis, and, eventually, molecular tests ,3,4Cervical US is an essential test for the evaluation of TNs since it is accessible, noninvasive, and cost-effective . Since Cytological analysis is the method with the greatest accuracy and cost-effectiveness for the assessment of TNs , and thThyroid cancer (TC) can occur in 5 to 15% of all TNs . The twth and 13th cause of cancer in women and men, respectively  in relation to the types of health care, comparing the SUS, the SH and the PHS, assess the performance of cytologic analysis as a screening test for TC and determine the prevalence of TC in the study sample.The Regional Health Department of Franca – DRS VIII, located in the northeastern region of the State of São Paulo, covers 22 municipalities with a population of 649,607, according to the 2010 census of the Brazilian Institute of Geography and Statistics (IBGE) . The daData of patients with TNs submitted to FNAB from January 1, 2014, through December 31, 2014, were collected at the three pathology services located in the municipality of Franca. These services handle all cytological and histological analyses of DRS VIII, which are performed by the same pathologists.post hoctest, Kruskal-Wallis non-parametric test and Dunnpost hoctest. Categorical variables were compared using the Chi-Square test. Statistical analysis of the data was conducted with the use of SPSS software, version 22.0 , and the level of significance was set at p < 0.05.Descriptive analyses consisted of mean, standard deviation, median and range for numerical variables, and percentage and frequency for categorical variables. Numerical variables were compared using the analysis of variance (ANOVA) with BonferroniThe performance of the cytologic analysis was evaluated with the calculation of sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) . BethesOverall, 210 nodules were identified in the pathological specimens of the 125 surgical patients. In 162 of these nodules, we were able to verify the cytologic report against the pathology report to estimate the risk of malignancy according to the 2017 Bethesda system . We excFundação Santa Casa de Misericórdiaof Franca with CAAE (Certificado de Apresentação para Apreciação Ética) number: 59 358416.2.0000.5438. Waiving of informed consent was requested.The study was approved by the Research Ethics Committee ofThe study sample consisted of 597 patients, of whom 536 (89.8%) were females and 61 (10.2%) were males. The mean age was 52.5 ± 15.6 years, and the median age was 53 (13–89) years. The mean age was 52.2 ± 15.3 years among females and 55.6 ± 18 years among males. Overall, 229 (38.3%) of the study sample underwent FNAB in the SUS, 312 (52.3%) in the SH, and 56 (9.4%) in the PHS, including 538 (90.1%) who underwent US-guided FNAB and 46 (7.7%) who were submitted to palpation-guided FNAB. In 13 patients (2.2%), the FNAB technique used could not be identified. The percentage of patients submitted to US-guided FNAB was 75.1% in the SUS group, 99.4% in the SH group, and 100% in the PHS group (p < 0.0001). During FNAB, only one TN was aspirated in 442 of the 597 patients (74%), while more than one nodule was aspirated in 155 (26%) patients, yielding a total of 803 cytologic results .Data on the size of the TNs could not be obtained in 215 cases (26.7%). In the remaining 588 TNs in which the size was known, the mean size was 1.8 ± 1.2 cm, and the median size was 1.5 cm (0.3 – 8 cm). A total of 111 (18.9%) of these nodules were smaller than 1 cm. The percentage of TNs of known size was lower in the SUS (27.3%) compared with the SH (92.6%) and PHS . The mean size of the evaluated TNs was significantly larger in the SUS compared with the SH . Compared with the SUS and SH, the mean size of the TNs in the PHS (2.0 ± 1.2 cm) was intermediate and not significantly different. The percentage of TNs measuring less than 1 cm was comparable between groups (p = 0.46).The percentage of Bethesda I cytologic results among patients submitted to US-guided FNAB was greater is SUS (38.3%) compared with SH (12.9%) and PHS (7.1%), p < 0.001. There was no difference between SH and PHS, p = 0.66.versus11.2% men among the surgical patients and 90% women and 10% men among the nonsurgical patients; p = 0.9) or TN size . However, the mean age of the surgical patients was significantly lower (48.6 ± 14.5 years) than that of the nonsurgical ones . The prevalence of TC in the overall cohort was 9.2%.A total of 125 patients (20.9%) underwent thyroidectomy, and TC was diagnosed in 55 of them. A comparison between the 125 patients who underwent surgery versus the 472 who did not undergo this procedure revealed no difference in the proportion of men and women  compared with those evaluated in the SH . The mean time elapsed between both procedures in the PHS group (n = 6) was 45 ± 22 days. Among patients with Bethesda V and VI cytologic results, the mean time elapsed between evaluation and surgery was also longer in the SUS group  than in the SH group . The corresponding mean time in the PHS group (n = 3) was 42 ± 24 days. The mean size of the TNs described in the pathology report was larger in the SUS group  than in the SH group . The corresponding mean size in the PHS group (n = 6) was 1.1 ± 0.7 cm. Eleven patients with benign pathological results for whom the size of the nodule was not available were excluded from this analysis, including 7 in the SUS group and 4 in the SH group. The size of the largest resected malignant TN was greater in the SUS group  than in the SH group . The corresponding mean size in the PHS group (n = 4) was 1.3 ± 0.8 cm.Of the 55 patients with TC, 46 (83.6%) were females and 9 (16.4%) were males. Their mean age was 46.9 ± 16.1 years and median age was 45 years (20–82 years). Histologically, the resected TCs comprised 51 (92.7%) PTCs, 3 (5.5%) minimally invasive FTCs, and 1 (1.8%) MTC. In 17 (31%) patients with PTC, the largest tumor measured ≤ 1 cm (microPTC).Among the 51 patients with PTC, the tumor was unifocal in 30 (58.8%) and multifocal in 21 (41.2%) cases. From the total of 79 PTCs resected, 48 (60.7%) were classical variants, 23 (29.1%) were follicular variants (FVPTC), 7 (8.9%) were oxyphilic variants, and 1 (1.3%) was a tall cell variant. The mean and median sizes of the PTCs, which could be analyzed in 77 tumors, were 1.3 ± 1.1 cm and 1 cm (0.15–5.5 cm), respectively. Among the 23 FVPTC, 7 (30.5%) were EFVPTC, 10 (43.5%) were nonencapsulated, and 6 (26%) had no description about encapsulation. The 7 EFVPTCs occurred in 4 patients and represented 7.3% of the TC cases in the study sample.The calculated performance of cytology was: sensitivity 93,6%, specificity 95,8%, accuracy 94,7%, PPV 69,5%, NPV 99,3%, LR+ 22,4 and LR- 0,06 .th edition of the American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System (AJCC/TNM) published in 2018  published in 2015 , along in 2018 , syntheIn the present study including 597 patients, the proportion of patients submitted to FNAB in the SUS and the SH  differed from the proportion of patients with SUS and SH coverage in the DRS VIII region . This inconsistency was possibly due to unequal access to consultations and specialized tests between the public and private systems and to a greater concentration of specialized physicians in the private health sector , which Of the TNs of known size evaluated in this study (n = 588), 18.9% were smaller than 1 cm. According to recent guidelines , TNs smi.e., categories in which the cytologic analysis typically has a better performance in distinguishing between benign and malignant lesions. On the other hand, 34.1% of the results were nondiagnostic (Bethesda I) or indeterminate (Bethesda III and IV). In other published series, the corresponding percentages were 32.4% , with a higher percentage of this diagnosis established in the SUS (36.7%) compared with the SH (8.4%) and PHS  groups . In lar5, with aRegarding the group of 125 patients who underwent surgery, some important differences were detected between types of health care coverage, such as time elapsed between the cytologic diagnosis and surgery, the size of the nodule that based the surgical recommendation, and the size of the malignant nodule; all these parameters were greater in the SUS compared with the SH group. This may be explained by unequal access to consultations and specialized tests in the public and private systems in Brazil and by issues involving continued medical education.The prevalence of TC in the present sample was 9.2%, which is comparable to the prevalence rates of TC reported in the literature 5–15%)  was higher than that estimated by the Bethesda classification system (0–3%), with 3 patients with PTC detected among 49 resected TNs with a Bethesda II cytology.i.e., 10–30% and 25–40%, respectively. This is an important result of the present study. Professionals involved in the care of patients with TNs should be aware of these statistics and inform them to the patients, since they may help managing decisions in terms of choosing between conservative and surgical treatment and defining the extent of the thyroidectomy.Indeterminate cytology results showed risks of malignancy of 21.9% (Bethesda III) and 25% (Bethesda IV), which are within the values estimated by the Bethesda classification system,Bethesda V and VI cytologic results had a high risk of malignancy , confirming that the surgery is indeed the most appropriate management for this TN category.In this study, cytologic analysis showed a sensitivity of 93.6%, specificity of 95.8%, and accuracy of 94.7% in the detection of TCs when Bethesda III and IV categories were excluded, and was considered a good screening test for TC. In published series, the sensitivity and specificity of the cytologic analysis range from 65–98% and 73–100%, respectively , indicating a need for management of issues such as access to consultations and specialized tests, and effective application of recent guidelines. The prevalence of TCs in the study sample was 9.2% (31% were ≤ 1 cm), and 23.6% of the TC cases were treated surgically in the SUS. The cytologic analysis showed a sensitivity of 93.6%, specificity of 95.8%, and accuracy of 94.7% in the detection of TCs when Bethesda III and IV categories were excluded, reinforcing its role as a good screening method for Bethesda II, V, and VI nodules.