To assess the incidence and causes of persistent thigh pain and peri-implant fractures after union in patients of intertrochanteric fractures treated with short cephalo-medullary nails.A retrospective observational study conducted at a Level 1 Trauma centre. A total of 122 patients of intertrochanteric fractures who were operated using short cephalo-medullary nails (170mm and 200mm lengths) between January 2018 to June 2019 were included in the study. Main outcomes measured were the incidence of thigh pain and peri-implant fractures.Out of the 122 patients with a mean follow-up of 14.1 month, 12 patients had persistent thigh pain. Six patients had the helical blade protruding from the lateral cortex, two of them had distal tip of nail abutting on the anterior cortex and four cases had prominent proximal segment of nail which may explain the cause of their pain. Five of these patients had a combination of these findings. Two patients had pain for which no other obvious cause was found. There were no cases of peri-implant fractures in our study.Thigh pain associated with the use of short cephalon-medullary nails is often unrelated to nail length and can be prevented by using proper surgical technique. There seems to be no association between the use of short nails and peri-implant fractures. Management has evolved from conservative management to early surgical intervention wherever feasible, to allow early mobilisation. Most of the older literature suggests the use of long proximal femoral nails for intertrochanteric fractures in elderly osteoporotic patients, the rationale being splintage of entire femur using a long nail reduces the chances of peri-implant fractures and also negates the chances of thigh pain due to impingement of nail tip against the anterior femoral cortex3. However, using long nails for all such cases is fraught with its own problems and risks. Use of short nails have numerous advantages like shorter operative and anaesthesia time, less blood loss, less reaming (reduced chances of emboli) and reduced chances of distal perforation, all of which have been proven in numerous studies7. In spite of all these advantages there is a theoretically increased risk of peri-implant failures and thigh pain with the short nails. Clinical results of short nails are comparable to their longer counterparts even with theoretical biomechanical handicap. Many surgeons have also begun to use distally unlocked short nails in intertrochanteric fractures with good clinical outcomes9.Fractures around hip are debilitating injuries. They are associated with high mortality rates, reported to be around 10% in some studies as well as morbidity associated with immobilisation in elderly patientsThere are far too few studies focussing on the aspect of thigh pain and re-fractures after surgery because of which there is huge void in our knowledge about the incidence, aetiology, and ways to prevent these complications associated with short nails. Also, there are many conflicting views about the aetiology of pain in these patients which cannot be attributable to the nail size alone.In this study we have tried to find the answer to the question that whether there is any significant increase in the incidence of thigh pain and peri-implant fractures in patients of intertrochanteric fractures operated using short cephalomedullary nails. We have also tried to ponder about the probable causes of pain when present and whether it can be attributed to the size of the nail used.10 managed operatively using short cephalomedullary nail with clinical and radiographic signs of union with a minimum follow-up of 12 months were included in the study. We excluded patients of polytrauma, pathological fractures, revision surgery, non-union and implant failure.After institutional review board approval, a retrospective study was conducted on patients of intertrochanteric fractures operated at our institute with short cephalomedullary nails (170mm and 200mm) between January 2018 and June 2019. The aim of the study was to assess the incidence and causes of thigh pain and peri-implant fractures in these patients. All patients over 60 years of age with closed isolated intertrochanteric fractures After adequate effect of anaesthesia, patient was positioned on the traction table and closed reduction attempted. After successful closed reduction, internal fixation was done using standard technique of cephalo-medullary nailing with short nail with helical blade  . Post-op11 and was compared it to its pre-trauma status. Descriptive statistics were elaborated in form of mean/standard deviations for continuous variables and frequency/percentage for categorical variable. Group comparisons for continuously distributed data were made using independent 't' test. Chi-squared test was used for group comparisons of categorical data. In cases where the expected frequency in contingency table was less than 5 for >25% cells, Fischer's exact test was used instead. Statistical significance was kept at p value <0.05.Medical records were studied for obtaining the demographic data, surgical details, radiographs, and information regarding the implant. Outpatient records were studied to retrieve data regarding follow-up. SPSS v23 [IBM corp.] was used for data analysis. At each follow-up visits the patients were enquired regarding thigh pain. Intensity of thigh pain when present was quantified using visual analogue scale (VAS). If they complained of thigh pain, we further enquired about the site of pain, onset of pain (since post-operative period or after some time lapse), nature of pain and its relationship to ambulation (whether pain is relieved on rest or not). Mobility status of the patients were quantified using the modified Harris hip score (mHHS)A total of 122 patients of intertrochanteric fractures satisfying our inclusion criteria was found in our records. There were 79 males and 43 females. The mean (SD) age of patients included in the study was 70.18 (6.94) years. The basic demographic data of our patients is showed in The mean (SD) of Age (Years) in the group with thigh pain was 70.67 (4.66) with an age range of 64 - 78 years. The mean (SD) of Age (Years) in the group without thigh pain was 70.13 (7.16) with the age range of 60 - 89. There was no significant difference between the groups in terms of Age (Years) . Mean time for radiographic union was 20.2 weeks.Fisher's exact test was used to explore the association between 'Thigh Pain' and 'Gender' as more than 20% of the total number of cells had an expected count of less than five. There was no significant difference between the various groups in terms of distribution of Gender .11 of 82.5. The pain was localised to proximal thigh in all the patients and not associated with groin pain or tingling or paraesthesia ruling out any other causes like meralgia paraesthetica, co-existing hip arthritis, blade cut through which was confirmed by evaluation of their radiographs.Twelve patients (9.8%) complained of thigh pain at follow-up. Out of the twelve patients eight of them independently mobile while four patients needed cane/stick. None of the patients had peri-implant fractures, even though five patients had history of fall at home after surgery. The mean pain score using visual analogue scale was 3.25 with individual scores ranging between 2-4. The pain was mild to moderate in intensity and did not affect their mobility or ability to perform activities of daily living with an average modified Harris hip scoreSix patients had prominent proximal blade due to improper length of the helical blade. Five of them had point of maximum tenderness over the proximal blade insertion site while others had diffuse pain over proximal thigh. However, only two of them had long blade as the only radiographic finding while the rest had some other associated findings.2 = 0.063, p = 1.000).Two cases had too posterior an entry point which led to nail abutment at the anterior cortex while three cases had excessive bowing of femur that led to similar finding. Four cases had a prominent proximal nail segment, out of which in only one patient was it the only associated finding. Five of the twelve patients had one of the above causes as isolated finding. The other five had a combination of findings as summarised in Thigh pain and peri-implant fractures has been reported as drawbacks of using short nails. Advantages offered by short nails are alluring but at the same time apprehension of these pitfalls often creates a dilemma in the mind of treating surgeon regarding ideal choice of implants. Hence, we conducted this study to assess the actual magnitude of these impediments while using short CMN.In our study, we observed that the short versions of the cephalo-medullary nail (170mm and 200mm) was associated with thigh pain in 12 patients (9.8%). We did not encounter any cases of peri-implant fractures even though five patients reported low energy trauma  after surgery. We further examined and analysed the radiographs of each patient who complained of thigh pain at follow-up. We found that majority of the cases had a finding  which can explain the reason for thigh pain apart from the nail length. The most common findings were improper length of helical blade with lateral overhang of the blade, causing irritation of the vastus lateralis and tensor fascia lata muscles . This waet al12 on proximal thigh pain after femoral nailing with Grosse-Kempf nail for diaphyseal fractures observed that heterotrophic ossification was a major cause of persistent thigh pain. However, we did not encounter any case of heterotrophic ossification in our study. The study also sheds light on other probable causes, but the underlying point being that thigh pain is also associated with long nail and short nail length may not be a risk factor as has been the common notion.There is a lacuna in our current understanding on the subject of thigh pain and peri-implant fractures after proximal femoral nailing due to lack of objective data and quality evidence. A study by Dodenhoff et al13 highlighted the problem of mismatch of nail and femur geometry. In their study they encountered problems related to the mismatch of the proximal end of the nail in 11 cases. Nine of these patients presented with thigh pain due to the redundant proximal end of the nail. In another study by Rosen et al14, they commented that lateral hip pain from proximal locking device insertion and prominence continues to be one of the most frequent complaints following this surgical procedure. Another factor for thigh pain is the length of the nail chosen. There is no Level I or II evidence that favour one nail length over other . In a randomised controlled trial conducted by Parker and Cawley15 they concluded that there was a trend toward greater residual pain for those treated with the shorter nail, although this was not statistically significant and cautioned about the excessive use of these short versions of the nail. Though there is no biomechanical study that has determined the ideal length of nail for cephalo-medullary nailing, there has been a trend of decreasing size of the implants from 220-250mm nails to the shorter versions (170-200mm nails). Nails as short as 160mm have been used in some situations with good clinical results16. In this study we did not find any significant difference in the incidence of peri-implant fractures or thigh pain between 170mm and 200mm nails.A study by Jin-Song Pu et al17, they concluded that though peri-implant fractures were rare incidences, chances of its occurrence were 3.7 times higher with PFN compared to DHS. Numerous studies have attempted to evaluate these factors but have their own set of flaws, like use of previous generations of nails (gamma nails were used in most of the studies), longer length of nails (240-250mm nails were more commonly used in the past) and nail-femur geometry mismatch. In a study by Robinson et al18, they found that the risk of femoral peri-implant fracture after hip surgery was 40 times more than general population. However, these previous generations of short nails used, had many flaws. They were rigid, stainless-steel implants with large locking bolts at the distal tip of the nail in the diaphyseal region. Also, there was frequent mismatch of the nail and femoral geometry that frequently created stress risers. In addition, these original relatively large diameter short nails were associated with intra-operative insertional fractures. The problems have largely been addressed in the newer generations of nail which have taper stem, oblique distal bolts and more anatomical bend leading to lesser incidence of peri-implant fractures.In a study by Muller Another important and upcoming problem is the exponential increase in total knee arthroplasties. With the increased in longevity, more and more patients suffering from knee osteoarthritis are opting for arthroplasty. Use of stem in femoral component would not be possible in presence of long nail and hence we need to consider short nails in these patient populations. This makes it even more important to understand in detail, the pros and cons associated with the use of short nails in geriatric population.The lifestyle and mobility of elderly population in Asian countries differs significantly from the western populations. Most of the elderly population, even before the trauma are confined mostly to low demand home-bound activities like stair climbing, morning walks and kneeling for prayers. In contrast, the elderly in western countries lead a more demanding lifestyle including independent driving, routine exercises and in some cases participation in active sports. This may explain the lower incidence of peri-implant fractures and thigh pain in our study compared to other studies involving western populations. However, this demographic and lifestyle differences may change when the current generations born after 1990s ages as their lifestyle and mobility expectations are quite similar to the western populations. It would be interesting to see if the short nails survive this test of time.The limitations of the study, firstly, relatively small sample size, which may affect the quality of final outcome. Another limitation is the short duration of follow-up (mean follow-up of 14.1 months). Though we believe that more than 12 months of follow-up is sufficient for peri-trochanteric fractures for union and clinical outcomes, the incidence of peri-implant fractures and thigh pain need longer periods of follow-up. We plan to continue the study on our patients and document the long-term results with regard to the parameters considered in this study.Thigh pain associated with the use of short cephalomedullary nails is often unrelated to nail length and can be prevented by using proper surgical technique. There is no association between the use of short nails and peri-implant fractures. Modern short nail designs are much safer with respect to peri-implant fractures as evident by no cases in our study. However, further better designed clinical studies with larger sample size and longer follow-up are required to make the evidence unequivocal.


Persistent Idiopathic Facial Pain (PIFP) is a pain syndrome with missing evidence-based therapy recommendations. According to the biopsychosocial pain model, multidisciplinary pain treatment (MPT) offers a promising therapeutic option for chronic pain syndromes. MPT is an interprofessional treatment procedure, consisting of medical, physiotherapeutic and psychotherapeutic treatment units, which has not yet been studied in PIFP.This retrospective study included 25 patients with PIFP, who had been treated with MPT. Pain intensity on the numerical rating scale (NRS), perceived disability, habitual well-being, as well as anxiety/depression and stress scales were recorded. Moreover, the patients evaluated the efficacy of each type of the single therapeutic interventions.There was a highly significant decrease in the characteristic pain intensity. Also habitual well-being improved significantly, as did anxiety and depression. The perceived disability and stress also improved, but without statistical significance. Physiotherapy was rated as the most effective therapeutic unit. Among the medical measures, consultations took first place (40% of the participants). Nearly three-fourths of the patients (72%) would recommend MPT.The present study shows beneficial outcomes in patients with PIFP following MPT. Patients evaluate physiotherapeutic treatment as particularly efficacious. Therefore, MPT can be considered as a therapeutic option in patients with PIFP. Persistent Idiopathic Facial Pain (PIFP), formerly called atypical facial pain, was described for the first time in 1924 . MoreoveThe International Headache Society (IHS) describes PIFP as “Persistent facial pain that does not have the characteristics of [...] cranial neuralgias [...] and is not attributed to another disorder” . MoreoveTo date, there are no evidence-based recommendations for the pharmacological treatment of PIFP . NonethePIFP is a chronic pain syndrome. Chronic pain has to be regarded as an entity of its own, which cannot be characterized solely by the duration of its presence. Affective, sensory, psychological and social factors which can cause or sustain the pain syndrome must also be considered . All theMultidisciplinary pain treatment (MPT) is an effective procedure in the treatment of chronic pain . AccordiThe present study sought to examine whether MPT could be an effective treatment option for PIFP and whether an amelioration of pain, depression and anxiety as well as habitual well-being would be found. To that end, 25 patients diagnosed with PIFP who had undergone MPT in the Interdisciplinary Pain Centre of the University Hospital (City Name) were examined regarding the effects on subjective perception of their pain state. Moreover an evaluation of the single therapeutic units was performed as a Patient Reported Outcome Measurement (PROM). Primary outcomes under study were pain, depression, anxiety and habitual well-being. Secondary outcomes were the individual ratings of each type of the single therapeutic interventions.The present retrospective study was performed at the Interdisciplinary Pain Center, University Hospital (city name). The study was approved by the Ethics Committee of the University Hospital (city name) (No.473/16). The study was performed in accordance with the Declaration of Helsinki.First, a preliminary selection of the potential study collective by means of electronic search of all discharge notes in the years 2009 to 2015 was performed, regarding the following ICD codes: R51, G50.0, G50.1, G50.9, G50.8, K10.8, K08.88. This first step served as a filter to preselect patients with orofacial pain syndromes. Then, the hits were individually controlled for the diagnosis PIFP. All clinical features of PIFP had to be present for inclusion in the study. Patient with competing diagnoses such as trigeminal neuralgia were excluded. According to common clinical terminology, terms such as “continuing” or “ongoing” were included, as were paraphrases of idiopathic such as “without identifiable cause” or “etiology not proven”. Also, the former diagnosis of atypical facial pain was included. Moreover, the clinical description in the files was checked regarding the presence of criteria of PIFP based on the IHS definition according to the ICHDII.diagnosed PIFPage between 18 and 80 yearsparticipation in a 5-week MPT between 01.01.2009 and 31.07.2016Facial pain not meeting criteria for PIFPInability to perform telephone interviewIncomplete questionnaireMPT of less than 5 weeksMultidisciplinary pain treatment was carried out according to the German Operations and Procedure Key (OPS) -Code 8–918 (interdisciplinary multidisciplinary pain treatment) over a five-week period in a day hospital setting. This program meets the requirements of the OPS and is therefore comparable to corresponding programs in Germany . TreatmePsychotherapy was also offered as both individual and group therapy. Psychotherapy was based on a behavioral approach. The identification of pain-sustaining cofactors, as well as acceptance of and coping with pain were topics of the therapy. Moreover, occupational therapeutic and sociomedical treatments were available as necessary. An example of a weekly schedule for individual patients is shown in fig. All data collected by telephone interview in the period between 05.12.2016 and 19.01.2017 and from the patient files] were included. Prior to the interview the patients gave informed consent to participation in the study. None of the patients stood under legal guardianship.In the telephone interview, first the criteria of PIFP prior to and after MPT were asked. The telephone interview included pain scores  on an 11-point (0–10) numeric rating scale (NRS) as principal primary outcome. Further depression, anxiety and stress were measured by the depression, anxiety and stress scale (DASS) . This scPerceived disability was measured with the disability score, a shortened version (3 items) of the 7-item Pain Disability Index (PDI) for the experience of impairment, in which scale items are rated on an 11-point scale ranging from 0 to 10. The mean value of these three items multiplied by 10 gives the value for the disability score.The PDI was developed particularly for patients with pain –27. FactHabitual well-being was recorded after MPT by means of the MFHW (Marburger Fragebogen zum Habituellen Wohlbefinden), a 7-item questionnaire questionnaire on habitual health findings with a 6-point scale for each item , 24, 31.This questionnaire has proven a good internal consistency (Cronbach’s α = 0.91) and test reliability after an 8-week interval (rtt = 0.81). The one dimensional test scale is showed a good reproducibility and factor structure with an explanation of variance of at least 65%. The construct validity has been evidenced by correlations with indicators for chronification .Further, patients were asked for their individual evaluation of the efficacy of the single therapeutic measures on an 11-point-scale . The data acquisition by telephone interview ensured that there were no missing data. All interviews were conducted by the same person in order to minimize potential interviewer bias.From the patient files, the discharge notes and the German pain questionnaire  , which pFor our study, all patients matching to the study criteria were telephoned and 42 patients could be contacted. Finally, 25 patients could be included Fig.. With 25p < 0.05  and p < 0.01 . A Bonferroni correction was calculated to correct multiple testing in case of measures with multiple single measures.First, data were controlled for normal distribution (Kolmogorov-Smirnov-Test). The analysis regarding age, sex, diagnosis, concomitant medication and therapies and prior operations was made by categorization and descriptive statistics (absolute frequencies (n) and percentages (%)). For the parameters, media were calculated prior to therapy and median values, minima and maxima, mean values and standard deviations as well as absolute and relative frequencies after therapy. The t-test for paired samples was used to examine the pre/post differences in case of normally-distributed values, the Wilcoxon rank sum test in case of missing a Gaussian distribution. Levels of significance were The study sample consisted of 25 patients (16 women/9 men). The mean age was 56.6 ± 12.7 years. The median duration of the pain anamnesis was 9.7 years, interquartile range (IQR) 5.7; 16.5 years  (Table p = 0.001). Also all single pain measures decreased significantly after therapy . The perceived impairment regarding daily living, leisure time and work, as measured by the disability score showed no statistically significant difference before and after therapy, neither in the three single areas, nor in the sum score. The sum score of the MFHW, which was calculated from seven single items showed a statistically significant improvement (p0 0.016) while the single items except the item “feeling comfortable” showed no statistically significant differences. The depression and anxiety, but not the stress scores showed a statistically significant decrease after MPT  , a combination of physiotherapy and psychotherapy 6 24%), a combination of psychotherapy, physiotherapy and medical treatment 6 (24%), psychotherapy alone 3 (12%), no single measure 2 (8%) and medical treatment alone 1 (4%)  [The effects of MPT on psychological parameters such as anxiety and depression may be considered equally important to the pain-relieving effects. DASS)  and due s. DASS) . A studys. DASS) . In the s. DASS) . Anxietys. DASS) .The results as recorded by the DASS hint at a positive impact of MPT. In patients with temporo-mandibular disorders it has been shown that a multidisciplinary pain treatment approach is required due to psychological distress . The impPatients rated physiotherapy to be the most efficacious therapeutic measure. Also among the single ratings, physiotherapy attained the highest scores of the three measures physiotherapy, psychotherapeutic treatment, medical therapy. This reflects the result of a randomized controlled study (RCT) which demonstrated the efficacy of physiotherapeutic exercises for orofacial pain . ApparenA number of limitations have to be discussed: first, the small sample size reduces the generalizability of the results. However, as PIFP is a very unusual diagnosis, higher sample sizes are difficult to acquire at a single institution. In fact, many studies of PIFP deal with comparable or smaller sample sizes –49. FurtIt could be objected that the details of individualized therapy in MPT  are not standardized. This probably holds true for most studies on MPT. MPT however should not only be understood as a completely standardized therapy. Rather it could be characterized as an organizational structure allowing pain therapy under consideration of the individual comorbidities , 50. FurA strength of the study is the detailed examination of all patients, comprising the investigation of multiple parameters and the analysis of the effects of MPT on different areas of life.In summary, the present study shows beneficial outcomes in patients with PIFP following MPT. MPT therefore may also be efficacious in PIFP, corresponding with many other chronic pain syndromes. These findings should be replicated in further studies with numbers of participants. Due to the rarity of the disorder a multicentric controlled study design would be desirable. These studies should also aim to analyze how the individual therapeutic measures, respectively their composition in the context of MPT, can contribute to further increase the efficacy of MPT.


To establish a scoring system to predict the residual back pain after percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fracture (OVCF).We retrospectively reviewed the clinical records of 98 patients who were diagnosed of single-vertebral OVCF and underwent PKP surgery in our department from January 2015 to December 2017. The following clinical characteristics including age, gender, disease course, fracture location, fracture type, segmental kyphosis, and bone cement volume were all recorded, and the effects of these factors on postoperative pain (at 1-month and 6-month postoperative) were also analyzed respectively. Based on 6-month postoperative VAS score, the included patients were divided into two groups, namely the residual back pain group (19 patients) and the non-residual back pain group (79 patients). The independent risk factors of residual back pain after PKP were screened and the scoring system was established by the multivariate logistic regression analysis. The performance of this scoring system was also prospectively validated using the clinical data of 45 patients with single-vertebral OVCF from January 2018 to December 2019.P = 0.021), fracture location = thoracic or lumbar (P = 0.002), fracture type = OF4 type (P = 0.018), segmental kyphosis ≥20° (P = 0.014), and bone cement volume <5 ml (P = 0.001). Patients in the residual back pain group showed a significant higher score than the non-residual back pain group , and the optimal cut-off value for the scoring system was 5 points. The sensitivity and specificity of the scoring system for predicting residual back pain after PKP were 84.21% and 87.34%, respectively, in derivation set and 78.57% and 83.87% in validation set.The scoring system was consist of five clinical characteristics which were confirmed as significant predictors of residual back pain after PKP, namely, age ≥60 years (This novel scoring system showed satisfactory diagnostic efficacy in predicting residual back pain after PKP for single-vertebral OVCF. Patients with the score of 5–9 had a high risk of postoperative residual back pain, while the patients with score of 0–4 was low. Osteoporosis is a systemic bone disease manifested by the decrease of bone density and quality, the destruction of bone micro-structure, and the increase of bone fragility, and often result in fractures . OsteopoThe treatment of OCVF included conservative treatment and surgical treatment. Conservative treatment mainly included bed rest, wearing waist brace, and analgesic drugs . HoweverIt was reported PKP can effectively relieve pain, and thus promote the early activities after surgery, shorten the time in bed, and reduce the risk of postoperative complications . TherefoTherefore, we conducted this study to identify the clinical characteristics which can predict residual back pain and develop a novel scoring system to help spinal surgeon to predict residual back pain after PKP. We also validated the performance of this scoring system and confirmed its satisfactory ability in predicting residual back pain after PKP in OVCF.This study was approved by the Ethics Committee of the Second People's Hospital of Chengdu and carried out in accordance with the Declaration of Helsinki. All of the participants provided their written informed consent to participate in this study. The work has been reported in line with the STARD criteria .We retrospectively reviewed the medical records of hospitalized patients diagnosed of OVCF in our department from January 2015 to December 2017 to form the derivation set.Inclusion criteria: (1) Acute single-vertebral OVCF ; (2) Bone mineral density (BMD) examination  confirmed osteoporosis (T score ≤−2.5); (3) The fracture type was OF2, OF3, or OF4 according to the Classification of Osteoporotic Thoracolumbar recommended by the Spine Section of the German Society for Orthopaedics and Trauma (DGOU) .Exclusion Criteria: (1) Previous history of spinal surgery; (2) Long-term use of analgesics before hospitalization, such as NSAIDs, opioids; (3) Pathologic vertebral fracture caused by tumor, infection; (4) Less than 12-month follow-up or incomplete medical record data.According to the patients selection criteria, a total of 98 patients were finally included in the derivation set with 29 males and 69 females. The average age of the included patients was 64.72 ± 7.89 years and the average disease course was 3.01 ± 1.45 months. The detailed clinical characteristics of the included patients were shown in (1)Patient related data: (a) Age of patient: age ≥60 years or <60 years; (b) Gender of patient: male or female; (c) Disease course: ≥6 weeks or <6 weeks.(2)4–T9), thoracolumbar vertebrae (T10–L2), or lumbar vertebrae (L3–L5); (b) Fracture type: OF3 type, OF3 type, or OF4 type; (c) Segmental kyphosis: the kyphosis angle was defined as the angle between the superior and inferior endplates of the fractured vertebra, kyphosis angle <20° or ≥20°.Preoperative imaging data: (a) Fracture location: thoracic vertebrae (T(3)Surgery related data: bone cement volume <5 ml or ≥5 ml.(4)Follow-up outcomes: VAS score at preoperatively, 1 month postoperatively, and 6 months postoperatively. Postoperative residual back pain was defined as the VAS score at 6 months postoperatively was more than four or the patients still need analgesic medication to contribute a good sleep.Based on previous studies and our experience, we included the following predictors for residual back pain after PKP. In addition, postoperative VAS scores at different follow-up time were also recorded.P < 0.05 were considered the final predictors for postoperative residual back pain and, thus, determined as the items of the scoring system. Then, we established the weighted score of each item based on the relative size of Odds Ratio (OR) according to the method reported by previous research  were all analyzed respectively. Secondly, all the included patients were divided into two groups, namely, non-residual back pain group and residual back pain group according to the 6-month postoperative follow-up outcomes. Next, multivariate logistic regression analysis was performed. According to the results of multivariate logistic regression analysis, the indexes with research . FinallyFrom January 2018 to December 2019, we prospectively included patients to validate the accuracy of the scoring system. The following criteria were used to select patients to form the validation set. Inclusion criteria: (1) MRI suggested acute single-vertebral OVCF; (3) BMD examination showed T score ≤−2.5; (4) OF2, OF3, or OF4 type fracture. Exclusion Criteria: Exclusion Criteria: (1) Previous history of spinal surgery; (2) Long-term use of analgesics before hospitalization; (3) Pathologic vertebral fracture caused by tumor, infection.Patients signed informed consent and then underwent PKP surgery. Before discharge, surgeon predicted whether the patient will suffer from residual back pain at 6 months postoperatively according to the scoring system (predictive outcome). At 6 months after surgery, the patient will be assessed whether they truly develop residual back pain (true outcome). The accuracy of the scoring system was evaluated by comparing the consistency between the predictive outcome and the true outcome.t-test. The significant predictors of residual back pain at 6 months postoperatively were evaluated by multivariate logistic regression analysis. The items of the scoring system were determined by multivariate logistic regression, and the weighted score of each item was based on the relative size of the OR. The optimal cut-off point was made by using ROC curves. P < 0.05 was set of statistical significance. The SPSS version 10.0 software was used for statistical analysis.The effects of clinical characteristics on postoperative back pain at different follow-up point were analyzed by independent-samples P = 0.03 and P = 0.02, respectively), course of disease ≥6 weeks , fracture location = thoracic or lumbar , fracture type = OF4 type , segmental kyphosis ≥20° , and bone cement volume <5 ml , all had negative effects on postoperative back pain at both 1 month and 6 months postoperatively (It was showed that age ≥60 years (ratively .P = 0.021), fracture location = thoracic or lumbar (P = 0.002), fracture type = OF4 type (P = 0.018), segmental kyphosis ≥20° (P = 0.014), and bone cement volume <5 ml (P = 0.001) were significant predictors of postoperative residual back pain . The optimal cut-off value of the predictive scoring system was 5 points, and the area under curve (AUC) was 0.931   .Finally, a total of 45 patients were prospectively included in the validation set, including 14 cases in residual back pain group group and 31 cases in non-residual back pain group according to the 6-month postoperative follow-up outcomes. Comparison of the performance of the score system on derivation set and validation set was shown in In this study, we first evaluated the clinical efficacy of PKP for OVCF. During the 6-month follow-up, we found that PKP was an effective procedure, with significant short-term relief of patients' pain symptoms. Although the VAS score of at 6 months postoperativbely was higher than that at 1 month postoperatively, the difference was not statistically significant, and the VAS score at 6 months postoperativbely was significantly lower than that before surgery, which further confirmed the efficacy of PKP for OVCF.Moreover, we further analyzed the predictors of postoperative residual back pain. We found that the postoperative residual back pain 6 months after PKP was more obvious in OVCF patients aged ≥60 years than in patients aged <60 years. There might be the following reasons: (a) the degree of osteoporosis was more serious in the elderly ; (b) theIn addition, the results of this study showed that there were significant differences in pain relief in different types of OVCF. First of all, patients with OF2 or OF3 type fracture had more obvious pain relief, while patients with OF4 type fracture had higher VAS scores after PKP. Secondly, we also found that OVCF patients with kyphosis had higher postoperative VAS scores and less pain relief. We speculate that this may be related to the severity of vertebral fracture , namely,Surgical factors are important factors affecting the postoperative pain. Röder et al. conducted a retrospective analysis of 276 patients with single-segment vertebral fractures, and found that bone cement volume was an important factor influencing pain relief after PKP (OR = 0.36), meanwhile, they suggested that bone cement volume in PKP should be >4.5 ml in order to better relieve the pain . The aboThere are some limitations of our study. First, it was a retrospective study. Second, the number of patients included in this study was small and the postoperative follow-up time was short. Third, this study did not evaluate other factors that might affect postoperative pain relief, such as comorbidities.In summary, our study suggested that PKP can significantly relieve pain in OVCF patients. Age ≥60 years, fracture location = thoracic or lumbar, fracture type = OF4 type, segmental kyphosis ≥20°, and bone cement volume <5 ml were the predictors for residual back pain after PKP. Due to the limitations of the study, further studies are needed to confirm the above conclusion.


NCT02848651), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB–IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( The randomized B-F1RST trial evaluating the clinical utility of blood tumor mutational burden as a predictor of benefit from atezolizumab in patients with advanced lung cancer did not meet its pre-specified primary objective, underscoring the need to further investigate the significance of bTMB as a relevant biomarker for patient selection. EGFR/ALK wild-type squamous or non-squamous locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have high programmed death ligand 1 (PD-L1) expression. The phase 3 IMpower110 trial (n = 572) included patients who had PD-L1 expression on ≥ 1% of tumor cells (TCs) or ≥ 1% of tumor-infiltrating immune cells (ICs) assessed by the SP142 immunohistochemistry assay (Ventana). Patients with the highest PD-L1 expression (on ≥ 50% of TCs or ≥ 10% of ICs) had a median OS of 20.2 months with atezolizumab monotherapy versus 13.1 months with platinum-based chemotherapy (hazard ratio (HR) = 0.59  0.40, 0.89); P = 0.0106)1.Atezolizumab monotherapy is effective in the first-line treatment of patients with 5. TMB also appears to identify patients with NSCLC who benefit from anti-PD-L1/PD-1 treatment and patients who express low levels of PD-L1 (refs. 6). However, as many as 30% of patients with NSCLC may not have enough high-quality tissue biopsied at diagnosis for biomarker analyses7, clearly indicating a need for a non-invasive cancer immunotherapy biomarker assay. An advantage of bTMB is that the source material is readily available and is less susceptible to sampling bias due to tumor heterogeneity of biopsies obtained from single sites at a single time point9.In addition to PD-L1, TMB may also be a useful biomarker for cancer immunotherapy benefit. tTMB, as determined by whole-exome sequencing and targeted panels, is associated with clinical benefit from multiple checkpoint inhibitors, particularly in the monotherapy settingNCT02848651) used the Foundation Medicine bTMB assay to evaluate TMB status in clinical blood samples. The assay uses a hybridization capture-based method that targets 1.1 megabases (Mb) of genomic sequence10. The assay can detect bTMB, provided there is adequate ctDNA, defined as an MSAF ≥ 1%. The bTMB score is expressed as the total number of single-nucleotide mutations in the genes targeted by the assay after germline and driver mutation filtering. The bTMB cutoff score of ≥ 16  (16 mut/1.1 Mb)) was defined in the phase 2 POPLAR training set and validated in the phase 3 OAK study in 2L + NSCLC10. In OAK, the HR for PFS in patients above the cutoff of ≥ 16 who were treated with atezolizumab monotherapy versus docetaxel was 0.65  compared to 0.98  for patients with bTMB < 16 (ref. 10).B-F1RST (1). PFS in the any-PD-L1-expression (intent-to-treat (ITT)) population who received atezolizumab versus chemotherapy was 5.7 versus 5.5 months  and, in the bTMB ≥ 16 group, was 6.8 versus 4.4 months , suggesting that bTMB ≥ 16 is predictive of improved outcomes with atezolizumab but also that it is prognostic of worse outcomes with chemotherapy.In the IMpower110 study, exploratory analyses showed that the median OS in patients with PD-L1-positive tumors who had a bTMB score ≥ 16 (14.5 mut/Mb) was 13.9 months in the atezolizumab monotherapy arm versus 8.5 months in the chemotherapy arm  compared to an HR of 1.07 for patients with bTMB < 16  follow-up, updated results for the non-biomarker-evaluable patients12 and additional exploratory biomarker analyses of the genomic landscape and association of the most prevalent alterations with bTMB and efficacy outcomes.B-F1RST was the first study to evaluate bTMB prospectively in patients with locally advanced or metastatic NSCLC treated with atezolizumab monotherapy in the first-line settingThis study was conducted from 21 September 2016 through 14 May 2019. The final analysis included all patients with at least 18 months of follow-up at the clinical cutoff date of 26 July 2019, resulting in a median follow-up of 20.9  months. A follow-up analysis of OS  was conducted with a median follow-up of 36.5 months.EGFR mutations or ALK alterations (Supplementary Methods). The ITT population excluded one enrolled patient who was not treated , consistent with previous observations in OAK and POPLAR10. However, it should be noted that 36% of patients in the ITT population were missing a PD-L1 result.B-F1RST enrolled patients with immunotherapy-naive stage IIIB–IVB NSCLC, regardless of PD-L1 status, excluding those with The primary efficacy endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The ORR in the ITT population was 17.1% . ORR (95% CI) in the bTMB ≥ 10 versus bTMB < 10 groups was 20.4%  versus 7.1% . ORR (95% CI) for bTMB:≥ 20 versus bTMB < 20 was 47.4%  versus 6.0% .In a secondary biomarker analysis, ORR in the bTMB ≥ 16 versus bTMB < 16 subgroups was 35.7%  versus 5.5%  , with 29% missing PD-L1 results.The patients with bTMB ≥ 20 and bTMB ≥:16 to bTMB < 20 were predominately clustered in the responder groups Fig. . There wP = 0.41), whereas, at bTMB ≥ 18, the PFS HR was 0.62 , and, at bTMB ≥ 20, the PFS HR was 0.59 . Similar trends were noted for OS where, at bTMB ≥ 10, OS HR was 0.98 , whereas, at bTMB ≥ 18, the PFS HR was 0.49 , and, at bTMB ≥ 20, the HR was 0.44  were non-evaluable for bTMB and were defined as the MSAF < 1% population. These patients had a higher response rate than patients with MSAF ≥ 1%  = 4.2, 95% CI: 1.7, 10.7; Fig. % were no12. We compared baseline characteristics between the MSAF < 1% and MSAF ≥ 1% subgroups and calculated P values. Baseline characteristics with a notable difference between subgroups  included median age , current smokers , PD-L1-positive status , mean number of target lesions  and tumor size  and were included in the IPW model  model to explore potential differences among groups in baseline characteristics that could account for the higher ORR seen in the MSAF < 1% populationP = 0.56) and were not significantly different. The unadjusted PFS medians for the MSAF < 1% and MSAF ≥ 1% populations were 6.8 months and 3.6 months  was 97.7% , and a median of six  doses were administered.Treatment-related adverse events (AEs) occurred in 76% of patients (Supplementary Table n = 148). Patients with any MSAF values were included, as well as those with either driver or insertion and/or deletion mutations .An exploratory analysis was conducted on the molecularly evaluable population (MEP), defined as patients who had an evaluable blood sample at baseline . Atezolizumab monotherapy was well tolerated, and no new safety signals were observed.The B-F1RST study was designed to evaluate bTMB and its association with clinical outcomes in patients with advanced or metastatic NSCLC treated with first-line atezolizumab. At the pre-specified bTMB cutoff of ≥ 16, PFS was not statistically different between the high versus low groups, although a numerical improvement in PFS was observed. The lack of statistical significance may be attributed to the smaller biomarker-evaluable population of 119 relative to the originally planned 150 patients, resulting in a reduction in statistical power. With this population size, a PFS HR of 0.55 between high versus low groups would have been needed to detect a statistically significant difference . Althoug2. In CheckMate227, low-dose ipilimumab plus nivolumab significantly improved median PFS versus chemotherapy in patients with tTMB ≥ 10 mut/Mb but not with tTMB < 10 mut/Mb. The OS benefit was similar regardless of tTMB status, PD-L1 status or any combination of the two16. In MYSTIC, the OS benefit for durvalumab plus tremelimumab versus chemotherapy was greater in patients with bTMB ≥ 16 mut/Mb than those with bTMB < 16 mut/Mb17. Finally, in IMpower110, bTMB ≥ 16 was associated with a longer PFS benefit than bTMB < 16 in patients treated with atezolizumab versus chemotherapy1. It should be noted that IMpower110 enrolled only PD-L1-positive patients; therefore, the bTMB ≥ 16 patients were selected for two biomarkers. The results from B-F1RST, on the other hand, suggest that bTMB may be associated with atezolizumab benefit in a PD-L1-unselected, bTMB-high population. However, as B-F1RST did not require collection of tumor tissue, the independent roles of bTMB versus PD-L1 in the first-line setting cannot be definitively addressed.The B-F1RST bTMB results are consistent with data from other first-line studies of checkpoint inhibitors in NSCLC that have evaluated TMB. In CheckMate026, patients with PD-L1 > 5% of TCs and high tTMB who were treated with nivolumab had longer PFS and higher ORR than patients treated with chemotherapy, but the difference in OS was not significant18.bTMB has been prospectively evaluated in the phase 3 randomized Cohort C of the BFAST trial as a predictive biomarker in the first-line treatment of NSCLC with atezolizumab versus platinum-based chemotherapy. Although Cohort C did not meet its primary endpoint, there was a trend toward a PFS benefit in patients with bTMB ≥ 16 who received atezolizumab19. Moreover, TMB has been shown to have predictive value in later lines of therapy and in other indications, which is supported by recent approval of pembrolizumab in the TMB-high metastatic pan-tumor setting20. However, the strength of TMB as a predictive biomarker has been variable.Considering the totality of the recent data in the field, tTMB and bTMB are relatively weak predictive biomarkers for first-line treatment of NSCLC in chemotherapy-free combination immunotherapy or monotherapy settings but may still be of value in patients whose tumors do not express high levels of PD-L1 or in the case of patients who have high bTMB and inadequate tissue for PD-L1 testingPart of the reason for the variability in TMB results may be that tTMB and bTMB are surrogate biomarkers in that they measure a phenotype that is indirectly related to neoantigen load, which itself is distal to the direct action of anti-PD-L1/PD-1 therapies. Moreover, tTMB and bTMB do not provide information on the antigenicity of the relevant neoantigens involved in tumor/immune response, nor do they provide information on the capacity of tumors to present antigens, both of which are likely to be relevant to the overall response to anti-PD-L1/PD-1 therapy. As such, the biological difference between a surrogate such as TMB and the actual biological variable  is likely to vary between tumors.21, and the fact that insertion/deletion mutations were not included in the bTMB assay used in this study could have influenced the findings. In addition, biomarkers that may inform new bTMB algorithms are being investigated22. Variables such as clonality of neoantigens, MHC-1 genotype23, human leukocyte antigen loss of heterozygosity, T cell receptor repertoire, other genomic alterations that might affect immune response and other immune considerations, including T cell levels24, have shown promise for informing new bTMB algorithms in the future. Another factor that may need to be re-evaluated is the cutoff, and using a higher threshold than bTMB ≥ 16 might have shown improved PFS and OS, as the high versus low subgroups at bTMB ≥ 18 and bTMB ≥ 20 cutoffs derived significant benefit on both of these outcomes, albeit in smaller patient populations. The ORR for the high versus low subgroups at bTMB ≥ 20 was also improved compared to the ORR for the subgroups at the bTMB ≥ 16 cutoff. Finally, bTMB might also be used to predict the benefit of checkpoint inhibitor therapy in combination with other biomarkers, including PD-L1. Although the dataset for PD-L1 status in B-F1RST is incomplete (36% of patients had unknown PD-L1 status), the higher baseline prevalence of PD-L1-negative patients in the bTMB ≥ 16 group, together with the higher prevalence of PD-L1-positive patients in the bTMB < 16 group, support the concept of PD-L1 expression and bTMB as independent predictive biomarkers with a limited overlap between high-TMB and high-PD-L1 patient populations25. Therefore, PD-L1-positive patients who benefit from atezolizumab may be a distinct group from bTMB-high patients, who also may benefit. However, further study is needed to determine how these two biomarkers might be used in combination to predict patient outcomes.Furthermore, developments in assay technology and a deeper understanding of TMB and its biological consequences may be needed to select the population that will benefit most from checkpoint inhibitors. Insertion/deletion mutations may produce more antigenic neoantigens than single-nucleotide variants27. Indeed, low MSAF is associated with favorable prognostic factors, such as lower age, current non-smoking status, PD-L1-positive status, fewer lesions or lower overall tumor burden (Supplementary Table Patients with low ctDNA levels (MSAF < 1%) also had significantly longer PFS with atezolizumab monotherapy than patients with MSAF ≥ 1%  and ethics committee for each participating center, including Advarra and WCG IRB , and was performed in full accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki, and all patients gave written informed consent.B-F1RST is registered with ClinicalTrials.gov as P < 0.15) were included in a model to adjust for baseline imbalances using the IPW method. Factors were included in a propensity score model to estimate probability of being in either the MSAF < 1% or MSAF ≥ 1% group. The IPW used probabilities from the propensity model to estimate efficacy by adjusting for imbalances in baseline factors. It was used because prognostic and predicted factors could not be directly adjusted due to the small sample sizes of the MSAF < 1% (n = 29) and MSAF ≥ 1% (n = 119) groups. The model was used to estimate ORR and PFS, adjusted for baseline imbalances.Baseline factors were compared between the MSAF < 1% and MSAF ≥ 1% subgroups. Factors with notable difference between the groups  and filtering out germline events by comparing against the dbSNP and ExAC databases in samples where the MSAF was ≥ 1%. Rare germline events were filtered using the somatic-germline-zygosity algorithmAn exploratory computational pipeline was developed to call alterations using the bTMB sequencing data. Non-synonymous single-nucleotide variants and insertions and/or deletions were analyzed. Copy number variants were not determined. Single-nucleotide variants were validated to 0.5% allele frequency. Insertions and/or deletions were not validated in this platform but are validated at 1% on FoundationOneCDx (Foundation Medicine), which uses the same bait set as the bTMB assay.Somatic-germline-zygosity filtering was not applied to MEP, so germline alterations and clonal hematopoiesis of indeterminate potential mutations may be present, and driver mutations were not removed. Quality control of genes with prevalence of ≥ 2% was manually performed. Prevalence of genes in the B-F1RST MEP was compared to a Foundation Medicine database to identify artifacts. Normalization for gene size was not performed. Predicted known and likely alterations are shown in Extended Data Fig. SAS (version 9.4) software was used for all analyses except for the exploratory biomarker analysis, which used R (version 3.5.3).Efficacy and safety analyses included all patients who received at least one dose of study drug. Biomarker analyses included all patients who received at least one dose of study drug and had a baseline biomarker assessment.The primary efficacy endpoint of this study was confirmed investigator-assessed ORR, defined as the proportion of patients whose confirmed best overall response was either a partial response or a complete response per RECIST 1.1. An estimate of the ORR for all patients who received study drug and the exact 95% CI were calculated by using the Blaker method.Kaplan–Meier curves and a log-rank test were used to evaluate the differences in investigator-assessed PFS between bTMB-high (bTMB ≥ 16) and bTMB-low (bTMB < 16) groups. Tests were two-sided at a significance level of 0.10 for this phase 2 study.Secondary efficacy endpoints included OS, investigator-assessed duration of response and PFS per RECIST 1.1. Secondary biomarker cutoff points included baseline bTMB at various cutoff points  besides 16.Kaplan–Meier curves and log-rank tests were used to evaluate the differences in PFS and OS between bTMB-high and bTMB-low groups at various cutoff points. Descriptive statistics for PFS and OS curves, including median PFS time and 6-, 9- and 12-month PFS probabilities, were estimated for various cutoff points as well. The Brookmeyer–Crowley methodology was used to construct the 95% CI for the medians for PFS and OS. The Greenwood formula was used to construct the 95% CI for the landmark PFS. Association between confirmed investigator-assessed ORR and baseline bTMB were evaluated at various biomarker cutoff points using the Cochran–Mantel–Haenszel test.P values were adjusted using the false discovery rate adjustment method to address multiple gene testing.Associations between gene mutation and bTMB-high and bTMB-low status at the bTMB cutoff of 16 were also explored. Further information on research design is available in the Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-022-01754-x.Supplementary InformationSupplementary Tables 1–4.Reporting Summary.Supplementary DataThe final version of the B-F1RST trial protocol.


Pain occurs in the majority of patients with late onset Pompe disease (LOPD) and is associated with a reduced quality of life. The aim of this study was to analyse the pain characteristics and its relation to a small nerve fiber involvement in LOPD patients.In 35 patients with LOPD under enzyme replacement therapy without clinical signs of polyneuropathy , pain characteristics as well as depressive and anxiety symptoms were assessed using the PainDetect questionnaire (PDQ) and the hospital anxiety and depression scale (HADS), respectively. Distal skin biopsies were analysed for intraepidermal nerve fiber density (IENFD) and compared to age- and gender-matched reference data. Skin biopsies from 20 healthy subjects served as controls to assure validity of the morphometric analysis.Pain was reported in 69% of the patients with an average intensity of 4.1 ± 1.1 on the numeric rating scale . According to PDQ, neuropathic pain was likely in one patient, possible in 29%, and unlikely in 67%. Relevant depression and anxiety symptoms occurred in 31% and 23%, respectively, and correlated with pain intensity. Distal IENFD (3.98 ± 1.95 fibers/mm) was reduced in 57% of the patients. The degree of IENFD reduction did not correlate with the durations of symptoms to ERT or duration of ERT to biopsy.Pain is a frequent symptom in treated LOPD on ERT, though a screening questionnaire seldom indicated neuropathic pain. The high frequency of small nerve fiber pathology in a treated LOPD cohort was found regardless of the presence of pain or comorbid risk factors for SFN and needs further exploration in terms of clinical context, exact mechanisms and when developing novel therapeutic options for LOPD.The online version contains supplementary material available at 10.1186/s13023-022-02327-4. GAA) and consequent lysosomal α-glucosidase deficiency [GAA genetic mutations have been identified and the clinical phenotypes show a high variability without clear relation to a certain genotype [Pompe disease OMIM 232300) is an autosomal recessive disease due to mutations in the α-1,4-glucosidase gene  is a validated screening tool that discriminates between neuropathic and nociceptive pain . At the On the same day as the skin biopsy, the Hospital Anxiety and Depression Scale (HADS) was assessed in the validated German version, including two scores for the degree of depression (HADS-D) and anxiety (HADS-A), respectively  , 30.To determine the intraepidermal nerve fiber density (IENFD) 3 mm skin punch biopsies were taken 10 cm above the lateral malleolus  in all included patients. Additionally, from twenty healthy controls skin biopsies were obtained from the same location assure validity of the morphometric analysis. Skin samples were fixed with Zamboni, washed in PBS, transferred to 10% sucrose, and stored at − 80 °C in a freezer until further use. From each biopsy, 50 µm-thick frozen sections were stained using a free-floating protocol with primary antibody anti-protein gene product , and secondary antibody goat anti-rabbit Alexa Fluor 488  , 31. SecAccording to published counting recommendations, IENFD was determined in at least six sections from each biopsy and was compared to published age and gender-related reference values . In addi2), density , and branch density  were analyzed and compared to normative data [Corneal confocal microscopy (CCM) was available in only one of the study centers and as a proof of concept four patients underwent additionally a detailed assessment of the corneal innervation by CCM. Four CCM images from the left eye of each patient were manually analyzed using an established software  to visualize the corneal subbasal nerve plexus. The average corneal nerve fiber length ). P-values < 0.05 were regarded as significant.The correlation between pain scores and HADS subscores, z-scores and further clinical data were analysed by calculating the Pearson’s correlation coefficient to assess possible linear associations between the variables. Differences between patients with and without pain regarding the HADS subscores and differences between patients and controls regarding IENFD were analysed using Mann–Whitney U test. The distribution of nominal variables was tested using the chi-squared test. To assesses whether pain scores, duration from symptoms onset to biopsy (symptoms to biopsy), duration from symptoms onset to onset ERT therapy (symptoms to ERT) and duration from onset ERT therapy and biopsy (ERT to biopsy) differ between patients with normal or reduced IENFD were submitted to analysis of multivariate variance (multivariate ANOVA) using the standard ‘manova’ function of the R software package. Statistical analysis was performed using IBM SPSS Statistics, version 24 and R software package  were included in the study. All patients were compound heterozygote for GAA, with the most prevalent mutation being c-32-13 T > G in 88%. In one patient, the exact genetic results were missing (Table Twenty-four patients (69%) reported pain within the last 4 weeks with an average intensity of 4.1 ± 1.1 on the NRS with the anchors 0–10  including axial and joint pain in most cases, and the distal leg only in one case  reported relevant anxiety and/or depression symptoms according to HADS Table . Only onThe average IENFD of patients was 3.98 ± 1.95 fibers/mm (zscore: − 2.12 ± 0.825), whereas the average IENFD of healthy subjects was 7.50 ± 1.95 fibers/mm (zscore: − 1.09 ± 1.02), the latter being in the range of published normative data. Patients differed significantly (p < 0.05) from controls regarding their IENFD confirming the overall loss of fibres in LOPD patients. Compared to an established age- and gender-matched reference data IENFD was considered reduced (< 5th percentile) in 57% of the patients  has not been performed. This prevents final conclusions about the presence of small fiber neuropathy or neuropathic pain per definition , 52, 53.To summarize, pain is a common symptom in LOPD that interferes with psychological aspects and the patients’ quality of life. We found reduced small nerve fiber density in a large number of LOPD patients under ERT. Thus, our results indicate that the peripheral nervous system may represent another system affected in Pompe disease, which is in line with few previous reports on neuropathy in Pompe disease , 16. HowAdditional file 1: Table S1: Clinical and demographic findings in 35 patients with LOPDAdditional file 2: Table S2: Self-reported data on pain, anxiety and depression symptoms in 35 patients with LOPDAdditional file 3: Table S3: Morphometric analysis of skin biopsies from 35 patients with LOPDAdditional file 4: Table S4: Morphometric analysis of skin biopsies from twenty healthy controlsAdditional file 5: Fig. S1: Four patients with LOPD underwent detailed assessment of the corneal innervation by corneal confocal microscopy (CCM): While P3 showed a reduction of small nerve fibers only in the distal skin biopsy, P5 presented with abnormalities only in the corneal innervation.


Temporomandibular dysfunction is characterized by the presence of painful joint/muscular symptoms muscle in the face. The main justification for the use of lasers in laser therapy dysfunction is its analgesic effect, which was observed in most studies in the literature.Aim: We evaluated the effectiveness of laser therapy in the treatment of temporomandibular disorders.Methods: 50 volunteers with temporomandibular disorders were divided into two groups  had amplitudes of movements of mouth opening, right and left laterality recorded before and after laser application. Was also recorded, the score the individual gave to pain by visual analog scale and, through physical examination, the pain points. We used the AsGaAl laser with a 40mW power, with 80J/cm2 for 16 seconds at four selected points for just one session with reassessment after a week. Study design: Clinical.Results: It was noted that laser therapy increased the mean amplitude of mandibular movements (p = 0.0317) and decreased significantly (43.6%) the pain intensity measured by the visual analog scale.Conclusions: The laser decreases the painful symptoms of the patient after application through its analgesic and/or a placebo effect. Temporomandibular joint dysfunction (TMJD) or temporomandibular disorder (TMD) is characterized by facial muscle/joint pain, especially in the acute phaseThe main justification as to the use of low intensity laser (laser therapy) on TMD is its analgesic effect reported by most of the studies found in the literatureAccording to MedeirosThe low intensity laser is, in many cases, a new treatment mode for the treatment of maxillofacial region disorders such as joint pain, neuralgias and paresthesiasDespite the numerous treatment modes available for TMD, only low intensity laser has proven capable of relieving pain in minutes after administration, bringing about a significant improvement to the patient. Despite all these benefits brought about by laser treatment, it is not the definitive treatment for TMD. It works as a coadjuvant in the treatment alleviating pain thanks to the laser's analgesic effect, which allows the patient to promptly resume her/ his functions, providing greater comfort6. Nonetheless, for a safe use of laser with patients, the professionals must be trained to use the equipment, thus reducing the possibility of iatrogenic effects.The goal of the present study was to assess the efficacy of laser treatment in the management of TMD by means of the Visual Analogue Pain Scale (VAPS) and measuring the range of mandibular movements.This study was made up of a descriptive survey of the clinical picture and results obtained after the exam and administration of laser treatment, with later reassessment of the laser use, in TMD patients feeling pain. We had 50 volunteers who agreed to sign the Free and Informed Consent Form (FICF). This study followed the requirements established on Resolution # 196/96 from the National Health Board/Ministry of Health – Brazil, and was approved by the Ethics in Research Committee of our Institution, under protocol # 137/2004.The patients were broken down in two groups of 25 patients each – study and control groups. According to the methodology advocated by Kulekcioglu et al.After filling out the guided questionnaire and undergoing physical exam, we assessed the individual's pain intensity through the EVAD before using the laser and after one of week of use (reassessment) according to what was done in other studiesWe used the Ultrablue dental laser (D.M.C. Equipment®), with a maximum power of 120 J/cm2, diode laser power of 800 mW, with beam divergence of 8°x28°, with irradiation area of 5mm2 without the application tip and an area of 4 mm2 with the administration tip, there was a 20% power loss with the 830 nm wavelength (visible in red) and AsGaAl diode laser semiconductor, it was punctually deployed on the TMJ and smaller muscles, based on shooting the laser on strategic points over the affected area and using the scanning technique, in which the laser is moved up and down throughout the entire affected area. In the control group the device was off during the application. In order to make sure the patient would not perceive it, he/she was asked to close the eyes, besides wearing goggles – as a means of eye protection. The laser therapy efficacy was also assessed through measuring the range of motion of the maximum mouth opening the patient could get, as well as left and right laterality.We carried out a descriptive analysis with a quantitative approach of the Visual Analogue Scale (VAS) values, mouth opening amplitude, lateral movements and main places which were most affected by sensitivity/pain. We used the Epi Info 3.2 software, through which we did the ANOVA statistical tests  -in order to assess pain intensity; and that of Wilcoxon -in order to assess the range of mandible motion.From the study group we obtained an initial average value of the pain score, through the Visual Analogue Pain Scale, of 5.14. After the reassessment we had the mean score of 2.9. According to the ANOVA test, the result was statistically significant (p=0.0317), which was different from that of the control group, which initial mean value was 5.4 and after reassessment it was 4.25 – a statistically significant result (p=0.2371).According to Of the studied patients, 92.0% had pain in one or more points on the Masseter muscle  and/or in two on the TMJ  .Table 2PIn the study group 72.0% of the patient had a mandibular cracking sound upon initial visit and, after undergoing laser therapy, it dropped to 33.0%. Therefore, there was a 54.1% reduction in the cases of patients with the cracking sounds .Graph 1JThe mean value of the initial mouth opening range of motion of the volunteers in our study was 41mm, while the final, measured one week after using the laser was 42.28mm, which represented an improvement of 1.28mm (3.12%). According to the Wilcoxon test it was statistically significant (p= 0.0409). The initial and final right side laterality were: 7.44mm and 7.6mm respectively, while those for the left wide were: 7.12mm and 7.88mm .Table 3VDespite the recent growing use of laser therapy, its action on the tissues is still inaccurate. It is known that, according to wavelength, the laser light has the capacity to alter cell functions  and, depending on the dose, it can inhibit or stimulate some of these functionsDespite the lack of scientific evidence regarding its mechanism of actionLopezPlacebo studies are paramount as long as ethics are respected. Refraining from using placebo can lead to the indication of inefficient treatment – to be considered as unethical behavior. Studies have shown that placebo, in fact, causes a biological response, as well as a behavioral one in a broad variety of medical conditionsIn the present study, there was a 43.6% reduction in pain in the individuals of the study group, in the control group, the reduction was only of 21.3%. However, since there was only one laser application, this result can be largely attributed to the positive psychological effect of the laser treatment in accordance with the studies from Pinheiro et al.The 54.16% reduction in the cases of patients with cracking sounds is corroborated by the study of LopezThe results from this study, as well as those from other studies showed that there was a greater mean mandible range of motion after laser administrationTMJ and the masseter muscle are the sites most affected by pain in patients with TMJD. The masseter and sternocleidomastoid muscles are frequently the most painful in those with joint noise. Laser therapy caused a reduction in the pain symptom after administration, by its analgesic action or a placebo effect resulting from an increase in the mean value of mandible movements. We found similar results in the control group, representing the positive psychological effect of laser therapy in these patients.


To assess the analgesic efficacy of the circumferential periosteal block (CPB) and compare it with the conventional fracture hematoma block (HB).This study was a prospective single-center randomized controlled trial performed in a national orthopedic hospital. Fifty patients with displaced distal radius (with or without concomitant ulna) fractures requiring reduction were randomized to receive either CPB or HB prior to the reduction. Pain was sequentially measured using the visual analogue scale (VAS) across three stages; before administration of local anesthesia (baseline), during administration (injection) and during manipulation and immobilization (manipulation). Further, the effect of demographic factors on the severity of pain was analyzed in multivariate regression. Finally, complications and end outcomes were compared across both techniques.p =  < 0.0001). There were no significant differences between groups at baseline (P = 0.55) and injection (P = 0.40) stages.Patients receiving CPB experienced significantly less pain scores during manipulation (VAS = 0.64) compared with HB (VAS = 2.44) (The CPB provides a superior analgesic effect over the conventional HB with no documented complications in either technique.Therapeutic Level II.The online version contains supplementary material available at 10.1007/s00068-022-02078-8. Fractures of the distal radius and ulna are among the most common in orthopedic trauma . They arInitial management often entails closed reduction and manipulation followed by immobilization, which if successful, may deter further operative management. Adequate analgesia is essential during reduction, as painful manipulation may hinder patient cooperation and preclude successful reduction . Thus, vAn ideal analgesic technique should result in safe, easy, and painless fracture manipulation. In 2015, Tageldin et al. described a novel circumferential periosteal block (CPB) technique for the reduction of radius and ulna fractures . The stuThis was a single center, prospective randomized controlled trial. Informed consent was obtained from eligible patients prior to their inclusion in the study. Plain radiographs were reviewed and the Frykman classification was utilized to classify their fractures. The study was conducted in accordance with the 1964 Helsinki Declaration, approved by our local ethical committee board (UID 1733/2021) and registered on the Research Registry (UIN: 6639). This study adheres to the appropriate CONSORT guidelines.Eligible patients were over 12 years of age presenting acutely for the first time with a displaced distal radius fracture  requiring reduction via manipulation. Exclusion criteria entailed known allergy to local anesthesia, multiple fractures, polytrauma, head trauma, unconsciousness, open fractures, neurovascular deficit, any evidence of compartment syndrome or ipsilateral upper limb fractures precluding effective reduction or analgesia. All included participants had presented to the emergency department within 6 h of injury, to ensure the presence of a viable hematoma. The sample size calculation for this study was based on the repeated-measures ANOVA design for two groups (HB vs CPB) measured at three observations . A study with an effect size of 0.5 and a power of 95% required a total sample of 38 to test the association at a 5% alpha level. The power calculation was carried out using G*power 3.1.9. A total of 50 patients were included in the study.Patients were selected consecutively in the emergency department of a tertiary orthopedic center if they met the inclusion criteria. Patients were block randomized to receive either HB or CPB by computer-generated lists equally distributed to two trained orthopedic surgeons.Patients were positioned supine with the elbow extended on a dressing table. Precautionary measures including oxygen, intravenous access and intra-lipid emulsion were available. The affected arm was draped and sterilized. For both techniques, lidocaine 1% without epinephrine was used.For the CPB, a 10-ml syringe with a (25G) needle was used to infiltrate the subcutaneous tissue under an aseptic technique on the radial aspect of the radius approximately 6 cm proximal to the wrist joint (2–3 cm from the fracture). Once the entire radial aspect  is infiltrated, the needle is changed to a (22G) needle. The next injection followed the parallel plane of the dorsal and volar surfaces of the radius, ensuring contact with bone whilst advancing to avoid any soft tissue or neurovascular structures. Rolling of the skin allowed for a single injection to access both surfaces. In the presence of a concomitant ulnar fracture, the process is repeated on the ulnar aspect. Finally, manipulation was performed 15 min after the block, whilst recording the required data.The hematoma block was performed in the traditional way. A 22G needle is inserted on the dorsal aspect of the radial fracture, aspiration of the hematoma to confirm location, followed by subsequent injection of lidocaine within the hematoma. Techniques to minimize pain on injection of local anesthesia were utilized in both blocks .The primary outcome was pain measured using the visual analogue scale (VAS 0–10). Measurements were taken across three stages; before administration of local anesthesia (baseline), during administration (injection) and during manipulation and immobilization (manipulation). Post-reduction radiographs were obtained. Patients were subsequently monitored in the emergency department for 1 h to assess for any acute complications. Further, patients were evaluated for secondary outcomes according to age, sex, definitive treatment (within 6 weeks), Frykman classification, radiographic assessment, need for re-manipulation and the presence of any intervention-related complication. Complications were defined as any procedure-related adverse effects including; distal sensory or motor deficit, vascular deficit, local infection, nausea, vomiting, respiratory distress and weakness derived from tendon injuries.χ2) for categorical variables and the Mann–Whitney test for age due to its non-parametric distribution  and Graphpad Prism 9. Descriptive statistics shown in Table R2 of 52.3% and a P value of 0.0005 for the overall regression. Individual P values for each of the predictors along with the coefficient and 95% Confidence Intervals (95% CI) are reported in Table P = 0.9520) Kolmogorov–Smirnov (P =  > 0.1000) and Shapiro–Wilk (P = 0.9864) tests confirmed normality, and the assumption of lack of multicollinearity was verified using the Variance Inflation Factor (VIF). A P value of less than 0.05 was considered to be statistically significant.In addition, a multivariate linear regression analysis was carried out to assess the relationship of pain during manipulation as the dependent variable, with the independent variables of age, gender, operator, baseline level of pain, fracture type and Frykman classification. The regression model Table  yielded Between January 2021 and June 2021, a total of 56 patients were consecutively considered for inclusion to receive either an HB or CPB , the latter being an indicator of achieved analgesia regardless of method. In addition, the significant interaction effect (P < 0.0001) indicates that the differences between block methods vary across the stages of analgesia. Post-hoc comparisons using a Bonferroni correction confirmed that a difference between block methods is only found during the manipulation stage (P < 0.0001). Finally, within-subject variation was also significant indicating effective control of within-subject variation (P = 0.0003).Repeated measures 2-way ANOVA (Table P =  < 0.0001). The lack of a difference at baseline confirms the comparability of both groups. There was no difference during the injection stage (P = 0.55). The mean pain score during manipulation for HB was 2.44 and for CPB 0.64 , baseline pain score (P = 0.0349) and block method (P < 0.0001). Overall, CPB reduced pain during manipulation by 1.789 points (VAS score), whilst keeping all other variables constant.Predictors of pain during manipulation using multivariate regression analysis are displayed in Table The management of distal radius and ulna fractures remains largely non-operative, emphasizing the necessity of adequate reduction . FracturThe variability in the analgesic effect of the HB may necessitate supplementary analgesia. In our study, the HB displayed a wider, less predictable range of analgesic effect VAS 0–5) than the CPB (VAS 0–3). The lack of predictability encountered in our study is in keeping with previous literature  than the, 11. SimYet it is worth mentioning that the degree of force in manipulation techniques is normally tailored to the nature of the fracture itself and the subsequently predicted difficulty in reduction. The latter may influence variation among pain scores in different studies. Our institutional practice of closed reduction attempts in all distal radius fractures enabled the inclusion of higher Frykman grades in our study. However, growing evidence supports a more selective approach in assessing which fractures may benefit from closed reduction , 14. FraFurther, our analysis has shown that a higher baseline pain score predicts greater pain during manipulation. This may reflect a higher sensitivity to pain in a specific subset of patients. Increasing age also exerted a statistically significant, yet inconsiderable effect on pain during manipulation.Our results have reproduced Tageldin et al.’s  findingsAn initial concern was the risk of neurovascular injury while entering the volar surface of the radius. However, no complications of this nature arose during close follow-up and examination. The CPB also offers the hypothetical advantage of providing distance from the fracture hematoma. Unlike the hematoma block which has the theoretical risk of converting a closed fracture into an open fracture by directly accessing the hematoma, thereby increasing the risk of infection, the CPB is performed 2–3 cm proximal to the hematoma site. Future direction should focus on operator experience-dependent reproducibility of the technique. Further, larger sample sizes should aim to uncover potential complications.This study included a limited number of operators and did not take into account experience with the technique. There was no difference in definitive outcomes after reduction, which perhaps indicates the effectiveness of analgesia may not affect end-outcomes. However, this may be an artefact of relatively small sample size, and future research may benefit from matching fracture characteristics to assess outcomes accurately. While participants were unaware of the allocated blocks during administration, there was no feasible method of blinding the operators from the interventions, which is a potential source of bias.The circumferential periosteal block offers a superior analgesic effect and a potentially equally safe alternative to the traditional hematoma block during manipulation of distal radius and ulna fractures.Supplementary file1 (DOC 218 KB)Supplementary file2 (DOCX 195 KB)Below is the link to the electronic supplementary material.


Chronic low back pain is a common musculoskeletal disease. With the increasing number of patients, it has become a huge economic and social burden. It is urgent to relieve the burden of patients. There are many common rehabilitation methods, and aquatic physical therapy is one of them. The purpose of this systematic review and meta-analysis is to summarize the existing literature and analyze the impact of aquatic physical therapy on pain intensity, quality of life and disability of patients with chronic low back pain.Through 8 databases, we searched randomized controlled trials on the effect of aquatic physical therapy on patients with chronic low back pain. These trials published results on pain intensity, quality of life, and disability. This review is guided by Cochrane Handbook for systematic reviews of interventions version 5.1.0. The level of evidence was assessed through GRADE.P < 0.00001) and improved quality of life , and reduced disability . However, aquatic physical therapy did not improve patients' pain at rest . We found very low or low evidence of effects of aquatic physical therapy on pain intensity, quality of life, and disability in patients with chronic low back pain compared with no aquatic physical therapy.A total of 13 articles involving 597 patients were included. The results showed that compared with the control group, aquatic physical therapy alleviated the pain intensity (Visual Analogue Scale: SMD = -0.68, 95%CI:-0.91 to -0.46, Z = 5.92, Our systematic review showed that aquatic physical therapy could benefit patients with chronic low back pain. However, because the articles included in this systematic review have high bias risk or are unclear, more high-quality randomized controlled trials are needed to verify.The online version contains supplementary material available at 10.1186/s12891-022-05981-8. Chronic low back pain was defined as back pain with or without leg pain for more than 12 weeks between the lower ribs and the folds above the buttocks . TherefoThe treatment of chronic low back pain is still in constant exploration. Scaturro et al.  have obsThis systematic review protocol has been registered on PROSPERO as CRD42021265891. The methods was conducted according to the method described in the Cochrane Handbook , and theWe searched 8 databases, including: PubMed, Embase, The Cochrane Library, Web of science, China National Knowledge Infrastructure (CNKI), Wanfang data, Chongqing VIP (CQVIP), Chinese Biomedical Literature Database (CBM). There are no restrictions on languages and countries, the search date is from the beginning to July 15, 2022. The following terms were used for retrieval: 'low back pain,' 'aquatic exercise,' 'aquatic therapy,' 'hydrotherapy'.Inclusion and exclusion criteria are based on PICOS standards: see Table Two researchers independently checked the titles and abstracts of the retrieved studies and downloaded those that might meet the requirements. By reading the full text, the eligible studies were selected according to the inclusion and exclusion criteria. This process was completed by two reviewers, and a third reviewer was sought for discussion to resolve disagreements.Two reviewers checked eligible studies and extracted characteristics of included studies, including: the first author, year, country of study, the sample size of the intervention group, the sample size of the control group, the type of exercise in the intervention group, the type of exercise in the control group, intervention time, follow-up time, and outcomes measures.The quality of the literature was evaluated by two independent people using Cochrane bias risk assessment tool  respectiMeta-analysis was conducted on the same result variable of more than two groups of data. If the mean and standard deviation cannot be directly obtained, the relevant data shall be converted according to the evidence-based medicine conversion formula . The res2 statistic to test the heterogeneity of the included articles. If Ι2 > 50%, we think there is heterogeneity between articles, and use random effect model for statistical analysis. If Ι2 < 50%, the heterogeneity between articles was considered acceptable, and the fixed effect model was used for statistical analysis [We use RevMan (version 5.3) software to analyze the data. Mean ± SD was used as the effect index for continuous variables, 95% confidence intervals (CI) were given for all variables, if the same research tool is used in the included literature, the mean difference (MD) analysis is used. If different research tools are used, the standardized mean difference (SMD) analysis is used. We used Cochran's Q statistic and Ιanalysis . SensitiWe used the search strategy to search 543 articles in the database. After excluding the repetitive literatures, we read the titles and abstracts of the remaining literatures, and selected 26 literatures to read the full text. Five non randomized controlled trial was excluded, three in the control group also used aquatic physical therapy, and five articles have unrelated outcome. Finally, 13 articles were confirmed to meet the inclusion criteria. Figure This paper includes 13 articles, and the basic characteristics of each article are shown in Table For details of bias risk assessment, see Figs. P < 0.00001, Ι2 = 41%, Fixed Effect Model). .. Fig. .Fig. 5APP < 0.00001, Ι2 = 9%, Fixed Effect Model). . Fig. .Fig. 6APP = 0.02, Ι2 = 69%, Random Effect Model). .  . . Fig. .Fig. 10AP = 0.005, Ι2 = 56%, Random Effect Model). . Fig. .Fig. 11AP = 0.04, Ι2 = 8%, Fixed Effect Model)  Fig. .Fig. 12AP = 0.16, Ι2 = 82%, Random Effect Model)  Fig. .Fig. 13AP = 0.0009, Ι2 = 0%, Fixed Effect Model)  Fig. .Fig. 14AP = 0.02, Ι2 = 0%, Fixed Effect Model).. Fig. .Fig. 15AP = 0.17, Ι2 = 0%, Fixed Effect Model)  Fig. .Fig. 16AP = 0.30, Ι2 = 77%, Random Effect Model)  Fig. .Fig. 17AAs there were no more than 10 included literatures for each outcome, publication bias was not performed.For the evidence quality of the measured results, see Table This meta-analysis summarizes in detail the effects of aquatic physical therapy on pain intensity, quality of life, and disability in patients with chronic low back pain. In this meta-analysis, we included 13 randomized controlled trials. The results showed that compared with no aquatic physical therapy, aquatic physical therapy can reduce pain intensity, improve quality of life and disability of patients in the short-term.Pain is the main symptom of patients with chronic low back pain. A VAS was used to assess the patient's pain intensity . It was The quality of life was assessed by short form 36 health survey or short form 12 health survey. SF-36 or SF-12 can detect the health changes of the general population. It is a simple and cheap method to measure the health results. It is a continuous ruler to detect the health changes. However, in this review, because other aspects of the data can’t be summarized, we only analyzed the effect on the physical component and mental component. On the physical component and mental component, it can be considered that aquatic physical therapy can improve the physical and mental condition of patients with chronic low back pain in the short-term. This result was confirmed in subgroup analysis. Aquatic physical therapy can help patients relieve their physical and psychological burden.Low back pain has an impact on a patient's disability because pain limits its activity . DisabilAquatic physical therapy is often used as a rehabilitation therapy for patients with musculoskeletal diseases . MoreoveThis systematic review included the latest studies for meta-analysis, including 13 randomized controlled trials, while the recently published systematic review only included 8 studies. In addition, this systematic review analyzed the short-term and medium-term effects of aquatic physical therapy on patients with chronic low back pain. However, this review still has some limitations. First, some outcome indicators are measured with different research tools, and there may be measurement bias. Secondly, the modified Jadad tool was planned to be used to evaluate the quality of the included studies at the initial registered protocol. Later, we was considered that the Cochrane bias risk assessment tool was domain-based evaluation. In addition, it requires the evaluation results of each risk bias to have specific judgment reasons and achieve transparency .ThereforAquatic physical therapy may be effective and safe in improving pain intensity, quality of life and functional ability in patients with chronic low back pain. Aquatic physical therapy can provide some reference for patients with chronic low back pain when making exercise plans, and encourage patients to carry out aquatic physical therapy. However, more high-quality randomized controlled trials are needed to verify the effectiveness and safety of aquatic physical therapy.Additional file 1:Appendix 1. PRISMA check list. Appendix 2. Search strategy for Pubmed.