Stroke patients frequently suffer from chronic limb pain, but well-suited treatment approaches have been not established so far. Transcranial direct current stimulation (tDCS) is a safe and non-invasive brain stimulation technique that alters cortical excitability, and it has been shown that motor cortex tDCS can reduce pain. Some data also suggest that spasticity may be improved by tDCS in post-stroke patients. Moreover, multiple sessions of tDCS have shown to induce neuroplastic changes with lasting beneficial effects in different neurological conditions. The aim of this pilot study was to explore the effect of multiple anodal tDCS (atDCS) sessions on upper limb pain and spasticity of stroke patients, using a within-subject, crossover, sham-controlled design. Brain damage was of similar extent in the three patients evaluated, although located in different hemispheres. The results showed a significant effect of 5 consecutive sessions of atDCS, compared to sham stimulation, on pain evaluated by the Adaptive Visual Analog Scales -AVAS-, and spasticity evaluated by the Fugl-Meyer scale. In two of the patients, pain was completely relieved and markedly reduced, respectively, only after verum tDCS. The pain improvement effect of atDCS in the third patient was considerably lower compared to the other two patients. Spasticity was significantly improved in one of the patients. The treatment was well-tolerated, and no serious adverse effects were reported. These findings suggest that multiple sessions of atDCS are a safe intervention for improving upper limb pain and spasticity in stroke patients, although the inter-individual variability is a limitation of the results. Further studies including longer follow-up periods, more representative patient samples and individualized stimulation protocols are required to demonstrate the efficacy and safety of tDCS for improving limb symptoms in these patients. Chronic limb pain and spasticity are common muscle symptoms in stroke survivors . RehabilSeveral non-invasive brain stimulation (NIBS) techniques are available with potential to induce long-term potentiation like-plasticity associated with clinical and therapeutic effects, such as transcranial magnetic stimulation (TMS)  and tranBeyond its effects on post-stroke motor function rehabilitation , some exConsidering this background, we did explore the effect of anodal tDCS (atDCS) on upper limb pain and spasticity via a multi-session protocol (5 consecutive days), in which a bilateral electrode configuration  was evaluated in chronic stroke patients using a within-subject, crossover, double-blind, sham-controlled design. Thus, we aimed to identify the effects of anodal vs. sham tDCS on pain and spasticity in stroke patients not undergoing conventional physical or rehabilitation therapy.Participant eligibility was based on the following inclusion and exclusion criteria. Inclusion criteria were the diagnosis of stroke, presence of post-stroke upper limb pain and spasticity after the acute phase, not being under physical or rehabilitation therapy before inclusion in the study, and provision of informed consent before participation . Exclusion criteria were motor paresis, any metal implants, shunts or artifacts with a possible impact on current flow, diagnosis of other neurological or neuropsychiatric diseases, and any symptoms affecting understanding of the instructions and conduction of the study . The study was approved by the regional Ethics Committee for Biomedical Research (CEI), Huelva (PI 010/15), Spain, and conformed to the principles of the last version of the World Medical Association Declaration of Helsinki.2) saline-soaked sponge electrodes at an intensity of 1.5 mA (0.075 mA/cm2). A gradual ramp up and down of stimulation for 10 s at the beginning and the end of stimulation, respectively, was programmed. The procedure was identical for sham condition, except that real current was only applied during the first and last 10 s to ensure the typical tDCS tingling sensation but avoid after-effects of stimulation. The electrodes were fixed onto the head by elastic rubber bands. After each intervention, participants were asked about any sensation related to tDCS application during stimulation. Participants were blinded to the respective stimulation conditions and were asked about a possible recognition of the specific condition in each case. A researcher not involved in data recording and analyses programmed each tDCS condition.Anodal and sham tDCS were performed by a battery-driven constant-current stimulator   with conSimNIBS 3.1.2 (Simulation of Non-Invasive Brain Stimulation) was used for modeling the intensity of the electric field induced by the different electrode configurations. SimNIBS is frequently used as computational modeling software to calculate the intensity of the electric field induced by tDCS . Figure Pre-tDCS (before stimulation) and post-tDCS (after stimulation) pain measures were taken in each stimulation session for anodal and sham conditions. The Adaptive Visual Analog Scales of pain intensity and improvement (AVAS)  were appt-tests  recruited from the J.R. Jiménez Hospital , with upper limb chronic post-stroke pain and spasticity but without motor paresis, met all inclusion criteria and voluntarily participated in this study. The interval between stroke onset and diagnosis and the start of the study was between 9 and 15 months.Considering the neuroimaging data, lesion size was similar in all patients, without structural M1 affection, but lesions were localized in different hemispheres (right hemispheric in two of the patients and left hemispheric in the third patient). Pain  and spasticity  symptoms were moderate in all patients at the start of the study. The patients were not under rehabilitation therapy before participation or throughout the trial. Three or four weeks before the intervention, pain and spasticity symptoms of two patients were treated by botulinum toxin. Apart from this, no systematic pharmacological analgesic therapy was conducted in these patients at the start of the study. During the course of the study, the patients did not receive any other treatment.According to the electric field modeling , the higp > 0.05 in all cases). The Wilcoxon-Mann-Whitney test revealed significant differences between the pain intensity mean values of the anodal and sham tDCS conditions in all patients , with reduced pain intensity values after anodal tDCS in patients 1 and 2. The autocorrelation values of the ACF method for anodal and sham stimulation conditions indicated that there was no serial dependency of data for pain intensity and pain improvement in any of the patients , but not in patient 3 (p = 0.08)  . The PND = 0.08) . FiguresZ = 1.06, p = 0.142) and 0% in the sham condition . In patient 2, the percentage of spasticity improvement between pre- and post-stimulation in relation to the highest score of the Fugl-Meyer scale was 38.63% in the anodal condition  and 0% in the sham condition . In patient 3, the percentage of spasticity improvement between pre- and post-stimulation was 4.5% in the anodal condition  and 13.63% in the sham condition .p < 0.001). A trend toward spasticity improvement was also observed after atDCS in patient 1 , but this difference was not significant (p = 0.142)  in three patients who did not receive concurrent physical therapy. The overall results indicate a significant effect of the stimulation on pain in two patients after atDCS , 3, and = 0.142) . These h= 0.142) .Other studies in which tDCS was applied over M1 have also found variability in results . To reduOverall, the results of the present study support the therapeutic potential of atDCS applied over M1 on chronic pain that has been reported in previous studies , and proThe analgesic effect of tDCS has also been explored in other chronic pain conditions such as phantom limb pain. A single session of anodal tDCS applied over the sensorimotor cortex region , with concurrent imaginary movement of the missing hand, induced long-lasting phantom limb pain relief . In thisRegarding safety and tolerability of the interventions, the patients of the present study did not report or experience any serious adverse effects during or after tDCS, and only the typical tingling and itching sensations over the scalp associated to this technique were reported. These effects were verbally mentioned by the three patients in both stimulation conditions, i.e., anodal and sham tDCS. This good tolerability is in accordance with the known excellent safety profile of tDCS , which iThe small number of participants is a limitation of this study. Upper and lower limb pain and spasticity are usually treated in post-stroke patients by physical rehabilitation . We recrThe treatment of motor symptoms in post-stroke patients has been investigated in previous studies by non-invasive brain stimulation methods, including tDCS . Most tD


Identify risk factors for poor pain outcomes six months after primary knee replacement surgery.Observational cohort study on patients receiving primary knee replacement from the UK Clinical Practice Research Datalink, Hospital Episode Statistics and Patient Reported Outcomes. A wide range of variables routinely collected in primary and secondary care were identified as potential predictors of worsening or only minor improvement in pain, based on the Oxford Knee Score pain subscale. Results are presented as relative risk ratios and adjusted risk differences (ARD) by fitting a generalized linear model with a binomial error structure and log link function.Information was available for 4,750 patients from 2009 to 2016, with a mean age of 69, of whom 56.1% were female. 10.4% of patients had poor pain outcomes. The strongest effects were seen for pre-operative factors: mild knee pain symptoms at the time of surgery , smoking 12.0% , living in the most deprived areas 5.6%  and obesity class II 6.3% . Important risk factors with more moderate effects included a history of previous knee arthroscopy surgery 4.6% , and use of opioids 3.4%  within three months after surgery. Those patients with worsening pain state change had more complications by 3 months (11.8% among those in a worse pain state vs. 2.7% with the same pain state).We quantified the relative importance of individual risk factors including mild pre-operative pain, smoking, deprivation, obesity and opioid use in terms of the absolute proportions of patients achieving poor pain outcomes. These findings will support development of interventions to reduce the numbers of patients who have poor pain outcomes. Knee replacement surgery may be offered to patients with knee osteoarthritis who have not responded to conservative treatment . Over 10It is important to identify which patients are at greatest risk of similar or worse pain after knee replacement. When healthcare professionals and patients are making decisions about treatment options, knowledge of the chances of benefit and the risk of harms, or of no benefit, is key to informed choice. Although previous research has explored predictors of outcomes of knee replacement , most stThe aim of this study is to identify pre- and post-operative risk factors for whether or not a patient has a poor pain outcome after knee replacement surgery, by analysing a wide range of potential factors from the UK Clinical Practice Research Datalink (CPRD) primary care GOLD database linked to English Hospital Episode Statistics (HES) hospital admissions and to Patient Reported Outcomes Measures (PROMs) data.Retrospective observational study using anonymised linked data from CPRD, HES and PROMs.st April 2009, HES provides PROMs data before and six months following knee replacements. Linkage of CPRD-HES-ONS-PROMS data is done by NHS Digital as a ‘trusted third party’.CPRD GOLD contains anonymised individual patient data from electronic primary healthcare records from practices across the United Kingdom . CPRD isWe included all patients receiving a primary total or uni-compartmental knee replacement between 2009 and 2016. Inclusion in the analysis was limited to those patients with HES linked data (England only) who completed both the pre- and six-month post-operative Oxford Knee Score pain subscale (see Flow Diagram The Oxford Knee score (OKS)  is colleThe Treatment Effect (TE = (pre-treatment score − post treatment score)/pre-treatment score) , 18 was In discussion with clinicians we sought to identify variables within this routinely collected dataset which may provide a wide range of potential predictors for the pain outcome.i.e. reordered to aid reporting). As a measure of comorbidity we used the Royal College of Surgeons’ (RCS) Charlson Score, which is calculated based on the presence of several chronic conditions identified using ICD-10 codes at the time of knee replacement surgery admission and all admissions in the preceding 5 years 2. INTRODUCTION - Globally, it is my opinion that the introduction section could be more complete, to provide an overview of the state-of-the-art in this field and to show the readership why the present study is warranted. What risk factors for poor outcomes have been analyzed in previous studies? Have the results been consistent across studies? Which risk factors are the most important? Which ones should be further investigated? It is not clear what the present study might add as novelty to the field. https://pubmed.ncbi.nlm.nih.gov/22532699/). Within the literature less is known about whether post-operative risk factors can help improve prediction. Most previous studies have focused on pre-operative risk factors when assessing predictors of patients reported outcomes. Many studies have looked at composite outcomes that combine information on pain, stiffness and function, whereas patients tell us that the most important outcome to them is pain. Our previous research found that the pre-operative risk factors were different for pain and functional domains. In particular, the discriminatory ability of the models to predict function were much better, than for pain outcome, where the discriminatory ability of pre-operative risks factors was poor  score. This is a relative measure of deprivation for small areas – termed lower super output areas (LSOAs) – which are defined as geographical areas of a similar population size, with an average of 1,500 residents [19]. The IMD comprises seven measures of deprivation: income deprivation; employment deprivation; education, skills and training deprivation; health deprivation and disability; crime; barriers to housing and services; and living environment deprivation. We used the IMD rank for a patient’s LSOA and categorised patients into quintiles based upon the national ranking of local areas, with quintile 1 being the least deprived group and quintile 5 being the most deprived group (i.e. reordered to aid reporting). 7. - In the same line, the Charlson Comorbidity Index should also be briefly explained. We agree and have added the following sentences:As a measure of comorbidity we used the Royal College of Surgeons’ (RCS) Charlson Score, which is calculated based on the presence of several chronic conditions identified using ICD-10 codes at the time of knee replacement surgery admission and all admissions in the preceding 5 years [20].8. - Why were these specific variables included in the model? There is no information concerning multicollinearity. In discussion with clinicians we sought to identify variables within this routinely collected dataset which may provide a wide range of potential risk factors/predictors for the pain outcome. We have assessed for evidence of collinearity using variance inflation factors and there was no evidence of multicollinearity. We have added statements regarding both points. Predictor variables: In discussion with clinicians we sought to identify variables within this routinely collected dataset which may provide a wide range of potential predictors for the pain outcome.We have assessed for evidence of collinearity using variance inflation factors and there was no evidence of multicollinearity.9. Statistical analysis – Line 1: Patients’ Amended 10. - What is the rationale to categorize the OKS score into 6 categories? One of the assumptions of a regression model is linearity of continuous variables with the outcome – we used fractional polynomial regression models to assess this and there was strong evidence of non-linearity of pre-op knee scores, so to satisfy the assumption we categorised the OKS score.11. - What is the rationale to exclude underweight BMI? We have added a sentence to clarify this point: We excluded nine underweight BMI patients, as there were too few patients in this category, leading to a small cell problem in the multivariable regression model, and it would be inappropriate to combine underweight and normal BMI categories together.12. RESULTS Page 6, Pre-operative predictors – Table 1: Why was the column “No” only filled in for some variables? Using age as an example, it would be possible to report the number of patients with poor outcomes who were “not” in the <60 group. Presumably, this would be the sum of patients who had a poor outcome and were in the other age groups. To clarify Table 1 column headings No and Yes refer to whether the risk factor is present or not, rather than whether pain is present or not. For example, for the hypertension row the No column refers to those with no hypertension who have pain. The Yes column those with hypertension and pain. Therefore, for those aged <60 years with pain (Yes column=15.7%), the No column would have to contain all those that are >=60 years with pain. We could remove the No column and add two rows per binary outcome (example below). However, for now we have left the table unchanged. We will revise the table should you feel strongly that it should be changed. 13. - What was the rationale to choose the reference category for each variable? For example, Pre-op OKS score groups are all only compared with the 8-10 score, age groups are all just compared against the <60 group… Our rational for choosing the reference category is the usual practice of selecting the group with the largest sample size, as our dataset is fairly large, we selected the lowest category for each variable, we are happy to change reference categories if you feel strongly regarding this point.14. - For age, it is stated that “those aged between 60-79 had a reduced risk of poor pain outcome compared with the oldest and youngest age groups”. However, there is no 60-79 group and these age groups (60-69 and 70-79 are not compared with older age groups (only with <60). Can the authors please clarify what is meant? The effect size is bigger in the middle age groups We have amended this sentence to clarify its meaning:A ‘U-shaped’ effect was observed for patient age at surgery, where those aged between 60-69 and 70-79 had a reduced risk of poor pain outcome compared with the youngest age group. The oldest age group was similar to the youngest.15. - I suggest rewriting the sentence “Poor pain outcomes were more likely in current smokers, males, people living in the most deprived areas and those with inflammatory arthritis”. As is, it seems to the reader that the authors are establishing these predictors as the most important ones. Also, I do not believe that these conclusions can be totally inferred from Table 1. I would suggest completing this table with additional statistical information for each predictor. At this stage of the results we are examining the descriptive statistics, looking at associations in the data and we are highlighting those that appear the most clinically relevant. There is no formal hypothesis testing being done, this is done with the regression modelling. Please see earlier response about missing data in Table 1. We have rewritten the sentence: The descriptive associations suggest poor pain outcomes were more likely in current smokers, males, people living in the most deprived areas and those with inflammatory arthritis (Table 1).16. - I could not find results concerning inflammatory arthritis in the tables or graphs. Inflammatory arthritis appears in Table 1 below the subheading ‘Comorbidities’. No individual comorbidities appear in the forest plot as they are rare, some of the categories are too small so we present findings for combined comorbidities in the Charleston score. We have added a sentence to the methods to clarify this: Composite variables were used if individual characteristics were rare.17. - For the remaining predictors, please note that, according to figure 3, effect is are non-significant for Charlson , Uni vs. Total arthroplasty  and Antidepressants  (the Cis include 1). https://www.bmj.com/content/322/7280/226.1.full). We are examining the strengths of association and not arbitrary measures of statistical significance with cut offs of for example p<0.05 or the related concept of whether the confidence interval includes the null value. To clarify we have added this sentence:Please see paper by Sterne et al BMJ  Amended 21. - Did the authors consider presenting the ROC curve for the model? I believe this would provide a more visual idea of the model. Thank you we agree and have now added the ROC curve to the Supplementary data file and Results, paragraph 7. 22. Page 8, Pain state change:- “we characterized the pre-operative and post-operative characteristics of those with worsening pain state change.” – Did the authors conduct any statistical test to compare the groups? These conclusions cannot be inferred from descriptive statistics alone. The complete results and p values should be detailed to the reader.This is descriptive not hypothesis testing so we have amended the language and made it clear in the methods and results.To describe their change in pain state before and 6 months after surgery, patients are categorised into pain groups, and descriptive statistics  used to describe the number (percentage) of patients that move between different pain states before and after surgery.… we describe the pre-operative and post-operative characteristics of those with worsening pain state change. 23. - “There were large differences in” – Was there a formal effect size calculation for between-group differences?We agree and have amended wording: There were some differences in length of stay, where those who moved to a worse pain state had much shorter length of stay24. DISCUSSION – “it may be worthwhile providing pre-surgical interventions to address modifiable risk factors ”. According to the results, there is a reduced risk of poor outcomes for yes vs. non smokers, but not for ex vs. non smokers. Therefore, this study does not seem to support pre-surgical interventions to address smoking. Also, the analysis of comorbidities did not show significant results . Though the identification of risk factors is important, this study mainly focuses on non-modifiable characterizes and thus the clinical implication should be reconsidered. We agree and have removed the statement. 25. - Most other studies have looked at composite outcomes combining symptoms of pain, stiffness and function.” – I believe that this may be an overstatement, since many studies in this field analyze pain as an outcome. Please reconsider if this is accurate information. Scores like the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Oxford Knee Score are commonly used composite outcomes. We have amended wording to clarify our meaning. Some other studies have looked at composite outcomes26. Reviewer #2: This manuscript reports the results of a study that uses an existing dataset to test for predictors for poor pain outcomes following total knee replacement (TKR). Such studies are common in the field of TKR, but with varying predictors, outcomes and methods. This study is a useful addition to the current body of evidence although, for a study that uses an existing dataset and fairly routine statistical methods, it is surprising to see 16 authors listed. Specific comments follow but these are minor comments and I have no major problems with the paper which is well written, well presented and well conducted. 27. 1. I think the abstract should contain the time point of the outcome Amended the objective to: Identify risk factors for poor pain outcomes six months after primary knee replacement surgery.[Abstract]28. 2. The study involves data linkage. This is a process commonly associated with surprisingly high error rates. Some data on the matching rates and processes would be useful. https://cprd.com/linked-data. The data linkage is done in-house by CPRD and not by the researchers themselves. Providers of data such as CPRD and NHS Digital provide the service for data linkage as a ‘trusted third party’ in a secure environment. This ensures the researchers themselves only have access to the anonymised linked data, and for information governance reasons, there is no need for sharing of personal data. Information on CPRD linkage is available here Hence researchers who use data provided by CPRD do not have information on the data linkage process itself. We now describe in the methods of the paper that: Linkage of CPRD-HES-ONS-PROMS data is done by NHS Digital as a ‘trusted third party’.29. 3. What was done about bilateral procedures – they should either have been excluded from the dataset or included in the model? Within this routine dataset, we do not have information on whether or not a patient received a unilateral or bilateral knee replacement. This is now described as a limitation in the discussion section.However, within this routine dataset, we do not have information on whether a patient received a unilateral or bilateral knee replacement and hence we are unable to exclude bilateral procedures from the dataset. 30. 4. Population selection: can any information be provided on the likely representativeness of this sample to the population as a whole? I know this is addressed in the discussion but this is based on previous analyses, not this exact dataset. https://reports.njrcentre.org.uk/Portals/0/PDFdownloads/NJR%2018th%20Annual%20Report%202021.pdf. For knee replacement in NJR mean age 68.9 (SD 9.6), 56.6% female. In our CPRD sample mean age of 69 (SD 9) of whom 56.1% were female. Hence very comparable in respect of age and gender. This has been added in the discussion section.Data from the national joint registry provides information on patients receiving hip and knee replacement where there is mandatory data collection nationally. To address the reviewers question, we have compared the mean age, and sex of patients in our CPRD sample, to that of the NJR This sample has also been compared with the mandatory National Joint Registry (NJR) in respect to knee replacement patient profile, for NJR mean age 68.9 (SD 9.6), 56.6% female. In our CPRD sample, the mean age was 69 (SD 9), of whom 56.1% were female. 31. 5. The study reports relative risk ratios . Just checking that this is correct – that the authors converted the Ors to RRs? We confirm that in this study we are indeed using relative risk ratios. Logistic regression is appropriate to use for relatively infrequent outcomes, whereas for more common outcomes, odds ratios are not a good approximation for relative risk. Hence in this paper, we have presented the results as relative risk ratios by fitting a generalized linear model with a binomial error structure and a log link function (log-logistic model) in order to estimate the relative risk.32. 6. Using the Oxford PS (pain score) as a predictor seems odd when this is the score used to define  the outcome. I realise that the Oxford PS score and the treatment effect (based on that score) are different but surely those with a worse pre-operative pain score will tend to have larger treatment effects because they have more “room” to improve? This is why I don’t like using treatment effect – I would rather know how much pain they have at 6 months. Pre-operative pain can be added to the model to adjust for its effect. But I am open to arguments to the contrary. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448885/We understand the point that the reviewer is making, and there is some debate in the literature as to how to define patient reported outcomes in observational studies with repeated measures repeated before and after surgery. This is discussed for example, in the article by Losina and Katz, as to whether interest is in the ‘journey’ , or the ‘destination’ . https://online.boneandjoint.org.uk/doi/pdf/10.1302/0301-620X.94B3.27425. Whereas our actual interest is in trying to identify the minority of patients at the tail of the distribution who do not achieve good improvement in symptoms, and hence to define a binary outcome according to whether or not patients had a good pain outcome after surgery. Our preference is to use the treatment effect to define outcome, and we have previously reported on this approach and validated it  > 0.2) externally validated in a large total hip replacement multicenter cohort (EUROHIP). Osteoarthritis and Cartilage 2016;24(3):480-3.)The limitation with a continuous OKS pain score outcome adjusting for baseline OKS as a covariate  is that, for knee replacement, the majority of patients achieve substantial improvements in pain, and we end up identifying predictors of patients with excellent improvement in pain, compared with patients receiving really good improvements of pain The rationale for our descriptive analyses, looking at pain state change, was to better understand the comment made by the reviewer, that patients with larger treatment effects have more room to improve. We noted that patients with the mildest pre-operative pain symptoms were most likely to not improve and their pain actually got worse. Specifically, they moved to a worse pain state following surgery, where 20% of patients had a poor pain outcome compared with around 10% in the other pre-operative pain states. We characterised why this might be, where these patients with mild pre-operative symptoms who experienced worse outcomes had more complications and re-operations. 33. 7. The pre-op associations were consistent with other studies and not surprising . I have a problem with using post-operative data to predict early post-operative outcomes. For example, those taking opioids post-operatively were more likely to have poor pain outcomes. These two variables are kind of measuring the same thing: post-op pain, and it is unlikely that ceasing these drugs will prevent pain at 6 months. Similarly, those who needed further surgery and had complications were more likely to have pain. These findings are expected and don’t point to any clinically useful knowledge, apart from avoiding complications. I am not asking the authors to remove them, but some comment in the discussion about the limited usefulness and obviousness of these findings should be mentioned. This study has been conducted as part of a wider NIHR programme grant on chronic knee pain, where the a priori aim was to see if identification and inclusion of post-operative risk factors, could help us to identify patients who are most at risk of chronic post operative pain, rather than using pre-operative risk factors alone. The funding application for the NIHR programme grant went through a rigorous process of peer review, and this is the research question we have been funded to address. The reviewers’ points relating to opioid use, early complications, and further surgery, are well made, and we have included this within the discussion section. However, knowledge of such post-operative factors would help us to identify patients earlier, even if by a few months, allowing us to intervene earlier and ensure such patients are receiving appropriate pain management services.34. Ian Harris Professor of Orthopaedic Surgery, UNSW Sydney Reviewer #3: The manuscript reports the findings from an observational study aiming to identify risk factors for poor pain outcomes after TKR. Pain outcomes were defined using the pain section of the OKS. 35. ABSTRACTIn the manuscript, complications seem important, but are not mentioned here? These have now been included in the abstract.Those patients with worsening pain state change had more complications by 3-months (11.8% among those in a worse pain state vs. 2.7% with the same pain state).36. INTRODUCTION1. Suggest modify sentence – ‘but around 1 in 5 will continue to experience pain…’ The 20% isn’t upheld in many studies. Suggest change to “the % experience ongoing pain is variable (add refs) with up to 20% experiencing…”. The current data also supports the finding that 20% is not often upheld. https://pubmed.ncbi.nlm.nih.gov/22357571/). We acknowledge the reviewer’s point that this was published some time ago now, and that this estimate will vary between studies and change over time. Hence, we have modified this statement as suggested.The figure of 20% was determined through a systematic review of the literature by Beswick et al  as this may explain why 20% seems an outdated value now) We agree with the reviewer that this will be a useful area for a future study, and have mentioned this in the discussion section, but is beyond the scope of this particular paper.38. METHODS 1. The introduction talks about TKA for people with OA. Clarify if only people with OA are in the dataset used. If not, change the Intro to be more inclusive of other indications for surgery. The reviewer is correct that this paper contains patients receiving a primary elective knee replacement for all indications, and not just osteoarthritis. We have changed the introduction to be more inclusive of other indications.Over 100,000 knee replacement operations are carried out each year in the UK for osteoarthritis and other surgical indications [2]39. 2. Justify inclusion of unicompartmental surgery. Its inclusion implies the same predictors will apply We included all patients receiving knee replacement surgery, whether total or uni-compartmental. We included total versus uni-compartmental as a predictor in the model, to see if this was associated with worse pain outcomes, with weak evidence of unicompartmental patients having lower risk of worse pain outcomes. A limitation of this, as the reviewer highlights, is that we are making an assumption - namely, that risks factors of poor pain outcomes, are the same for patients receiving uni-compartmental and total knee replacement. Investigating this would require tests for interactions, with all other risk factors in the model, but such multiple testing could lead to type 1 errors being made, and are in any case very low powered.We have therefore made it clear in the methods that the population comprises patients receiving primary total and uni-compartmental knee replacement . In the discussion, we describe this limitation, and the assumption being made for other risk factors identified.Another limitation is that we are making an assumption that risk factors of poor pain outcomes, are the same for patients receiving uni-compartmental and total knee replacement. Testing for this would require test for interaction, with all other risk factors in the model, but such multiple testing could lead to type 1 errors and are in any case very low powered. 40. 3. Please elaborate on justification for included complications. Were these defined by stakeholders? Were they chosen on severity? This is important as you include UTI (minor) to most severe and transparency is required here. https://www.oarsijournal.com/article/S1063-4584(14)01051-6/fulltextComplications were chosen a-priori in discussion with a number of orthopaedic surgeons, as to what were considered to be clinically relevant complications of knee replacement surgery. The chosen complications have been described and published previously We have added this reference to the Methods, Post-operative predictors.41. 4. Clarify total number of GP visits? From surgery to 3 months post-surgery Amended and calculated the total number of general practice visits between surgery and 3 months post-surgery 42. 5. Mention model fit statistics and performance test to be used here (mentioned in Results) Added to Statistical analysis: The C-statistic was used to describe the discriminatory ability of variables in the final model.43. 6. Clarify medication use includes pre and post-op. It gets confusing when talking about med use in Results. Amended We identified medications prescribed  pre- and post-surgery44. RESULTS 1. Missing data for alcohol consumption of 17% is high. Should do sensitivity analysis without that variable otherwise justify why that is not necessary. We have carried out a sensitivity analysis, re-fitting the final model excluding alcohol consumption, and the findings remain unchanged.45. 2. Clarify you checked for correlations between medication use pre and post-op. Same with opioid use and pain pre and post-op? There may be collinearity there. We have checked for evidence of multicollinearity using variance inflation factors as part of our model regression diagnostics, and found no evidence of this being an issue. See above point 8.46. Table 1Clarify that ‘complication’ is different to say surgery for MUA? I would argue MUA is a subset of complication (as this applies to some other complications too). By keeping them separate, this assumes different complications have different ‘weights’ so to speak. Can you justify/explain this approach. Seems like you have distinguished ‘medical’ from surgical and surgical is broken down further? In advance, we chose to separate out manipulation under anaesthetic, as this is treated as an operation using OPCS4 codes. Medical and surgical complications were considered as separate predictors. There was no specific reason for the approach we chose, and the reviewer is correct that others may have defined this differently. We have described this as a limitation in the discussion section.Medical and surgical complications were considered as separate predictors a priori and others may have defined complications differently from this study. 47. Fig 1 - Please justify exclusion of underweight BMI See above48. DISCUSSION1. Discussing use of opioids post-operatively as a risk factor along side pre-op factors is confusing. It makes sense that opioid use is assoc with persistent pain if the pain is driving use. On the other hand, pre-op BMI as a predictor is completely different. It may be a predictor as opposed to opioid use which may not ‘predict’, but rather be reactionary. Can the authors try to tease this out or dela with this better. We have tried to clarify our meaning regarding opioid use: We have identified a number of risk factors that are associated with an increased risk of poor pain outcome. The strongest pre-operative risk factors were: having only mild knee pain symptoms at the time of surgery, being a current smoker, obesity, and living in the most deprived areas. Opioid and antidepressant medication use were also associated with worse pain outcomes. The strongest post-operative factors were revision surgery and manipulation under anaesthetic within three months after the operation. We identified a range of other important risk factors with more moderate effects in terms of absolute risk differences in pain outcome, including a history of previous knee arthroscopy, and use of opioids within the three months after surgery, in addition to a number of other risk factors. Those with the least pre-operative pain were more likely to move to a worse post-operative pain state and were most likely to take pain relieving medicines both pre- and post-surgery, including opioids.We hope our responses are satisfactory, but please do not hesitate to contact us if more information is required. Yours sincerelyProfessor Andy JudgeAttachmentSTAR PLOS ONE response to reviewers 17Nov21.docxSubmitted filename: Click here for additional data file. 26 Nov 2021PONE-D-21-27576R1Risk factors associated with poor pain outcomes following primary knee replacement surgery:analysis of data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Patient Reported Outcomes as part of the STAR research programmePLOS ONEDear Dr. Judge,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by Jan 10 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.Please include the following items when submitting your revised manuscript:https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: We look forward to receiving your revised manuscript.Kind regards,Armando AlmeidaAcademic EditorPLOS ONEJournal Requirements:Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.Reviewer #1: (No Response)Reviewer #2: All comments have been addressedReviewer #3: All comments have been addressed**********2. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: YesReviewer #3: Yes**********3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: YesReviewer #3: Yes**********4. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: YesReviewer #3: Yes**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: YesReviewer #3: Yes**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: I thank the authors for their answers to my previous comments. I have some additional suggestions that are detailed below.INTRODUCTIONPage 3, first paragraph: “Many patients can expect to achieve reductions in knee pain and improvements in functional outcomes [3]. The percentage who experience ongoing pain is variable [4], with up to 20% experiencing knee pain that impacts their quality of life [5]. Patients who experience this kind of pain after surgery have not received the expected benefit and for some their pain is worse than it was before the operation .” – In this paragraph, the time point at which these patients still experience pain is not clear. I can assume that it refers to chronic pain, but it should it should be stated.Page 3, last paragraph: “There is limited research focusing solely on pain status”. In fact, there is a large body of research focusing on acute and chronic pain after surgery, including systematic reviews. I do not think that this sentence is an accurate depiction of the state of the art.Page 3, last paragraph: “This is important given that up to 20% of patients will have long-term pain after surgery [5].” – This information is already stated in the previous paragraph.Page 4: Please consider if the objective would be improved by stating that the aim was to “identify pre and postoperative risk factors”, since the authors present this strategy as a novelty.RESULTSTable 1: I appreciate the clarifications made by the authors concerning Table 1. However, it is my opinion that the information in the table is not very intuitive to understand. One suggestion would be to change the heading of the third column to “Proportion of patients with poor pain response with and without each risk factor”. And then change the “Yes” and “No” to “With” and “Without”.Also, please consider if using the term “risk factor” is adequate in this context. Only the statistical analyses tell us if each characteristic is a risk factor or not (and not the descriptive data).Since this table only presents descriptive information, do the authors believe that it is accurate to make claims about risk factors based on its information? Probably the most accurate way of stating the results would be, for example “The highest proportion of patients with poor pain outcomes were in the group of current smokers, males, people living in the most deprived areas and those with inflammatory arthritis.”The rationale to select reference categories should be clear in the statistical analyses section, even if it is usual practice.The information provided by the authors in the response letter concerning the analysis of strength of association should be stated in the statistical analysis section Reviewer #2: Comments addressed satisfactorilyReviewer #3: The authors have done well to address all the reviewer comments. Some reanalysis has been undertaken and substantial amendments to the manuscript have been made**********what does this mean?). If published, this will include your full peer review and any attached files.7. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  9 Dec 2021Dear Dr Almeida,Thank you for reviewing our manuscript at PLOS ONE as per your email dated 15 Oct 2021. We have considered these comments carefully, and our responses and amendments to the manuscript are reported below.Reviewer #1: I thank the authors for their answers to my previous comments. I have some additional suggestions that are detailed below. Thank you, we are very grateful for your comments.1. INTRODUCTION Page 3, first paragraph: “Many patients can expect to achieve reductions in knee pain and improvements in functional outcomes [3]. The percentage who experience ongoing pain is variable [4], with up to 20% experiencing knee pain that impacts their quality of life [5]. Patients who experience this kind of pain after surgery have not received the expected benefit and for some their pain is worse than it was before the operation .” – In this paragraph, the time point at which these patients still experience pain is not clear. I can assume that it refers to chronic pain, but it should it should be stated. Thank you for your comments we agree and have amended these sentences. Many patients can expect to achieve reductions in knee pain and improvements in functional outcomes following surgery [3]. The percentage who experience ongoing chronic knee pain post-surgery is variable [4], with up to 20% experiencing knee pain that impacts their quality of life after 3 months post-op [5]. Patients who experience this kind of pain after surgery have not received the expected benefit and for some their pain is worse than it was before the operation .2. Page 3, last paragraph: “There is limited research focusing solely on pain status”. In fact, there is a large body of research focusing on acute and chronic pain after surgery, including systematic reviews. I do not think that this sentence is an accurate depiction of the state of the art. We agree and have amended the sentence, to clarify our meaning. Although previous research has explored predictors of outcomes of knee replacement [8], most studies have focused on total scores encompassing several domains  and fewer studies have focussed solely on pain status [7].3. Page 3, last paragraph: “This is important given that up to 20% of patients will have long-term pain after surgery [5].” – This information is already stated in the previous paragraph. We agree and have removed the sentence. 4. Page 4: Please consider if the objective would be improved by stating that the aim was to “identify pre and postoperative risk factors”, since the authors present this strategy as a novelty. We agree and have added this statement.The aim of this study is to identify pre- and post-operative risk factors for whether or not a patient has a poor pain outcome after knee replacement surgery…5. RESULTS Table 1: I appreciate the clarifications made by the authors concerning Table 1. However, it is my opinion that the information in the table is not very intuitive to understand. One suggestion would be to change the heading of the third column to “Proportion of patients with poor pain response with and without each risk factor”. And then change the “Yes” and “No” to “With” and “Without”. We agree and have amended the table headings.Proportion of patients with poor pain response with and without each risk factorWithout With[Table 1]6. Also, please consider if using the term “risk factor” is adequate in this context. Only the statistical analyses tell us if each characteristic is a risk factor or not (and not the descriptive data). We agree and have clarified our wording for the descriptive data.The aim of this study is to identify pre- and post-operative risk factors for whether or not a patient has a poor pain outcome after knee replacement surgery, by analysing a wide range of potential factors from the UK Clinical Practice Research Datalink (CPRD) primary care GOLD database linked to English Hospital Episode Statistics (HES) hospital admissions and to Patient Reported Outcomes Measures (PROMs) data.Table 1. Descriptive statistics describing the total number of patients with each potential risk factor, and the proportion of patients with a poor pain outcome, according to whether or not they have the factor[Table 1]7. Since this table only presents descriptive information, do the authors believe that it is accurate to make claims about risk factors based on its information? Probably the most accurate way of stating the results would be, for example “The highest proportion of patients with poor pain outcomes were in the group of current smokers, males, people living in the most deprived areas and those with inflammatory arthritis.” We agree and have amended this sentence.The highest proportion of patients with poor pain outcomes were in the group of current smokers, males, people living in the most deprived areas and those with inflammatory arthritis (Table 1).8. The rationale to select reference categories should be clear in the statistical analyses section, even if it is usual practice. We agree and have added the following sentence.As our dataset is large, we selected the lowest category for each variable as the reference category.9. The information provided by the authors in the response letter concerning the analysis of strength of association should be stated in the statistical analysis section  We agree and have added this sentence.We examine the strength of associations and not arbitrary measures of statistical significance with cut offs of for example p<0.05 or the related concept of whether the confidence interval includes the null value.Reviewer #2: Comments addressed satisfactorily Thank you.Reviewer #3: The authors have done well to address all the reviewer comments. Some reanalysis has been undertaken and substantial amendments to the manuscript have been made Thank you.We hope our responses are satisfactory, but please do not hesitate to contact us if more information is required. Yours sincerelyProfessor Andy JudgeAttachmentSTAR PLOS ONE response to reviewers 2nd review 6Dec21 AJ.docxSubmitted filename: Click here for additional data file. 13 Dec 2021Risk factors associated with poor pain outcomes following primary knee replacement surgery:analysis of data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Patient Reported Outcomes as part of the STAR research programmePONE-D-21-27576R2Dear Dr. Judge,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Armando AlmeidaAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments: 20 Dec 2021PONE-D-21-27576R2 Risk factors associated with poor pain outcomes following primary knee replacement surgery:analysis of data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Patient Reported Outcomes as part of the STAR research programme Dear Dr. Judge:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofProf. Armando Almeida Academic EditorPLOS ONE


Acute pain is a prevalent problem for dementia residents in nursing homes. A variety of intervention strategies have been applied to address this problem. However, there remains an issue of inadequate pain control. This study aims to explore the analgesic efficacy of auricular acupressure (AA) for dementia residents with acute pain in nursing homes.  A multicenter, single-blind, randomized, and sham-controlled clinical trial was performed in three nursing homes in Yinchuan, China. All of the 206 eligible patients with acute pain were randomly divided into two groups for real AA therapy or sham AA (at sham point stimulation) therapy. The primary outcome was measured with a face pain scale revised (FPS-R) score before the procedure, 5 min after the start of the intervention, and 5 min after finishing the procedure. Secondary outcomes covered three physiological parameters, adverse reactions observed, satisfaction level of caregivers, acceptance of patients, and additional use of analgesics. p < 0.01). Pain score in the true AA group was 1.84 ± 0.23, compared with 2.22 ± 0.81 in the sham AA group. No adverse events were found during the whole procedure for all patients. The satisfaction level of caregivers and acceptance of patients in the real AA group were significantly higher than those in the sham AA group.  There was a significant difference in pain scores based on FPS-R between the two groups ( This study shows that real AA was an alternative analgesic modality in reducing acute pain in patients with mild dementia. It has been estimated that there are over 50 million patients with dementia around the world, and over 20% of them are in China , 2. By 2Pain is the most common complaint of residents with dementia in nursing homes. The prevalence of pain among residents is significantly higher than in other communities, with numerous studies indicating that as many as 40% to 80% of these residents with dementia were affected by pain . A studyThese guidelines recommend paracetamol as a first-line approach for dementia patients with communication problems, which aligns with systematic reviews –12. CurrThe use and safety of auricular acupressure (AA) have been well studied in managing acute postoperative pain after surgery, primary dysmenorrhea, and other medical conditions , 19, 20.This study is a multicenter, single-blind, randomized, and sham-controlled clinical trial of AA as described in a study protocol . The triNursing home residents who were recruited into the study must meet the following standards: 60 years or older, mild dementia  , the scoPatients eligible for recruitment were randomly assigned to an intervention or a control group. The intervention group received routine pain management plus real AA therapy , while routine pain management plus sham AA therapy (at sham points stimulation) was applied to the control group. Auricular-plaster therapy was an adhesive tape with a seed in the middle fixed to various auricular points, stimulating the auricular points with your fingers on both ears. There were significant differences in terms of the selected acupoints and function of acupoint combination between the two groups. In this study, Shenmen (TF4), Subcortex (AT4), Adrenal gland (TG2P), and two anatomical regions corresponding to the site of pain were selected to relieve pain in the intervention group. These five points  were selected in the control group. The main effect of these five points was to delay hearing loss. Two anatomical regions were selected by the inverted fetus map . Prior tAll of the 206 patients deemed eligible were randomized into the real AA group or the sham AA group by using a randomization list. Patients were assigned to two groups at 1:1 ratio. The randomization list was generated by an independent statistician with the random number generator in SPSS 22.0 . And only the project manager and operator had access to it. It was blinded for other researchers  as well as patients and medical workers to the subject's sequence number throughout the whole trial. To reduce bias, researchers were not allowed to communicate regarding data collection.β = 0.10 (a power of 90%). Considering a 20% dropout rate, we thought that increasing the sample size to 206 subjects was necessary to improve the validity of the study.Prior to the study, we conducted a pilot trial with a sample size of 30 patients in a nursing home in Yinchuan. The change of pain score was the primary outcome. The trial showed that the control group's mean score was 5.97 ± 1.81, and the intervention group was 4.79 ± 1.96. Therefore, the sample size of the two study groups was 172 subjects (each group 86 cases) with an alpha of 0.05 level  and Besides the patient's demographic data , the site of pain was recorded by data collectors as well. The primary outcome was measured by researchers at baseline , 5 min , and 5 min after treatment  with FPS-R. It consisted of six facial expressions sorting pain levels , which was reliable and valid in older adults with dementia . Secondat-test and were described as mean (standard deviation) or proportions. The chi-square test was used to analyze the ordinal categorical data. The repeated-measure analysis of variance was selected to describe three physiological parameters  and the FPS-R scores. The Mann–Whitney test was used for the non-normal distribution parameters (satisfaction level of caregivers and acceptance of patients). Two-sided p value <0.05 was considered statistically significant.All quantitative statistical analysis was conducted by SPSS 22.0 statistical software based on the intention-to-treat principle. Continuous data with normal distribution were analyzed by the independent sample p=0.24), gender , nationality (p=0.67), education background (p=0.08), marital state (p=0.58), occupation (p=0.55), the use of analgesic (p=0.61), and location of the pain (p=0.98). There were no statistically significant differences (p > 0.05).A total of 341 potential mild dementia patients with moderate-to-severe acute pain were screened for eligibility during the initial enrollment in three nursing homes in Yinchuan from April 2018 to March 2020, among which 135 dropped out, and 114 of them were further excluded as they did not meet the inclusion criteria. Subsequently, 20 were unwilling to participate in the study, and 1 was excluded owing to adhesive tape allergy. The 206 remaining patients completed the study, of which 103 patients were allocated in the real AA group and 103 in the sham AA group . The demp < 0.01), but there was no statistical significance at T0. Pain scores in episodes treated with true AA decreased from 5.19 ± 0.81 (at T0) to 2.51 ± 0.72 (at T1) and 1.84 ± 0.23 (T2). For patients treated with sham AA, pain scores ranged 5.33 ± 0.91 from 5.31 ± 0.52 to 4.22 ± 0.81 at T0, T1, and T2, respectively.Changes in pain scores based on the FPS-R for each group were summarized in p < 0.05). As summarized in Z = −11.653, p < 0.01; Z = −8.088, p < 0.01).The three physiological parameters were presented in In this present study, the real AA group has better results than the sham AA group in reducing pain intensity in dementia patients with acute pain. Furthermore, there are no side effects and complications associated with AA therapy.t = 32.187, p < 0.001) [F = 28, p=0.0001) than patients in the sham AA group, which demonstrates that AA is effective in reducing pain [Numerous studies have identified the safety and efficacy of AA therapy. The results of this study show that the use of AA is safe and effective for relieving acute pain, which was consistent with existing studies , 19. A s< 0.001) . There iing pain .p > 0.05) [Statistical analysis of this study demonstrates that there is no significant difference among the three vital signs, including blood pressure, heart rate, and oxygen saturation. A randomized controlled trial evaluated the effect of the intervention group (AA group) on physiological indicators of variability in hypertensive patients compared with the control group. No differences are shown between the two groups in blood pressure and heart rate ( > 0.05) . This st > 0.05) . Another > 0.05) .The Declaration of Montreal claims that access to pain management is a fundamental human right and the obligation of medical providers offering to a patient . HoweverThe Yellow Emperor's Classic of Internal Medicine written in Chinese) to nowadays days, auricular therapy as a complementary and alternative technology has been employed for approximately 2,500 years. AA is one of the common methods of auricular therapy. And it was more widely applied for controlling various types of pain since the advent of Nogier's somatotopic maps. The ear is where 12 meridians are directly or indirectly connected. Stimulating it can achieve the purpose of qi-blood circulation, dredge meridians, and then analgesia according to traditional Chinese medicine (TCM) theory [From the ancient record  theory . The mec) theory . In addi) theory , 30.Many studies , 31 haveOverall, the AA method has the undeniable advantages of safety, non-invasiveness (with less chance of infection), low cost, and even self-administration. Once AA tape is applied, it can stay in the auricular point for a long time. The patient can use his finger to gently press to stimulate the auricular points. AA seems to be a promising adjunct analgesic treatment for pain relief in nursing homes.The present study was designed to be single-blinded and performed in a single regional municipality. The pain level in the following hours after the procedure was not recorded in the study to evaluate the long-term effect . Furthermore, the study did not recruit different ages of patients, and our findings cannot be generalized to other patient settings. Thus, multiple regions and large-sample studies are warranted to determine the analgesic effect of AA therapy.This study shows that real AA was an alternative analgesic modality in reducing acute pain in patients with mild dementia. There are few side effects during the study period. Medical providers may take the AA method into consideration for alleviating acute pain in nursing home residents with dementia, especially in low-resource settings.


Neuro-reflexotherapy (NRT) is a proven effective, invasive treatment for neck and back pain. To assess physician-related variability in results, data from post-implementation surveillance of 9023 patients treated within the Spanish National Health Service by 12 physicians were analyzed. Separate multi-level logistic regression models were developed for spinal pain (SP), referred pain (RP), and disability. The models included all patient-related variables predicting response to NRT and physician-related variables. The Intraclass Correlation Coefficient (ICC) and the Median Odds Ratio (MOR) were calculated. Adjusted MOR (95% CI) was 1.70  for SP, 1.60  for RP, and 1.65  for disability. Adjusted ICC (95%CI) values were 0.08  for SP, 0.07  for RP, and 0.08  for disability. In the sensitivity analysis, in which the 6920 patients treated during the physicians’ training period were excluded, adjusted MOR was 1.38  for SP, 1.37  for RP, and 1.25  for disability, while ICCs were 0.03  for SP, 0.03  for RP, and 0.02  for disability. In conclusion, the variability in results obtained by different NRT-certified specialists is reasonable. This suggests that current training standards are appropriate. Subacute and chronic non-specific neck (NP) and low back pain (LBP) represent a major health, social, and economic burden ,4,5,6,7.Neuroreflexotherapy intervention (NRT) is a minimally invasive treatment for neck and back pain ,21,22,23NRT is one of the few treatments for neck and back pain which have been shown to lead to both statistically and clinically significant improvements in pain and disability ,21,22,23Estimating physician-related variability of results sheds light on validity of training standards, which is a pre-requisite for generalization. Therefore, the objectives of this study were to: (a) assess the variability of results obtained by different practitioners in routine practice, adjusting for patient characteristics, and (b) gain insight into the learning curve for this technology, by gathering data on the relationship between clinical results and physicians’ level of training.All procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 1983.Participants were asked for a written informed consent, which authorized the use of demographic and clinical data deriving from their care for the purpose of this study.This study consisted of a Clinical Audit which did not imply any changes to routine clinical practice, and data analyzed did not contain any personal data, which would allow identification of patients. Therefore, according to the Spanish law, this study did not require approval by an Institutional Review Board.This study was conducted in the Health Services of the Balearic Islands, Asturias, Cataluña, Murcia, and Madrid. These five regional Health Services belong to the Spanish National Health Service (SNHS) and cover approximately 17.6 million inhabitants, about 37.5% of the Spanish population .At the design phase of this study, it was decided to analyze the variability of results obtained by different practitioners once the first 9000 patients who sought care for NP or LBP within the SNHS, and had undergone NRT, had been discharged. All the patients who had been discharged after receiving NRT were included in this study, with no exclusion criteria.Patients were treated by 12 physicians (two supervisors and 10 trainees), none of whom authored this study.Indication criteria for NRT, are: neck, back pain, or referred pain ≥ 3 points on a 10-point visual analog scale (VAS) ; lastingPatients are referred by primary care physicians to specialized NRT Units in each region following a standardized protocol . SpecialTwelve weeks later, the surgical material is removed and patients are discharged, unless criteria for repeating the procedure are met  ,21,22,23All data analyzed in this study stem from post-implementation surveillance in routine practice. They are gathered through previously validated methods, and introduced into a database ,21,22,23Data provided by the referring physician include: duration of pain ; reason for referral ; date of referral; existence of referred pain (yes/no); history of spine surgery; diagnosis of failed surgery syndrome; radicular pain caused by symptomatic disc protrusion/herniation (yes/no) or symptomatic lumbar spinal stenosis (yes/no), “common” or “unspecific” syndrome (yes/no); concomitant diagnosis of fibromyalgia; other comorbidities; diagnostic tests performed ; imaging findings ; and treatments provided for the current episode .Data provided by the patient include; gender, date of birth, academic level , current pregnancy, employment status , involvement in NP, TP or LBP-related employment claims , involvement in NP, TP or LBP-related litigation , and satisfaction .Pain and disability are assessed at each visit to the primary care centers and the specialized NRT Units. Separate 10-cm visual analogue scales (VASs) are used for spinal pain  and referred pain . The RolTraining standards for NRT imply a 3-year education program, during which 850 supervised NRT interventions per year are performed . In ordeAfter certification, trainees obtain full privileges to perform NRT interventions in solo practice, and receive a code to access the software used for post-implementation surveillance. Until then, they use their supervisors’ personal code. Therefore, data from the interventions performed during training are assigned to each supervisor.Outcomes were spinal pain (SP), referred pain (RP), and disability . ChangesResults for each outcome were analyzed by using multilevel logistic regression models , with paData from patients treated for thoracic pain were excluded, since predictive models have only been developed for NP and LBP . Only thEmpirical Bayes’ residuals were calculated for each physician . In eachThe ICC quantifies the fraction of the total variability in outcomes which is attributable to the physicians. ICC values range from 0 to 1. The higher the ICC value, the greater the variability that can be attributed to physicians. For instance, an ICC = 0.06 shows that 6% of the total individual differences over the odds of improvement occurs at the physician level and might be attributable to contextual physician factors.Conceptually, MOR reflects the degree of variability in clinical results which stem from the fact that the patients are treated by different physicians. A higher MOR reflects a higher variability. The MOR quantifies the difference in results obtained by different physicians, by comparing clinical results from two patients treated by two different physicians selected randomly. For instance, considering two patients with the same covariates, selected randomly among cases treated by two different physicians, the MOR is the median odds ratio between the patient with higher odds and the patient with lower odds , and canA sensitivity analysis was performed, in which the models were repeated restricting data to patients treated by the trainees after they were certified as NRT specialists .Stata version 13.0 software was used for statistical analysis .This study was promoted by the Spanish Back Pain Research Network, a not for profit research Organization with no links to the health industry. No external funds were received to fund this study. Only the authors were responsible for the design and conduction of the study; data collection, management, analysis and interpretation; preparation, review and approval of the manuscript; or the decision to submit the article for publication. None of the authors received any payment for this work, and none harbor any conflicts of interest.Since post-marketing surveillance was applied simultaneously at centers in different geographic locations, when recruitment for this study stopped, 9023 patients had been discharged after having undergone NRT for neck or back pain. Therefore, all 9023 patients were included in this study. There were no losses to follow-up. The identity of the treating physician was missing for 157 (1.8%) patients. Among the 12 physicians who were identified, the median  number of patients treated in solo practice was 180 . The number of NRT interventions performed by, or assigned to, the two supervisors was 6763. Two trainees never qualified and are not identified in The proportion of patients who presented missing scores for spinal pain, referred pain or disability at baseline or discharge, or had a baseline score below the corresponding MCIC, were 8%, 32%, and 37%, respectively. Additionally, patients with missing completely at random (MCAR) scores for any of the independent variables, which were introduced in the full models, were 3379 for the model on spinal pain, 2418 for the one on referred pain, and 1537 for the one on the disability. Therefore, the model on spinal pain included data from 4791 patients, the one on referred pain included data from 3606 patients, and the one on disability included data from 4061 patients .Clinical results obtained by each physician are shown in Adjusted MOR (95%IC) was 1.70  for SP, 1.60  for RP, and 1.65  for disability. Adjusted ICC (95%IC) values were 0.08  for SP, 0.07  for RP, and 0.08  for disability. In the sensitivity analysis, adjusted MOR was 1.38  for SP, 1.37  for RP, and 1.25  for disability, while ICCs were 0.03  for SP, 0.03  for RP, and 0.02  for disability .Previous studies have shown that NRT improves pain and disability in 84–89% of subacute and chronic neck and back patients, and that this improvement is clinically relevant in 72–76% patients ,21,22,23Several factors can account for this reduction. In the complete dataset, the number of observations was higher and the number of years in practice and the number of patients assigned to each physician were skewed. Moreover, in the analysis of the complete data set, results from the interventions for which the worst and best results were to be expected  were identified with the same codes, which impeded analyzing them separately. All of the above may have contributed to the MOR and ICC values being larger in this analysis than in the analysis in which only data from certified specialists were included.Senior experts who participated in this study can be seen as those with the maximum level of competency in performing NRT interventions; they had ≥20 years of experience and had shown to obtain positive clinical results in RCTs and studies conducted in routine practice ,18,19,22Whether a shorter or less intensive training would be enough is unknown and could be explored in future studies. Nevertheless, this study reflects that current training standards are effective at ensuring that certified specialists obtain results which are similar to those obtained by senior specialists  14,15,1,21,22,23Concerns have been expressed about the feasibility of accurately assessing the clinical performance of physicians, especially for procedures requiring manual skills, given that awareness that their results are being monitored might result in changes in behavior or in avoiding treating patients they feel might have a worse prognosis ,42. HoweMost reports on learning curves or variability across practitioners for invasive treatments for neck or low back pain focus on interventions other than NRT, many of which lack high quality evidence supporting their efficacy and effectiveness. Moreover, they are based on small samples , do not use multi-level analyses to adjust results for patient prognosis as established by previously validated models, or have been conducted either retrospectively or outside routine practice conditions  ,52,53,54To date, although some invasive procedures used for neck or back pain have been assessed ,56,57, mData analyzed in this study stem from surveillance mechanisms in routine practice. These mechanisms encompass all patients who undergo NRT within the Spanish National Health Service, with very little losses to follow-up, and use previously validated methods ,21,22,23In conclusion, results from this study suggest that, at the end of their training period, NRT-certified specialists achieve clinical results, which, after adjusting for patient characteristics, are reasonably similar, which suggests that current training standards are valid for generalizing this technology.


Performing a careful but effective mobilisation of the hemiplegic shoulder is essential for optimal muscle activation and to preserve the passive range of motion (PROM) needed to perform functional tasks. Studies concerning passive mobilisation of the post-stroke shoulder are scarce.A randomised multiple treatment trial was conducted to compare the effects of different mobilisation techniques on shoulder PROM.Eleven participants with upper limb paresis in the subacute phase after stroke underwent three different mobilisation techniques (3 × 4 weeks):(1) combined soft-tissue mobilisation in the scapular plane, (2) scapular mobilisation without glenohumeral movement, (3) angular glenohumeral mobilisation in the frontal plane. Depending on the randomisation, the order of the techniques changed. Differences in outcome measures  were calculated between the beginning and end of each intervention period.p = 0.006). An average increase of 6.82° (± 9.20°) for shoulder external rotation was noted, whilst after the two other techniques, passive external rotation decreased .Using combined soft-tissue mobilisation in patients in the subacute phase after stroke with persistent arm paresis resulted in an increased passive shoulder external rotation (These preliminary findings, suggest that combined soft-tissue mobilisation technique might improve the PROM for external shoulder rotation in subacute stroke patients with persistent arm paresis.Performing a specific mobilisation technique might have positive effects on shoulder PROM. Research including larger sample sizes is necessary to confirm these findings and define the underlying mechanisms. Rehabilitation therapists are constantly challenged to strive for the optimal functional recovery of patients after stroke as well as the prevention and treatment of several complications. The often poor prognosis of upper limb (UL) recovery post stroke with the potential of mobility-related complications is one of the reasons why, in people with persistent arm paresis, therapists are inclined to apply more passive therapeutic interventions instead of active arm-oriented therapy modalities . The first sample (sample 1) received their mobilisation in the following order: technique 1-2-3. In the second sample (sample 2), the reverse order was applied (technique 3-2-1). Each technique was carried out for 4 weeks, resulting in a total intervention time of 12 weeks. Patients received their mobilisation for 5 days a week. The time spent on mobilisation of the shoulder joint was limited to a maximum of 20 min. The need for intra-articular injections of the shoulder joint or injections of shoulder muscles using botulinum toxin was assessed before participants entered our study. During our study period, these therapeutic procedures were not permitted. If any need for this kind of therapy occurred during our study, the patient would be withdrawn so as not to influence our results. All participants received the same conventional rehabilitation therapy in addition to the mobilisation techniques.Eleven participants (> 18 years) were recruited after adopting the exclusion criteria to the eligible 35 patients . PatientEach participant underwent the three different mobilisation techniques. Depending on admission to sample 1 or 2, the order of the intervention techniques changed , specifically trained to guarantee standardisation of the given measurement procedures. The assessor was blinded for the technique performed during the different intervention periods. If assistance was needed, a second physiotherapist helped to position the arm. A manual goniometer to measure PROM is a reliable method in healthy persons  to measure intensity of shoulder pain was used as a secondary outcome measure. Patients were asked to rate their shoulder pain during rest, during activities and during the night on a scale from 0 to 10 . There were no missing values. All participants were included in the statistical analysis.Statistical analysis was performed using the Statistical Package for the Social Sciences, version 24 (SPSS 24.0). Based on the Shapiro Wilk test, non-parametric tests were used. Data are presented as medians and interquartile ranges. To compare the different baseline variables between the two samples, a Mann-Whitney U test was used . To compThis study was approved by the medical ethics committee of the Ghent university hospital in accordance with the declaration of the world medical association and registered in a public repository. All recruited participants agreed and signed informed consent prior to our study.n = 6) or sample 2 (n = 5), the order of the intervention techniques changed. At the start of the intervention, the two samples were comparable for both the demographic data and baseline variables . After the combined soft tissue mobilisation, an average increase of 6.82° (± 9.20°) was noted whilst after the two other techniques, PROM external rotation decreased  ( 11.72]) . Pairwis 11.72]) .Preserving sufficient PROM of the hemiplegic shoulder , whilst a decreased PROM was noted after the scapular mobilisation  and after the usual care angular glenohumeral mobilisation . Measuring PROM of the hemiplegic arm has been shown to be reliable in patients after stroke  was conducted using the standard deviations of our own study. This analysis showed a large effect size (f = 0.57) with a power of 80% for the given sample size. Our results exceeded the SEM and the SDD indicated by Cools et al. , no significant differences could be detected. So, these variables did not influence the differences in PROM outcome.Finally, patients were also asked if they experienced any pain during the mobilisations besides an eventual feeling of stretch pain. Although the therapists were instructed to stay below the pain threshold when observing pain (different from stretch pain) in or around the shoulder joint during mobilisation, some patients did report the presence of sharp pain. Even though no significant differences could be detected between the different techniques for both types of pain, patients did experience more stretch pain relative to other pain types.Some limitations of our study need to be addressed. Because of the small sample size, the preliminary results described in this manuscript must be interpreted with appropriate reservation and need to be carefully addressed with respect to generalisation to all patients after stroke. The patients included in our study were in the subacute phase after stroke and suffered a persistent arm paresis as indicated by a mean score on the FMUE_SE of 7.45. However, if patients have better UL function, indicated by a higher score on the FMUE, passive mobilisation of the shoulder joint is less important as active task-specific training would be preferred for these patients. Because patients were in the subacute phase after stroke, it is unlikely that their condition had reached a stable state. However, as no difference could be detected in FMUE scores, it is unlikely that the change in PROM for external rotation is because of natural recovery. Not including a pure control group can be interpreted as a shortcoming, but not treating patients after stroke cannot be considered ethically acceptable. The PROM of our study population was already restricted at the start of the intervention. In future, studies comparing mobilisation techniques starting from the first week after stroke should be conducted. Finally, limitations in the use of a VAS for pain in patients after stroke should be taken into consideration. Because of sensory impairments, self-reported pain is not always considered reliable in patients after stroke. Unfortunately, as far as we know, there are no more objective ways available to measure pain in patients after stroke.Based on preliminary findings, it can be suggested that using the combined soft-tissue mobilisation in patients in the subacute phase after stroke who suffer persistent arm paresis results in an increased PROM for external shoulder rotation. After the other two interventions, a decrease of PROM for this movement direction was noticed. As external rotation is an essential biomechanical component in the prevention of HSP, combined soft-tissue mobilisation can be recommended.


Patients with bladder pain syndrome experience debilitating pain and extreme frequency of urination. Numerous therapeutic approaches have been tested, but as the molecular basis of disease has remained unclear, specific therapies are not available.Recently, a systematic gene deletion strategy identified interleukin-1 (IL-1) hyperactivation as a cause of severe cystitis in a murine model. Treatment with an IL-1 receptor antagonist (IL-1RA) restored health in genetically susceptible mice, linking IL-1–dependent inflammation to pain and pathology in the bladder mucosa. The study objective was to investigate whether IL-1RA treatment might be beneficial in patients with bladder pain syndrome.Patients diagnosed with bladder pain syndrome were invited to participate and subjected to daily IL-1RA injections for 1 wk, followed by a treatment break. Patients with other urological disorders accompanied by pain were included as controls.When symptoms returned, treatment was resumed and responding patients were maintained on treatment long term, with individualized dosing regimens. Symptom scores were recorded and molecular effects were quantified by neuropeptide and gene expression analysis. DNA samples were subjected to exome genotyping.p < 0.001). Substance P levels in urine were lowered, and responders returned to a more normal lifestyle. Neuroinflammatory-dependent and IL-1–dependent gene networks were inhibited, as well as regulators of innate immunity. Genotyping revealed disease-associated IL1R1, NLRP3, and IL1RN DNA sequence variants in the responders. Controls did not benefit from IL-1RA treatment, except for one patent with cystitis cystica.IL-1RA treatment reduced bladder pain and the frequency of urination in 13/17 patients  receptor antagonist is proposed for treating bladder pain syndrome, as it can result in symptom relief and increase quality of life. Reduced neuroinflammation and IL-1 signaling provided molecular evidence of the treatment effects. Interleukin-1 (IL-1) receptor antagonist immunotherapy is proposed as a new approach to treating bladder pain syndrome, a debilitating disorder. Treated patients experienced symptom relief and increased quality of life. Reduced neuroinflammation and IL-1 signaling provided molecular evidence of the treatment effects. Immune balance is easily lost, however, as host deficiencies may cause the immune defense to underperform or overachieve. Immunotherapy has the potential of restoring balance to the immune system, by compensating deficiencies or inhibiting excessive immune activation and progression to chronic disease The bladder pain syndrome (BPS) has been associated with urinary tract infection (UTI) susceptibility Molecular studies have identified specific innate immune checkpoints that control the severity of UTI and serve as therapeutic targets in animal models of acute pyelonephritis and acute cystitis 22.1Patients diagnosed with severe BPS  Seventeen patients were included in the study . For a summary of patient characteristics, see Four patients diagnosed with other urological diseases were enrolled as controls. They were diagnosed with urethritis, prostate pain, chronic pelvic pain syndrome, or cystitis cystica (Supplementary Table 4).2.2Collection of samples and analysis of data were approved by the Regional Ethics Committee, Lund, and the Swedish Ethical Review Authority (2013-004961-14 and 2019-02746), and was performed in accordance with the principles of the Declaration of Helsinki. All included patients had read and signed informed consent forms.2.3Off-label Anakinra treatment was initiated after the receipt of written informed consent. The patients received daily subcutaneous Anakinra injections for 7 d (100 mg/dose). On day 7, treatment was transiently interrupted until symptoms reappeared. The patients were then invited to continue IL-1RA treatment or leave the study A. The fr2.4n = 3) were assessed only by the Swedish questionnaire, as the voiding frequency parameter in the O’Leary score could not be determined.To document treatment effects, patients were interviewed at each visit by the study physician. Symptom scores were recorded by the patients, using a self-assessment questionnaire in Swedish. The patients registered voiding frequency during 24 h and nocturia (mean frequency during 1 wk), and a questionnaire of global scoring for local pain and quality of life. Scoring was between 0 and 6, with 0 indicating no pain/high quality of life and 6 indicating severe pain/low quality of life . In addition, patients completed the O’Leary symptom and problem questionnaire in English 2.5Urine samples were obtained at the time of diagnosis and at each visit, during the study. Urine cultures were performed and leucocyte esterase was quantified. Urine Substance P levels were quantified using the commercially available Substance P parameter assay kit (R&D System) as per the manufacturer’s instructions (detection limit 31.5 pg/ml). Urine samples for Substance P analysis were also collected from six healthy controls.Blood samples were obtained for DNA extraction at the onset of the study. Blood samples for RNA extraction were obtained on days 0 and 7, and repeatedly during follow-up.For gene expression analysis, RNA was purified from peripheral blood using Tempus blood RNA tubes and purification kit (Applied Biosystems) and subjected to expression microarray analysis: 100 ng of total RNA was amplified using GeneChip 3′ IVT PLUS or GeneChip WT PLUS reagent kits. After fragmentation and labeling, cRNA was hybridized to Human Genome U219 or Human Clariom S HT arrays , either in house using the GeneAtlas system or by Eurofins Genomics. The data were normalized using Robust Multi Average implemented in the Transcriptome Analysis Console software . An absolute fold change of >1.5 compared with the pretreatment sample in individual patients was considered significant. Differentially expressed genes were examined using Ingenuity Pathway Analysis software . Heatmaps were constructed using the Gitools 2.1.1 software.https://www.well.ox.ac.uk/∼wrayner/strand/index.html#Illumina (GSAMD-24v2-0_20024620_A1-b37-strand.zip file). The dbSNP IDs or coordinates not present in the annotation file were extracted from the original IDs using standard pattern matching methods. To obtain dbSNP IDs (rs numbers), the coordinates were converted to dbSNP IDs using a local copy of the dbSNP database. Moreover, the reference alleles were included in the annotations using Samtools version 1.9 and in-house Python scripts DNA was extracted from peripheral blood samples using the QIAamp DNA blood kit as per the manufacturer’s instructions (Qiagen). Exome genotyping was by Illumina Infinium Exome bead chip technology with >240 000 markers from diverse populations. Single nucleotide polymorphisms (SNPs) were annotated using the Ensemble Variant Effect Predictor. ID extraction and data conversion were carried out using R A is the variant allele and AC is the total allele count. The AC was calculated across the samples by subtracting the number of missing genotype calls from the theoretical maximum allele count, which is two times the number of samples. The allele and genotype counts for the variants were retrieved from the genotype dataset using Tabix and in-house Python scripts The variant allele frequency of individual SNPs within these genes were calculated based on the formula: MMP7 (rs11225298), Il1R1 (rs10199359), or TACR1 (rs3771833).Patients XI–XVII were subjected to limited genotyping by pyrosequencing (PSQ96) after polymerase chain reaction amplification of chromosomal DNA using the PyroMark Gold Q96 SNP reagent. Biotinylated primers were designed to detect polymorphisms in 2.6p < 0.05. Clinical outcome variables were assessed by the Mann-Whitney U test and paired data using the Wilcoxon signed rank tests. Genotype data were compared using Fisher’s exact test.The data were analyzed by Prism (GraphPad version 6.01) and were considered statistically significant at 33.1Off-label IL-1RA treatment was offered to patients diagnosed with BPS , Table 23.2p < 0.001) and increased quality of life . Individual treatment regimens have varied from daily (four patients) to weekly (five patients) or monthly (two patients) injections. One patient stopped successful treatment after 28 d due to worsened migraine attacks, and one discontinued treatment after 80 d due to a waning effect (Supplementary Table 2).p < 0.001; The clinical response during the 1st week of treatment was accompanied by a reduction in Substance P levels  Patient DNA sequence variants were identified by whole-exome genotyping. Potential susceptibility genes were selected for analysis, based on known disease associations in the murine cystitis model , are the following: The authors hold shares in SelectImmune Pharma, a biotech company, with an interest in exploring the potential of IL-1RA treatment in cystitis and bladder pain.Funding/Support and role of the sponsor: Support was from national grants. Financial support was generously provided by the Swedish Medical Research council (#2016-01952), the 10.13039/501100002794Swedish Cancer Society (#140776), the Österlund Foundation, the Inga-Britt and Arne Lundberg Foundation, the Hedda and John Forssman Foundation for medical research (#40964), and the Royal Physiographic Society of Lund (#136260). The European Union’s Horizon 2020 research and innovation programme (#954360) provided support to the laboratory infrastructure. Patents have been filed for the use of IL-1RA as a treatment for cystitis and bladder pain.Acknowledgments: We gratefully acknowledge technical support of the Genome Institute of Singapore (DNA sequencing) and Jane Pullman at Genevia Technologies Oy , and clinical advice from Dr. M.C. Kapetanovic, the Rheumatology Division, Lund University Hospital, Sweden.