Polyneuropathy presumably lowers quality of life (QoL). However, there is a lack of systematic studies that assess QoL changes and biomarkers of polyneuropathy as determinants of QoL. We aimed to investigate the relationship between every specific aspect of QoL and the clinical parameters used to assess the impairment of motor, sensory , and autonomic nerves in polyneuropathy.Polyneuropathy patients were recruited from September 2013 to March 2014; QoL was assessed using (1) the WHO Quality of Life-BREF (WHOQoL), (2) the European Quality of Life-5 Dimensions, and (3) the Brief Pain Inventory Short Form. Neuropathy examinations included nerve conduction studies, autonomic function tests, quantitative sensory testing (QST), and intraepidermal nerve fiber (IENF) density assessment of skin biopsies.There were 61 polyneuropathy patients . Patients had a lower QoL than age-and gender-matched controls in the physical and psychological domains of the WHOQoL. Among the biomarkers for different nerve fiber categories, only the small fiber neuropathy assessments were significantly related to all domains of the WHOQoL. In contrast, the parameters of the large fiber neuropathy were independent of QoL. Patients with abnormal temperature thresholds and a lower IENF density had lower WHOQoL scores compared to patients with normal thresholds and IENF densities. Warm threshold of the foot in QST was linearly correlated with all domains of the WHOQoL.QoL scores were reduced in polyneuropathy, and biomarkers of small fiber neuropathy, i.e., warm threshold and IENF density were discriminating predictors of QoL.The online version of this article (doi:10.1186/s12955-015-0363-9) contains supplementary material, which is available to authorized users. Polyneuropathy resulting from different etiologies, such as diabetes, autoimmune diseases, and hereditary neuropathy, causes various impairments and presumably influences quality of life (QoL) , 2. The Studies investigating the QoL in polyneuropathy cohorts, however, have been limited and are often inconclusive , 4. AccoPeripheral neuropathy has been associated with increased mortality in diabetic patients . NeuroloPatients with polyneuropathy were recruited from the Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan from January 2013 to March 2014.The recruitment was consecutive case series where board-certificated neurologist examined all the patients with standard approach. Polyneuropathy was diagnosed according to 1) a symmetric and length-dependent symptoms and signs in the motor or sensory systems , and (2) a symmetThis study was conducted following the World Medical Association’s Declaration of Helsinki. The protocols were approved by the Institutional Review Board of National Taiwan University Hospital, Taipei, Taiwan (IRB No. 201306078RINC). Patients signed an informed consent document before participation. Procedures of the tests  followed established protocols and age-and gender-matched control subjects were retrieved from a previously described database . All theWe used the WHOQoL questionnaires to assess the global QoL in 4 domains, physical, psychological, social, and environment , 16. To It is a descriptive system to form an index score (EQ index) covering 5 dimensions of HRQoL, mobility, self-care, usual activity, pain/discomfort, anxiety/depression, with a 3-point scale  in each dimension , 18. In The Brief Pain Inventory short form (BPI-SF) Taiwan version consists of numerical scales 0 ~ 10) for 3 components: (1) pain severity score ‘within 1 week’ (2), pain severity ‘right now’, and (3) pain interference score    and the 5th percentile value (for cold threshold) according to our normative database [Quantitative sensory testing (QST) was performed using a Thermal Sensory Analyzer  to measure the thermal thresholds for warm and cold sensations using a previously established standard procedure . Thermaldatabase . In thisWe conducted skin biopsies to provide pathologic evidence of small fiber neuropathy. Following our published procedures, a skin biopsy was performed on the distal leg after an informed consent document was signed –23. SectFor each examined parameter, patients were classified into two groups, normal and abnormal. The scores for each item of the WHOQoL, EQ-5D, and BPI-SF between these two groups were analyzed accordingly. The parametric t-test or non-parametric Wilcoxon rank-sum test were used depending on whether the data followed a Gaussian distribution or not. Univariate and multivariate linear regression models were used to explore the relationships between each domain of QoL and examination parameter. A P<0.05 was considered statistically significant. SAS 9.3  was used for statistical analyses.There were 61 polyneuropathy patients  with a mean age of 58.14 ± 12.95 years and a mean disease duration of 4.34 ± 3.26 years. The underlying etiologies consisted of diabetes, immune-related, drug-induced, inherited, and idiopathic types. Neurological examinations assessed the functions of motor system (muscle strength on a MRC grade), sensory and autonomic system. Among small-fiber sensory impairments, proportion of impaired pinprick sensation, burning or tingling sensation and other small fiber characteristics (electric shock–like or cold-like pain) was 80.3 %, 77.0 % and 8.2 % respectively (Table p<0.0001). Among EQ-5D, polyneuropathy patients had significantly lower scores in all dimensions, index and VAS  and psychological domain , 33.4 % for the warm threshold of the hand (WT-hand), 15.1 % for the cold threshold of the foot (CT-foot), and 20.7 % for the cold threshold of the hand (CT-hand). Among these temperature thresholds, the warm threshold of the foot had the highest abnormal rate. For the IENF density analysis, the overall abnormal rate was 72.7 %, with a reduced IENF density in 80.0 % of the patients age <60 years and 66.7 % of the patients age >60 years.p values, were found in the physical domain (p = 0.014) and psychological domain (p = 0.007) , in both of the EQ-5D categories (index and VAS), and higher scores in the 2 pain dimensions of the BPI-SF (‘pain during the previous 1 week’ and ‘interference dimension’) , patients with small fiber impairment had significantly lower scores in (1) all domains of the WHOQoL, (2) the VAS category of the ED-5D, and 3) the interference dimension of the BPI-SF , Mobility (F9) and Activities of daily living (F10) in physical domain of QoL was strongly associated with abnormal QST and IENF; these served as major contributing factors to QoL reduction   of the BPI-SF  and BPI-SF (pain severity and pain interference dimensions). In contrast, only the IENF density demonstrated a linear association with the pain severity dimension  and a higher pain severity dimension (in the dimensions of within 1 week and right now) of the BPI-SF   of the patients had autonomic dysfunction. In similar analyses for the RRIV and SSR examinations, only the abnormal RRIV demonstrated a significant association with a lower EQ5D index , chronic inflammatory demyelinating polyneuropathy (CIDP), and Charcot-Marie-Tooth disease. Despite the documented reduction in QoL, no relationships among the electrophysiological measurements of the NCS, GBS disability score, and QoL score in the GBS were revealed . In a raThe association between small fiber impairment and QoL have received less attention than the association between large fibers and QoL , even thDespite the promising results of this study, several limitations are recognized. The comparison group for WHOQoL matched healthy subjects was retrieved from historical data. This study is a cross-sectional study performed at a single tertiary-care medical center and the etiologies of polyneuropathy in our studies patients were varied, which may limit the generalization of its findings to primary clinics. On the other hand, the diverse disease etiologies included in this study means that these observations might be applicable to polyneuropathy caused by different etiologies. Larger databases are necessary to identify the precise contributing factors leading to a reduced QoL, and may lead to the design of therapeutic approaches that improve treatment efficacy.How will the QoL measures assessed in this study benefit patient care? Our validation of QoL promotes its use as a follow-up instrument in patients with small fiber neuropathy. Physicians can monitor disease progression by repeated measurements of HRQOL in their clinical practice. In addition, temporal changes of HRQoL along with the lifetime course of the illness can reflect patient’s functional state  and utility , which aOur current study demonstrates biomarkers of small fiber impairment, including temperature thresholds in QST and the IENF density in a skin biopsy, were significant determinants of QoL in polyneuropathy patients. Furthermore, there was a linear correlation between the warm threshold of the foot and the QoL scores in the physical domain of the WHOQoL.


Metastatic lesions localized in the periacetabular area cause troublesome pain and reduced mobility of the patients. Radiotherapy effectively decreases pain, yet it does not restore the ability to load the joint. Surgical treatment involving resection of metastatic lesions and joint reconstruction using bone grafts is burdened with a high rate of complications. Modular tumor prostheses are being increasingly used. In some cases, it is possible to strengthen the acetabular roof with bone cement using vertebroplasty kits. The aim of the study was to demonstrate various methods of treatment of metastatic lesions localized in the periacetabular area together with the analysis of their results and effectiveness.Between 2010 and 2015, 27 patients with cancer metastases to the acetabulum were treated at our department. Qualification for surgical treatment was multifaceted with numerous aspects being considered. They included patients’ general condition, type of neoplasm, clinical stage, and prognosis. CT and MRI scans of the pelvis were performed in each case. Before the surgery and 3 months following the surgery, visual analogue scale (VAS) pain intensity, Karnofsky functional status, and motor ability according to the Harris scale were evaluated. Bone cement (PMMA)-augmentation was performed in 21 patients, of whom nine had cement injected precutaneously and 12 at proximal femur resection alloplasty. Hemipelvectomy Type II combined with implantation of LUMiC resection prosthesis of the acetabulum were performed in six cases.The quality of life improved in all the patients. After percutaneous cement injection, the mean pain intensity VAS score was 2.7, and the mean Karnofsky functional status score was 71.8. The mean postoperative Harris hip score (HHS) was 94 points. The patients who had undergone resection alloplasty on the proximal femur combined with periacetabular cement injection were walking using one crutch. In this group of patients, the mean postoperative pain intensity, functional status, and gait efficiency scores were 4.5, 65.7, and 82 points, respectively. The mean pain intensity VAS score in patients who had LUMiC prostheses implanted was 3.4. Their mean functional status score was 65 and the gait efficiency score 71 points. All the patients were able to walk on crutches.Strengthening of the acetabular roof with bone cement in a specific group of patients is an adequate method of treatment which decreases pain and allows for loading the affected limb while walking. Internal hemipelvectomy combined with LUMiC prosthesis implantation makes it possible for the patients to walk using crutches and significantly reduces pain. Bone metastatic lesions concern between 30 and 70 % of patients. The sites most commonly affected are the spine, the pelvic bones, and the proximal part of the femur and the humerus. Lytic and mixed metastases may cause tormenting pain, reduced mobility, and pathological fractures. Massive metastases to the pelvis, especially to the periacetabular area, are still a difficult treatment problem. They inhibit patients’ walking independently, thus forcing necessity to use crutches or a walking frame. Joint motion is usually significantly limited and related to pain. These infirmities are accompanied by imminent muscle atrophy. Bed-ridden patients are more likely to develop thromboembolism and infectious complications. The patients need constant care of the family or healthcare practitioners and require analgesic treatment –3.Until recently, the treatment of metastatic lesions localized in the pelvis was limited to radiotherapy which effectively decreased pain but did not restore the ability to load the affected joint .Treatment planning requires an in-depth analysis of patient’s general condition, stage of cancer, and prognosis. Qualification must be multifaceted and multidisciplinary. It is necessary to perform CT and MRI so as to carefully examine the extent of the lesions, infiltration of muscles, vessels, and nerves, and to plan bone reconstruction. The use of massive bone grafts to reconstruct losses in the acetabular area is controversial, because of high risk of infections and bone healing problems. Specially designed modular prostheses, the acetabular part of which is seated in the iliac ala or even in the lumbar vertebra, are being increasingly used. In the case of minor lytic lesions when the cortical bone is undamaged, it is a good solution to perform PMMA-augmentation with the use of vertebroplasty kits. Bone cement increases the resistance of the acetabulum and allows full loading of the affected limb. In some cases, it is possible to seat the acetabular part of the hip prosthesis without the need for complicated reconstructions –10.The aim of this study was to demonstrate various methods of treatment of tumor-induced losses localized in the periacetabular area together with the analysis of their results and effectiveness.Between 2010 and 2015, 27 patients with cancer metastases to the acetabulum were treated at the orthopedic oncology department in Brzozów. The following aspects were analyzed in the qualification for the treatment: patient’s general condition, type of cancer, clinical stage of cancer, and prognosis. Each time, CT and MRI were carried out prior to the surgery. What were analyzed were the extension of bone losses, the cortical bone condition, and the possibility of hip replacement. Before the surgery and 3 months following the surgery, visual analogue scale (VAS) pain intensity, Karnofsky functional status, and motor ability according to the Harris scale were evaluated. The analysis covered the course of the surgery and the perioperative period and complications and their causes. Follow-up radiographs were performed on postoperative day 1 and then on a 6-week basis. Careful attention was given to whether there were symptoms of local recurrence of the neoplastic disease, new foci of the disease, damage to implants, or their loosening.Bone cement (PMMA) augmentation was performed in 21 patients, of whom nine had cement injected precutaneously Figs. . Each tiThree weeks after the surgery, all the patients were subjected to a single radiation dose of 8 Gy. The observation period lasted between 4 and 49 months (mean 16 months).The majority of the treated patients (18) were women. There were nine men. The mean age was 63 for women (range 42–81) and 68 for men (range 54–82).In our study, the most common cause of the destruction of the acetabulum was a metastasis from breast cancer (11 patients), followed by multiple myeloma (seven patients), kidney cancer (six patients), and lung cancer (three patients). The mean time interval between the diagnosis of cancer and the occurrence of a metastasis was 22 months.The research has been performed in accordance with the declaration of Helsinki. As this retrospective analysis consists of anonymised clinical routine data, the Research Ethics Committee  deems the application for and issue of an Ethics approval not necessary. All the patients gave a written consent to the use of data for research.The patients who had undergone resection alloplasty on the proximal femur combined with acetabular cementation were walking with one crutch. The pain they experienced did not increase when loading the operated limb. In this group of patients, the mean preoperative and postoperative VAS pain intensity scores were 8.2 and 4.5, respectively. The mean Karnofsky functional status score was 47.2 before the surgery and 65.7 after the operation. The postoperative gait efficiency score (HHS) was 82 points.In the group of patients with LUMiC prostheses, the mean preoperative VAS pain intensity score was 8.1 and the mean preoperative Karnofsky functional status score was 40.2. The following mean scores were recorded after the surgery: VAS 3.4, Karnofsky 65, HHS 71  was not particularly troublesome. It was compensated using insoles for shoes.Results of the treatment of bone losses in the pelvis with bone cement (PMMA) using vertebroplasty kits are very encouraging. No inflammatory reactions in soft tissues after precutaneous injection of cement were noted. Follow-up radiographic results using this method were found satisfactory. No significant degrees of leakage of bone cement into the muscles or the hip joint were observed. Further radiograms did not reveal osteolysis in the area of bone cement, bone cement dislocation, or loosening within the hip bone. No fractures within the strengthened acetabulum were noted in any of the patients. The quality of life improved in all the patients as a result of reduced pain or its complete regression. The mean VAS pain intensity score in patients undergoing isolated acetabular cementation was 6.9 before the surgery and 2.7 after the operation. The mean Karnofsky functional status score was 52.5 before the surgery and 71.8 after the procedure. The mean postoperative Harris hip score (HHS) was 94 points. All the patients were walking unaided; loading the operated limb did not cause pain.The treatment for metastatic lesions localized in the periacetabular area depends on the patient’s general condition, prognosis, and the extension and localization of the lesion , 12.Non-surgical treatment is employed in patients in a poor general state of health who are not considered for surgery and in patients with a tumor localized in zones I and III according to the Enneking and Dunham classification. Radiotherapy is the most frequent method of treatment that reduces pain and rate of local recurrence. Radiotherapy is also used as adjuvant therapy after surgery. Embolization, which reduces tumor size and vascularization and causes tumor calcification, is another increasingly used method. Its analgesic effect lasts for half a year. Preoperative embolization reduces intraoperative bleeding, allows for a precise tumor dissection, and shortens the time of surgery. Preoperative embolization is particularly indicated for patients with hypervascular tumors .In the treatment of prostate and breast cancers and myeloma, multiplex bisphosphonates are used. They are effective in reducing pain and the number of subsequent fractures.Other less common treatment methods include electrochemotherapy, radiofrequency ablation, and thermotherapy .Surgical treatment most often is required in patients with tumor localized in zone II according to the Enneking and Dunham classification. Wide resection is used in patients with an extensive bone loss and in solitary bone metastasis, especially from breast, thyroid, and kidney cancers. Intralesional resection is performed in patients with diffuse pelvic involvement when wide resection is not possible. Ruggieri et al. have not demonstrated any statistically significant differences in the survival to death and survival to local recurrence between the patients after wide resection and the patients after intralesional resection .There are many ways of pelvic bone losses reconstruction which aim at achieving a good functional treatment outcome. The indications for different treatment methods depend on patient’s prognosis, tumor location and size, and experience and preferences of the surgeon.In the case of pelvic bone losses due to cancer, the use of massive bone grafts is debatable as burdened with a high risk of infectious complications and healing disorders. The patients are forced to unload the operated limb. For that reason, modular or custom-made prostheses are being increasingly used.Stem acetabular prostheses are particularly often used in patients with a good prognosis and solitary bone metastases. Patients in IV class according to the Harrington classification are candidates for this procedure. It is a relatively simple surgical technique, but instability or dislocation of a prosthesis may occur , 15, 16.In the Harrington I class, total hip replacement with or without acetabular support rings has been described. Very extensive bone loss requires custom-made endoprosthetic replacement.The Harrington technique of pelvic bone loss reconstruction requires a wide surgical approach and is associated with the risk of complications; however, it guarantees a good functional outcome. It is particularly often applied in patients in Harrington III class , 12.The injection of cement under pressure using vertebroplasty kits is to a certain extent a novelty. This method was applied and described by Georgy in 2009. He operated on 12 patients with lytic metastases to the hip bone and assessed the gait efficiency as well as the VAS pain intensity. The results were good. The mean preoperative VAS score was 8.6, while the mean postoperative VAS score was 3.8 . Good trWeil et al. succeeded in achieving positive results as regards pain which was reduced or erased in 83 % of cases in the group of 18 patients who had undergone reconstructive operation with the use of cement. The patients were able to walk unaided without taking analgesics .The LUMiC prosthesis was designed to treat bone damage that occurs during the course of the neoplastic disease in the periacetabular area. The classical method involves prosthetic implantation with no cement used. The specially shaped stem has the purpose of minimizing the rotating motion of the prosthesis in relation to bones. The surface of the prosthesis allows for growing of bones into it and secondary stabilization. It is also agreed to implant the acetabulum using bone cement, which ensures the primary stability of the prosthesis and facilitates immediate limb loading , 20, 21.As Capanna et al. see it, prosthetic implantation after resection of cancer metastases to bones can be performed with the use of cement which enables immediate and full limb loading. The additional merit of this method is that it reduces the risk of implant loosening after radiotherapy , 23.Similarly, Hoffmann et al., Grosheger et al., and Gebert et al. studies have demonstrated that the results of the treatment of bone metastases using cement-retained prostheses are good. The risk of their loosening in consequence of radiotherapy is low, and the incidence of infectious complications is similar when cement is not used. The patients can start walking, fully loading the operated limb immediately after the surgery. In the case of cement-free prostheses, full limb loading is recommended only after 6–12 weeks following the surgery –26.Some researches have shown a low rate of infectious complications (5.4–7.9 %) and aseptic loosening  among patients who had cement-retained prostheses implanted .Saddle prostheses have failed to meet the hopes they evoked. They loosened quickly or were primarily unstable. The incidence of dislocation was high; they also caused troublesome pain. Hip joint motion and the function of the limb were limited . WedemayWang et al. succeeded in achieving satisfactory functional results evaluated by MSTS in the group of 50 patients who had tumor prostheses implanted after resection of pelvic tumors. Despite that the center of joint rotation was moved superiorly and medially, the function of gluteal muscles was proper enough to allow good performance in walking. In 80 % of the cases, no symptoms of loosening were detected 3 years after the surgery [In our study group, six patients with LUMiC prostheses reported significant pain relief and their functional status improved. A large decrease in the strength of gluteal muscles was not perceived as particularly troublesome by the patients. No infectious complications, loosening and dislocation of implants, or local recurrences of the neoplastic disease were noted.The patients who had undergone cement augmentation appreciated a significant improvement in the quality of life. The pain significantly decreased, and the functional status improved. All the patients were able to walk unaided, fully loading the operated limb.Patients qualified for cement augmentation of the periacetabular area should be those with without very extensive bone losses and undamaged cortical layers which allows injecting cement under positive pressure. A correct titration cementing technique reducing the risk of uncontrollable leakage is of importance .Augmentation of tumor-induced losses in the periacetabular area is an adequate method of treatment which decreases pain and allows for loading the affected limb while walking.A condition necessary for qualification for the bone cement augmentation is undamaged cortical bone layer which enables injecting cement under positive pressure and prevents its leakage.The LUMiC prosthesis is a good solution for the patients who require resection of the periacetabular pelvic bone. The patients maintain walking ability with the use of crutches and they experience significant pain relief.


Neck pain is a common symptom in most patients suffering from cervical radiculopathy. However, some conservative treatments are limited by their modest effectiveness. On the other hand, surgical intervention for cervical disc disorders is indicated when symptoms are refractory to conservative treatments and neurological symptoms are progressive. Many patients use complementary and alternative medicine, including traditional Chinese medicine, to address their symptoms. The purpose of the present study is to examine the efficacy and safety of Qishe Pill, a compound traditional Chinese herbal medicine, for neck pain in patients with cervical radiculopathy.A multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of the Qishe Pill is proposed. The study will include 240 patients from five sites across China and diagnosed with cervical radiculopathy, according to the following inclusion criteria: age 18 to 65 with pain or stiffness in the neck for at least 2 weeks (neck disability index score 25 or more) and accompanying arm pain that radiates distally from the elbow. Qualified participants will be randomly allocated into two groups: Qishe Pill group and placebo group. The prescription of the trial medications (Qishe Pill/placebo) are 3.75 g each twice a day for 28 consecutive days. The primary outcome is pain severity. Secondary outcomes are functional status, patient satisfaction, and adverse events as reported in the trial.Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus. According to modern research and preparation standards, Qishe Pill is developed to improve on the various symptoms of cervical radiculopathy, especially for neck pain. As it has a potential benefit in treating patients with neck pain, we designed a double-blind, prospective, randomized-controlled trial and would like to publish the results and conclusions later. If Qishe Pill can alleviate neck pain without adverse effects, it may be a unique strategy for the treatment of cervical radiculopathy.Qishe Pill is composed of processed NCT01274936This study is registered at ClinicalTrials.gov,  Cervical radiculopathy is a distinct consideration in the evaluation of any patients who have neck pain and may be defined simply as an abnormality of a nerve root, which originates in the cervical spine . The typAs a complementary and alternative medicine, herbal medicines have the potential to avoid the adverse effects of medications and surgery . NaturalA number of studies on the effects of the Chinese herbal medicine on cervical radiculopathy have been proposed, but useful empirical research is insufficient. For chronic neck pain, with or without radicular symptoms, there is low quality evidence suggesting that herbal medicine is more effective than placebo for pain relief as measured at the end of the treatment . MoreoveUsing a well-designed clinical trial, we will survey the efficacy of concurrent use of this remedy in relieving neck pain. Therefore, the present study is designed to examine efficacy and safety of Qishe Pill, a traditional Chinese herbal medicine (TCM) compound, on neck pain in cervical spondylopathic radiculopathy in a randomized, double-blind, placebo-controlled trial. Results of this study will provide evidence regarding the value of Qishe Pill as an intervention to alleviate neck pain caused by cervical radiculopathy.Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus  The remaining drugs forma decoction is mixed with astragalus membranaceus soaked for 30 minutes and simmered in 10 times the amount of water, twice, for 2 hours each time. (3) The decoction is then vacuum filtrated to a concentration of relative density 1.24-1.26 (70°C). Ethanol is mixed into the concentrated decoction to reach 70% alcohol content. (4) After standing, filtering, and concentrating with recovery of ethanol, the decoction is crushed into a fine powder after vacuum drying. (5) In the reagent of 14 times the amount of 70% ethanol, Radix Stephaniae Tetrandrae and Caulis Sinomeniiare is extracted with the circumfluent alcohol three times, once 2 hour. (6) Volatile oil of Rhizoma ligustici wallichii is mixed with 4 times the amount of β-cyclodextrin and then dried in vacuum. (7) The porphyrization of Artificial Calculus Bovis Artifactus and Artificial Muscone is mixed with β-cyclodextrin and other accessories to be made into a piece, pelleted and coated pills. These pills are called Qishe Pill in drug name.The production process of Qishe Pill: (1) Volatile oil is extracted from The placebo is composed of β-cyclodextrin, colorants and food flavoring, to look and taste similar to Qishe Pill.This clinical trial is a multi-center, randomized, double-blind, placebo-controlled design. Participants will be enrolled by clinic recruitment at five hospital sites . Participants will be recruited in equal numbers (n=48) from each of the five sites.th 2011 (No: 2011LCSY031). All study participants will sign the written informed consent prior to participation. All patients will receive written and oral reassurance regarding the typical benign course of the symptoms. We will explain that placebo and treatment with Qishe Pill might be equally effective interventions. Patients in all treatment groups will be allowed to use painkillers when necessary. In general, paracetamol is selected with or without a non-steroidal anti-inflammatory drug. Patients will be asked to note their drug use, including over-the-counter analgesics, in a specially designed diary during the first four weeks following randomization.This study has been approved by the Institutional Review Board of Longhua Hospital, Shanghai University of TCM on November 30All participants will be selected from the general outpatient clinic offive hospital sites, where the patients willbe diagnosed with cervical radiculopathy confirmed by a neurologist, and then diagnosed based upon clinical manifestations , physical examination, and imaging .Inclusion criteria are age between 18 and 65 years, pain or stiffness in the neck for at least 2 weeks, neck symptoms reproducible during physical examination, neck pain on neck disability index (NDI) of 18 or more, and radiation of arm pain distal to the elbow, plus at least one of provocation of neck or arm pain by neck movements, Brachial plexus traction test, foraminal compression test, or foraminal separation test, sensory changes in one or more adjacent dermatomes, or muscle weakness in one or more adjacent myotomes. Further inclusion prerequisites are willingness for treatment and to adhere to measurement regimens, no involvement in litigation, and written informed consent.Excluded criteria are patients whose history, signs, and symptoms suggested a potential non-benign cause (including previous neck surgery) or evidence of a specific pathologic condition, such as malignancy, neurologic disease, fracture, herniated disc, or systemic rheumatic disease, clinical signs of spinal cord compression, previous neck trauma or treatment with surgery, obvious vertigo, pregnant women, lactating women, currently participating in other clinical trials, accompanied with hepatic, renal, hematopoietic system, endocrine system, cardiovascular, nervous system, primary and other serious diseases , tuberculosis, vertebral deformities, cancer and mental illness, and insufficient understanding of the Chinese language, and/or have been treated with physical therapy or manual therapy for neck pain during the previous 2 weeks.Patients with concurrent headaches, non-radicular pain in the upper extremities, and low back pain will not be excluded, but neck pain has to be the main symptom for all patients .Patients will be recruited from May 2012 to Oct 2013 from the five sites in China. The review board at each institution approved the protocol. The study is organized and coordinated by Longhua Hospital, Shanghai University of TCM in Shanghai, China.This study is to be conducted according to the protection of patients, as outlined in the Declaration of Helsinki, and approved by the appropriate Institutional Review Boards. Each participant will sign the written informed consent before undergoing any examination or study procedure, in compliance with Good Clinical Practice. Patients who initially meet these eligibility criteria are then to complete the additional baseline testing and will be randomized into either the treatment or the control group. An independent steering committee will oversee the study.At randomization, patients will be assigned to receive Qishe Pill (or matching placebo) at 3.75 g twice per day. In this study, the same outer packing will be used for both Qishe Pill and the matching placebo. Therefore, the treating physicians, participants and investigators will be blinded to treatment assignment. The Qishe Pill and matching placebo used in the trial are both manufactured and provided by a pharmaceutical company that meets the requirements of Good Manufacturing Practice. All significant medicine information, including ingredient composition, heavy metals, etc., is provided by the same company.Follow-up visits will be continued for 5 months. At each visit, data will be collected on the outcome events, compliance and adverse reactions leading to a discontinuation of study medications. All primary and secondary events will be documented and be centrally adjudicated with the use of standardized definitions.Treatment allocation occurs when the study participant meets the inclusion criteria and signs the informed consent form. All participating patients will be randomized using a computerized block randomization schedule with a multiple block size of four; 240 patients will be randomly generated and kept in sequentially numbered opaque envelopes. All of the Qishe Pill and placebo provided by the pharmaceutical company will be numbered with a label according to the randomization schedule. When researchers administer the intervention medicine (Qishe Pill or matching placebo), these should be administered according to the randomized number. Randomization and uncovering must be conducted by a statistician team as a third party. As a result, researchers and patients are totally blinded to treatment allocation; the only un-blinded individual is the statistician responsible for the randomization process. The treatment assignments are balanced within each block.The primary study outcome is pain severity ). Secondary outcomes are a composite of functional status (measured by NDI), patient satisfaction, and adverse events as reported in the trial. The VAS measures the amount of pain, which is a pain score ranging from 0 (no pain) to 100 mm (very severe pain) . OperatiThe measurements that need to be performed at each visit are listed in Table All subjects are to be questioned regarding adverse events during treatment at each visit; all reported adverse events will be analyzed in spite of the investigators’ assessments of causality and will be categorized according to the Medical Dictionary for Regulatory Activities .We calculated the sample size for this two arm trial on the basis of the comparison treatment (Qishe Pill) versus placebo, with equal allocation in the treatment arms and five repeated measurements , with an estimated correlation coefficient of the measurements of ρ=0.8 and a difference in the mean value of the VAS for neck pain of 12 mm, as a clinical relevant difference with an estimated standard deviation in each treatment group of 25 mm . As neckThe data will be collected and analyzed according to the intention-to-treat principle. Standard statistical techniques will be used to describe characteristics of patients in both groups. We will compare baseline characteristics in both groups and if incomparability appears, we will perform the secondary analysis, adjusting for differences. The primary outcome, amount of pain, will be compared between both groups using survival analysis and analysis of variance for repeated measures. If adjustment for possible baseline incomparability is needed, analysis of covariance will be performed. We will use multivariate analysis to do retrospective analysis with the baseline data of the effective cases and ineffective cases in the treatment group. Differences in the baseline data will be used to optimize the inclusion criteria. We will do subgroup analysis based on severity of pain (VAS=70 mm) and use of analgesics.Cervical radiculopathy is a significant public health problem worldwide, accounting for 60% to 70% of all cases of cervical spondylopathy; it is generally believed that most symptoms can be cured or relieved by non-surgical treatment . The chiAnalgesic and nutritive nerve medicine have considerable effects on neck pain. Analgesics, such as aspirin, seem to be relatively secure, but it is reported that gastrointestinal reactions often appear . MecobalQishe Pill provides specific benefits for “Qi and Blood”, terms in TCM, which can profit and activate blood circulation. Using the model animal pathology comprehensive validation, other effects have been found that indicate involvement in inhibition of disc inflammation factors and delayed disc cell apoptosis . AccordiRadix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus. Based upon the theory of TCM prescription, there is a leading, coordinating, auxiliary, and guiding effect in the remedy components. In Qishe Pill, Radix Astragali and Szechuan Lovage Rhizome have leading effects, Musconehas a coordinating effect, Radix Stephaniae Tetrandrae and Ovientvinehave auxiliary effects, and Calculus Bovis Artifactushas guiding effects. Each component of Qishe Pill is thought to be beneficial to neck pain patients. The ability of AS-IV, which can be found in Radix Astragali to inhibit the NF-qB pathway, might be one underlying mechanism contributing to its anti-inflammatory potential in vivo[Szechuan Lovage Rhizome extract has been found to have the ability to inhibit platelet surface activity and platelet aggregation [Radix Stephaniae Tetrandrae exerts anti-inflammatory effects by interfering with ROS production and Ca2+ influx through G protein modulation to prevent Mac-1 up-regulation in neutrophil activation [Calculus Bovis Artifactus could decrease the malondialdehydecontent in inflammatory exudates induced by carrageen an in rats [Qishe Pill is composed of processed l in vivo. The Szeregation . The Radtivation . Ovientvtivation . Calculu in rats . Pretrea in rats . Qishe P in rats .Outcome measures assessing patients with neck pain are used widely in research and in clinical settings to establish baselines, to evaluate the effect of an intervention, and to motivate patients to evaluate their treatment. Generally, the VAS measurements have been found to be both valid and reliable. In many studies, the VAS has been shown to be the easiest to use and is considered to provide the most reliable measurements of pain intensity; it is therefore used as the criterion standard against new rating methods . SimilarWe intend to conduct this well designed RCT to investigate both the efficacy and safety of Qishe Pill in patients with neck pain, and consider that conscientiously performed studies and positive outcomes can benefit patients with neck pain. If this study demonstrates the efficacy and safety of Qishe Pill in significant strides, it will contribute to a useful clinical therapy for relieving neck pain in cervical radiculopathy.Participant recruitment began in September 2012 and finished in three sites ; while 28 participants have been enrolled in Huadong Hospital, Fudan University and 30 in TCM Hospital of Suzhou city.We periodically organized meetings to give participants feedback(recruitment or follow-up) on progress and conducted regular quality controls of all the trial sites by means of telephone conversations with every participant to verify the case report form. Data collection will be recorded in an eCRF system during the clinical trial.NDI: Neck disability index; RCT: Randomized Controlled Trial; TCM: Traditional Chinese medicine; VAS: Visual analogue scale.The authors declare that they have no competing financial interests. We gratefully acknowledge the assistance of Michael R. Berger, M.S. Medicine-Acupuncture, Tuina, in revising the manuscript.XJC participated in the study design and critical revision of the manuscript. YLS drafted the manuscript. SFY participated in statistical design. WM and SL participated in the study design. QS formulated Qishe Pill. YJW was the general supervisor for this research and participated in both the study design and in the critical revision of the manuscript. All authors read and approved the final manuscript.


The decision to treat pain in the emergency department (ED) is a complex, idiosyncratic process. Prior studies have shown that EDs undertreat pain. Several studies demonstrate an association between analgesia administration and race. This is the first Midwest single institution study to address the question of race and analgesia, in addition to examining the effects of both patient and physician characteristics on race-based disparities in analgesia administration.This was a retrospective chart review of patients presenting to an urban academic ED with an isolated diagnosis of back pain, migraine, or long bone fracture (LBF) from January 1, 2007 to December 31, 2011. Demographic and medication administration information was collected from patient charts by trained data collectors blinded to the hypothesis of the study. The primary outcome was the proportion of African-Americans who received analgesia and opiates, as compared to Caucasians, using Pearson’s chi-squared test. We developed a multiple logistic regression model to identify which physician and patient characteristics correlated with increased opiate administration.Of the 2,461 patients meeting inclusion criteria, 57% were African-American and 30% Caucasian (n=2136). There was no statistically significant racial difference in the administration of any analgesia , or in opiate administration for migraine or LBF. African-Americans who presented with back pain were less likely to receive an opiate than Caucasians . Secondary outcomes showed that higher acuity, older age, physician training in emergency medicine, and male physicians were positively associated with opiate administration. Neither race nor gender patient-physician congruency correlated with opiate administration.No race-based disparity in overall analgesia administration was noted for all three conditions: LBF, migraine, and back pain at this institution. A race-based disparity in the likelihood of receiving opiate analgesia for back pain was observed in this ED. The etiology of this is likely multifactorial, but understanding physician and patient characteristics of institutions may help to decrease the disparity by raising awareness of practice patterns and can provide the basis for quality improvement projects. Analgesia administration in the emergency department (ED) involves complex decisions based on multiple conscious and subconscious factors. Disparities in healthcare are propagated by subconscious stereotypical beliefs about patients (implicit bias), the patient-physician interaction, and patient factors including attitude, intention, self-efficacy, and disclosure.A review of the literature found several studies that demonstrated a racial disparity in analgesia and opiate administration in the ED.8In contrast, other studies have failed to show a racial disparity in analgesia administration for LBF.16The purpose of this study was to assess ED analgesia-prescribing habits on both a department-wide and physician level at an academic institution. This study examines patient and physician characteristics, including patient race that may play a role in a physician’s decision to administer analgesia. Three diagnoses  that have varying degrees of objective sources of pain are included for comparison purposes.This was a retrospective chart review of patients seen between January 1, 2007, and December 31, 2011, at the adult ED of an urban university hospital in a Midwestern metropolitan area. The ED has 22 beds and the annual census ranged from 34,018 in 2007 to 37,362 in 2011 of which 64% were African-American and 51% were male. Forty-eight percent of our population was on Medicaid or was uninsured. The 30 physicians in this group were comprised of 16 full-time and 14 part-time attending physicians who practiced in the ED during this timeframe. All full-time attending physicians were trained in emergency medicine (EM), while some part-time attending physicians were trained in other medical specialties . The ED provides training for its EM residency program as well as rotations for non-EM specialties including internal medicine, psychiatry, anesthesia, orthopedics, and otolaryngology. Attending physicians are involved in every case and closely supervise residents. First-year residents (interns) must first discuss the patient and plan with the attending, prior to writing orders. Second- and third-year residents are allowed to write orders, including narcotic medications, prior to discussing patients with the attending. At the time of this study, there was no nurse-run pain protocol at triage. The university’s institutional review board approved this study.We used the International Classification of Diseases (ICD-9) codes to generate a list of medical record numbers and demographic information of all patients who presented to the ED with one of the following diagnoses: back pain or strain (ICD-9 724), migraine (ICD-9 346), or fracture of the humerus, femur, or tibia or fibula, . Inclusion criteria required participants to be aged 18 or older. We excluded patients with more than one fracture (such as humerus and tibia fracture) or multiple diagnoses.. Collectors were blinded to the hypothesis of the study. Their training included instruction on the structure of the electronic medical record, the definition of the study variables, and the data collection procedure. We performed an audit of each data collector’s results based on a randomly selected set of 10 charts to ensure the precision of each collector’s measurements and the interpersonal reliability of the results. In all, 40 charts were reviewed, 10 from each data collector. There was perfect agreement between the information gathered by the collectors and the auditor’s samples.We collected data following the guidelines of Gilbert and Lowenstein et al. including trained data collectors, standard data collection sheets, and inter rater reliability.A patient was considered to have received analgesia if an analgesic drug was administered in the ED or prescribed at discharge. The list of medications considered analgesia, those considered an opiate, and several drugs that notably were not considered analgesia, is presented below .The primary objective was to compare the proportion of African-Americans who received analgesia  to Caucasians, for each diagnosis. A secondary analysis measured the modifying effect of patient and/or physician characteristics on the administration of analgesia. The following attributes of the attending physician who was responsible for the patient’s care were examined: gender, congruence by race and gender , completion of an EM residency.We used a Pearson’s chi-squared test to compare baseline demographic characteristics between Caucasians and African-Americans, the proportion of patients receiving any type of analgesia by race, and the proportion of patients who received an opiate by race among patients who had received some form of analgesia.A multiple logistic regression model was created to identify patient and physician characteristics associated with opiate administration for the only diagnosis in which a racial disparity was observed. First, we employed a univariate analysis to estimate the odds ratios for each variable independently. The construction of a multiple logistic regression model then followed a two-step process in which we assessed statistically significant variables for inclusion in a final model based on how their inclusion affected the odds ratio for Caucasians with back pain to receive an opiate, as compared to African-Americans. Variables with no significant impact were excluded. In this way, the final multiple logistic regression model represents the most parsimonious model for estimating the effect of race on opiate administration, adjusting for likely confounders.In addition, physician level differences in opiate prescribing for Caucasians and African-Americans were calculated for those who treated at least 25 patients during the study period. We ranked physicians according to opiate-prescribing differences to illustrate the range of prescribing practice, but we made no adjustments for any patient-level attributes, such as acuity. Reporting of this descriptive analysis was limited to the diagnosis group(s) for which disparities were found.We performed all statistical tests using SPSS version 18.0  with the assistance of an independent statistical consultant. Statistical significance was defined using a two-tailed test with an alpha level of p<0.05. A Bonferroni adjustment ws applied to the interpretation of the study’s primary analysis regarding proportion of patients who received an opiate by two racial groups for three diagnoses; the adjusted alpha was 0.008.Of the 2,461 patients who met inclusion criteria, 741 (30.0%) were Caucasians, 1,395 (56.7%) African-Americans, 48 (2.0%) with race listed as “other,” and 277 (11.3%) patients with race listed as “unknown.” Baseline characteristics by diagnosis are compared in Of the 2,461 patients who met inclusion criteria, we analyzed a total of 2,136 patients: 1,850 (75.2%) cases of back pain, 238 (9.7%) cases of migraine, and 373 (15.2%) cases of LBF. Patients (n=325) with other or unknown race were excluded from analysis (13%) .There was no statistically significant difference between the proportion of African-Americans and Caucasians who received some form of analgesia for any of the three diagnoses. Of patients who received analgesia and were diagnosed with a migraine or LBF, there was no statistically significant race-based difference in the likelihood of receiving an opiate. However, among patients who were diagnosed with back pain and received analgesia, African-Americans were less likely to receive an opiate than Caucasians : 50% verBetween 2007 and 2011, the 1,850 patients presenting with back pain were seen by 30 attending physicians . The numSince univariate analysis showed that gender congruence was not a significant predictor of opiate administration it was removed from further development of the logistic regression model. Among patients presenting with back pain who received some form of analgesia, the final multivariate model estimated the odds ratio that a Caucasian patient would receive an opiate to be 2.41 , as compared to an African-American patient. This model controlled for acuity, age, physician gender, race congruence, and physician training in EM. This model revealed that higher acuity, older age, physician training in EM, and male physicians were positively associated with opiate administration . Given t18Racial and ethnic differences in pain management have been noted in many medical care settings , and for various types of pain .In fact, we found similar results to a study of the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 15 years ago. African-Americans (AA) and Caucasians received some form of analgesia at similar rates across all diagnoses .22Patient-physician communication and assessment of pain by the provider are important factors in the treatment of pain. Numerous studies have related that physicians underestimate pain more in racial/ethnic minorities, especially for patients reporting high pain severity.1Implicit bias that relies on unconscious racial stereotypes may influence pain management decisions such as assessment and credibility of pain, as well as possible misuse of opiate prescriptions.24Regarding approaches to improve pain management in the ED, clinical education shows promise.Looking forward, the question remains on the best ways to mitigate racial disparities in the ED for pain management, and ED healthcare in a broader context. Programs that may help include empathy training, communicating about expectations of pain relief in the ED, and cross-cultural training.Potential limitations include those associated with retrospective chart reviews and the single-institution study design that limits the generalizability of the results. Self-identification of race, perception of others’ race, and race relations differ regionally; accordingly, it is impossible to say whether the findings of the present study reflect only regional patterns, or if they are applicable to other areas of the country. Eleven percent of the study population had no recorded race documented in the medical chart (and 2% with “other” race) were excluded from analysis. It is unknown whether race, as recorded in the chart, was self-identified or assumed. Ethnicity (i.e. Hispanic white versus non-Hispanic white) was not elucidated from race although other studies have shown that ethnic minorities are also less likely to receive opiates.32Another limitation involves the use of diagnostic codes, as opposed to chief complaints, as inclusion criteria. Many conditions can cause back pain and the exact etiology cannot always be elucidated within one ED visit. Thus a diagnostic code of unspecified back pain may in fact be sciatica, nephrolithiasis, or an epidural abscess (that was not diagnosed in the ED), and be misclassified, although it is doubtful that there would be a differential by race. Along similar lines, selection bias may explain why there was no race-based disparity in opiate administration for migraines. It is plausible that only patients with a previous documented diagnosis of migraine or migraine recorded in their past medical history received this code. Thus, the complaint of pain may have been considered to be more objective evidence (compared to complaints of headaches of unclear etiology) due to their history.Finally, the retrospective review of medical records allows only a limited understanding of clinical decision-making. Factors that are not always captured in patients’ charts may have had a bearing on the decision to administer analgesia; these include nonverbal communication, verbal communication (asking to receive or not receive opiates), socioeconomic status, and education level. Other factors that may have impacted reception of opiates include mode of arrival, duration of pain, intoxication, and pain score. Pain scores can be extremely subjective with wide variability between patients and may not be able to discriminate between those who want pain medication and those who do not.The use of opiates for back pain and migraine conditions in this ED may seem high at 49% and 43%, especially in light of guidelines calling to limit opiate use for these conditions. The American Academy of Neurology guidelines from 2000 recommend opiate use only as a rescue medication after first-line therapy has failed, and the 2008 American College of Emergency Physicians clinical policy on headache makes no mention of opiate use.Furthermore, this study was performed at a teaching hospital, where both residents and physicians were involved with care of the patient. Either member of the team could give analgesia; however, the physician level factors were attributed to the primary attending responsible for the patient.No race-based disparity in overall analgesia administration was noted for all three conditions: LBF, migraine, and back pain at this Midwestern institution. However, we observed a race-based disparity in the likelihood of receiving opiate analgesia for back pain in this ED with Caucasians 1.5 times more likely than African-Americans to receive opiate analgesia. The etiology of this is likely multifactorial, but understanding physician and patient characteristics of institutions may help to decrease the disparity by raising awareness of practice patterns and can provide the basis for quality improvement projects. Additionally, this study provides an approach for identifying department-wide race-based disparities, allowing institutions to determine if steps addressing potential bias should be focused on a department as a whole or on specific members. More interdisciplinary research is needed to address ways in which racial disparities related to pain management in the ED can be mitigated.


P > 0.001) and predicted clinical outcome better than CCI (P = 0.059). In conclusion, FCI was more useful than CCI in predicting overall survival in elderly patients with myeloma.Multiple myeloma occurs primarily in elderly patients. Considering the high prevalence of comorbidities, comorbidity is an important issue for the management of myeloma. However, the impact of comorbidity on clinical outcomes has not been fully investigated. We retrospectively analyzed patients with newly diagnosed myeloma. Comorbidities were assessed based on the Charlson comorbidity index (CCI) and the Freiburg comorbidity index (FCI). The CCI is a summary measure of 19 comorbid conditions. FCI is determined by performance status, renal impairment, and lung disease. This study included 127 patients with a median age of 71 years. Approximately half of the patients had additional disorders at the time of diagnosis, and diabetes mellitus was the most frequent diagnosis (18.9%). The most significant factors for prognosis among patient-related conditions were a history of solid cancer and performance status (ECOG ≥ 2). The FCI score was divided into 3 groups , and the CCI score was divided into 2 groups (2-3 and ≥4). FCI was a strong prognostic tool for OS ( Multiple myeloma (MM) is a hematologic malignancy of plasma cells that results in bone destruction, marrow failure, and renal impairment. The median age at the time of diagnosis is 70 years, with 36% of patients younger than 65 years, 27% aged 65 to 74 years, and 37% older than 75 years . ConsideRisk stratification of myeloma using the international staging system (ISS) and host factors such as age, performance status, and comorbidities are thought to be important for determining prognosis and choosing treatment options –4. In 20Kleber et al. developed the Freiburg comorbidity index (FCI) to assess patient-related conditions as a risk factor for MM. The FCI is composed of three comorbidity factors: renal impairment, moderate to severe lung disease, and performance status. Interestingly, the FCI showed strong clinical relevance for overall survival (OS) and progression-free survival (PFS). Moreover, compared with other comorbidity indices, such as the Charlson comorbidity index (CCI), hematopoietic cell transplantation-specific comorbidity index (HCT-CI), Kaplan-Feinstein (KF), and Satariano index (SI), FCI was better able to stratify risk in patients with MM .Although CCI is a widely used tool for assessing comorbidity in malignancy, this comorbidity index is complicated and difficult to apply. Moreover, there is no proven cut-off value that divides patients into low- or high-risk groups. As a result, several studies have determined their own cut-off values –16. For Because of the increased incidence of multiple myeloma with aging and the fact that elderly patients have more comorbidity than younger patients, in the present study, we assessed comorbidities at diagnosis, the impact of host factors on OS, and compared CCI and FCI as prognostic factors in newly diagnosed elderly patients with MM.This study was a retrospective, single-center case series. OS was calculated as the time from diagnosis to death from any cause. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0. This study was reviewed and approved by the Institutional Review Board.A total of 127 consecutive patients aged 65 years and older who were newly diagnosed with symptomatic MM at the Samsung Medical Center, Seoul, South Korea, between January 1, 1999, and June 30, 2011, met the inclusion criteria for this study. We excluded patients with amyloidosis, those who were suitable for autologous stem cell transplantation (ASCT), and those who were lost to follow-up within 6 months from the time of diagnosis due to any cause except death. The last follow-up date was March 31, 2013.The CCI  is a sumIn addition, according to the original study, each decade of age over 40 would add 1 point to the risk value , and the age point would be added to the score of the comorbidity index. In this study, we used the method described by Kleber et al., which adds the age point to the CCI score .2, based on the modification of diet in renal disease (MDRD) study equation [Renal impairment is defined as estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 mequation . Poor peequation . Each ofχ2 test. OS was estimated using the Kaplan-Meier methodology. Uni- and multivariate Cox regression analyses were applied to assess factors affecting OS. Components with a P value less than 0.05 in univariate analysis were included in the subsequent multivariate analysis.Numerical variables are summarized by median and range and categorical variables are described by count and relative frequency (%) of subjects in each category. Comparison of the distribution of categorical variables in the different groups was performed with either Fisher's exact test or the P values were less than 0.05.These analyses were performed using PASW statistics 18.0.0 . Null hypotheses of no difference were rejected if During the study period, a total of 159 patients aged 65 years or older were newly diagnosed with symptomatic MM. Among them, 22 patients were excluded because of a combined diagnosis of amyloidosis, early follow-up loss, or ASCT. Therefore, data from 127 patients were included in the analysis.n = 24, 18.9%). The median CCI score, including age points, was 3 (range: 2 to 13). The CCI score was divided into two groups based on the median score; CCI scores of 2-3 were classified as the low CCI score group, and CCI scores ≥4 were classified as the high CCI score group. In this study, 53 and 74 patients belonged to the low and high CCI score groups, respectively. When using the FCI classification, 59, 54, and 12 patients belonged to the 0, 1, and 2-3 score groups, respectively.The prevalence of comorbidity at the time of diagnosis was 48.8% . The mosWe analyzed the impact of host factors, such as age, sex, performance status, and each of the comorbidities on OS . The resP < 0.001). The median survival times were 55.0 months, 29.5 months, and 19.5 months for FCI scores of 0, 1, and 2-3, respectively. Although the P value was not statistically significant, CCI also distinguished between the two score groups for OS . However, OS based on CCI without age points did not demonstrate clinical relevance (P = 0.147). In contrast, FCI was significant in subgroup analysis for age groups Figures n = 35, 30.0%) followed by neutropenia and anemia . Grade ≥3 nonhematologic adverse events occurred in 50% of patients, whereas grade ≥4 hematologic adverse events occurred in 22.9% of patients. Grade 5 adverse events due to any cause occurred in 6.8% of the patients, as shown in We defined serious adverse events as grade ≥4 for hematologic adverse events and grade ≥3 for nonhematologic adverse events, according to NCI-CTC version 4.0. The most frequent serious adverse event was infection , presence of any tumor, metastatic solid tumor, and cerebrovascular disease were significant factors. However, azotemia as defined by CCI (serum creatinine ≥ 3 mg/mL) was not a prognostic factor. In multivariate analysis, azotemia, as defined by impaired eGFR or chronic lung disease, was not shown to be a significant risk factor in our study. In contrast, a history of cancer, regardless of whether metastasis occurred, was the strongest prognostic factor for elderly patients with myeloma. Unfortunately, use of novel agents over conventional drugs did not significantly improve OS, although this might reflect the relatively short period of use of novel agents.Univariate analysis revealed that performance status, ISS, and several comorbid conditions such as chronic lung disease, azotemia (eGFR < 30 mL/min/1.73 mP < 0.001). The CCI score including age points was not statistically significant but was still valuable and superior to the CCI without age points. As briefly mentioned above, the CCI score without age points did not discriminate for OS.Although two components of FCI-renal impairment and moderate or severe lung disease failed to demonstrate significance in multivariate analysis, when we compared both comorbidity indices and overall survival, the FCI showed a greater ability to separate OS among the three score groups (FCI provides a clear definition of each component and all three components were statistically significant, at least in univariate analysis. In contrast, CCI is more subjective and only 4 among 19 conditions were significant. Most importantly, at the present time, CCI does not have any standard cut-off value. Various studies have divided CCI scores into groups of 0, 1-2, and ≥3; 0, 1, and ≥2; or 0 and ≥1. Some studies included an age point, but others did not –14. ThesMoreover, FCI is also very simple to apply. FCI consists of performance status, moderate or severe lung disease, and azotemia, and each of these factors is worth 1 point. The FCI score is, therefore, a simple summation of these three factors. In contrast, CCI consists of 19 comorbid conditions, and, within the same disease, scores are weighted based on severity ranging from 1 to 6 points. In addition, an age point is calculated and added to the CCI score. Comorbidity definitions frequently use a symptomatic grade.In this study, all 118 patients who were treated with chemotherapy received a full dose of chemotherapeutic agents as scheduled. Interestingly, the profile for serious adverse events showed that treatment was relatively safe and adverse events were easily controllable. In fact, since the approval of various novel agents, clinical outcomes such as survival and toxicity profiles have improved in transplant-ineligible elderly patients with multiple myeloma –27. ThusThere are some limitations in this study. First, the follow-up duration was short and the sample size was small. Second, this is a retrospective single center study. Third, there were no patients with peripheral vascular disease, dementia, DM with end organ damage, or AIDS. Despite these limitations, this study successfully applied the FCI and the CCI to newly diagnosed elderly multiple myeloma patients and revealed the superiority of FCI to CCI in predicting OS.In this study, approximately 50% of elderly patients with newly diagnosed multiple myeloma had at least one comorbid disease at the time of diagnosis. Among host factors tested, performance status and a history of malignancy were the most important prognostic factors. The Freiburg comorbidity index is very simple to use and predicts overall survival better than the Charlson comorbidity index.


This study investigated the efficacy of low level laser therapy (LLLT) for managing alveolar osteitis (AO).Sixty patients with alveolar osteitis of mandibular third molars were randomly divided into three groups. In group 1, socket irrigation was followed by alvogyl placement, and the treatment was repeated 48 hours later. In group 2, socket was irradiated with a low power red laser for 3 consecutive days . The subjects in group 3 underwent treatment with a low power infrared laser with the same parameters as group 2. A visual analogue scale (VAS) was used to record the degree of pain at the morning  and at 6 (T1) and 12 (T2) hours later for 3 days.p<0.05). At T2 point on day 2 and on day 3, VAS became significantly lower in the red laser group compared to the other groups (p<0.05). The infrared laser was not more efficacious than the other groups at any of the treatment intervals, but it reduced VAS to an acceptable level.Pain was significantly lower in the alvogyl group than the other groups at T1 and T2 points on day 1 and at T0 and T1 points on day 2 (LLLT displayed good results in this study for treatment of alveolar osteitis and should be further investigated as an alternative to alvogyl for AO management.Key words:Low level laser, low power laser, therapy, alvogyl, dry socket, alveolar osteitis, mandibular third molar. Alveolar osteitis (AO) or dry socket is the most common complication of dental extraction. It occurs with the incidence of 1-4% after routine dental extractions , althougBecause of the severe pain, the treatment strategies for AO are mainly palliative and are based on attenuating patient’s pain/discomfort over the period that healing spontaneously occurs. However, accelerating the healing process should also be considered as the secondary aim of the treatment. A widely used dressing for management of AO is alvogyl which contains eugenol , iodoform , and butamen (anesthetic) . Other tWith introducing low power lasers, their applications have been remarkably increased in different aspects of dentistry including oral surgery procedures. Low level laser therapy (LLLT) has a proven efficacy in accelerating the wound healing process ,15, reduThere are only few studies regarding the effectiveness of LLLT in the treatment of dry socket and comparison of low power red and infrared lasers for this purpose has not been performed according to the authors’ knowledge. Therefore, this study was conducted to compare the effects of low level red and infrared lasers and alvogyl in managing patients affected with dry socket.The sample consisted of sixty patients affected with alveolar osteitis of mandibular third molars, who referred to the Department of Oral and Maxillofacial Surgery of Mashhad Dental School, Mashhad University of Medical Sciences, Mashhad, Iran. The patients were 34 females and 26 males with mean age of 35.3 years (age range 23 to 65 years). The inclusion criteria consisted of subjects with at least 18 years old age in whom the definite diagnosis of dry socket in a mandibular third molar was made by an oral and maxillofacial surgeon according to the following criteria: the presence of severe pain in and around the socket initiated 1 to 3 days post operatively, and the observation of an alveolar socket devoid of blood clot with exposed bone. The study design excluded patients who had a background of radiotherapy or were affected with systemic diseases that could interact with the treatment process such as bone pathologic conditions, hematologic diseases, diabetes mellitus and etc. Furthermore, subjects who were smokers, affected with psychiatric disorders or had conditions that laser therapy could be contraindicated such as pregnancy were excluded from the sample. The protocol of the study was reviewed and approved by the Ethics Committee of Mashhad University of Medical Sciences, and each participant signed and informed consent document after being aware of the treatment process.This was a prospective randomized clinical trial. The participants were divided into three groups of 20 each according to a random number table, and underwent the following treatments:- Group 1 (Alvogyl): In this group, after local anesthesia with 2% lidocaine combined with 1:100,000 epinephrine, the extraction socket was thoroughly irrigated with 0.9 % sterile saline solution to remove debris and bacteria from the denuded bone. Afterwards, a sufficient amount of alvogyl  was inserted within the socket. Saline irrigation was repeated 48 hours later and alvogyl was refreshed.- Group 2 : The patients in this group received treatment from a low power indium-gallium-aluminum-phosphide (InGaAlP) diode laser  for 3 consecutive days. The outcome of our pilot study (the data have not been presented) revealed that laser therapy on every other day resulted in severe pain experience between irradiations, so LLLT was performed on consecutive days. The apparatus emitted a wavelength of 660 nm and operated at the power of 200 mW and continuous-wave mode. The irradiation was accomplished on three areas  for 30 seconds each, delivering 6 J of energy per area. The energy density at the surface of the probe was calculated to be 85.7 J/cm2 . However, the probe was held at an approximate distance of 1 cm and the beam was divergent, so the energy density at the target area would be lower than that calculated at the surface of the probe. Both patient and therapist wore safety goggles during treatment.- Group 3 : The device used in this group was a low level gallium-aluminum-arsenide (GaAlAs) diode laser (Thor), emitting a wavelength of 810 nm. Similar to group 2, the laser was applied at the power of 200 mW and continuous-wave mode and irradiation was performed for 30 seconds on each target area . The energy of 6 J was delivered per area, with energy density of 21.4 J/cm2 considering the spot size of 0.28 cm2 at the surface of the probe. However, the laser hand piece was approximately 1 cm far from the target area and so the actual energy density would be lower than that calculated at the probe surface. The patients attended therapy for 3 consecutive days and eye protection was taken with safety goggles.-Outcome assessmentThe patients were followed-up for 3 days after diagnosis and initiating treatment measures. Each patient was requested to record the pain level experienced at the morning  and at 6 (T1) and 12 (T2) hours later for 3 days. A visual analogue scale (VAS) was used to quantify pain, consisting of a 10-cm horizontal scale, with 0 (the left side) indicating the absence of pain and 10 (the right side) representing the most severe pain possible. Additional follow-ups were set for some patients if required.-Statistical analysisp>0.05), while those of days 2 and 3 were not (p<0.05). Therefore, a repeated measures analysis was run to detect any significant differences in pain intensity between the study groups and between the different evaluation times in each group on day 1. For days 2 and 3, the Kruskal-Wallis test, Mann-Whitney U test (with Bonferroni correction), Friedman test and Wilcoxon signed-rank test were used for inter- and intra-group comparisons of pain level. The statistical calculation was performed by SPSS  software, and the significance level was determined at p<0.05.The Kolmogorov-Smirnov test indicated that the pain data relating to the first day of the experiment were normally distributed . Figure p<0.05) with no significant alteration between 6 and 12 hours later. Both laser groups also showed significant decreases in VAS scores after 6 hours of intervention (p<0.05). Between T1 and T2 time points, VAS significantly decreased in the LPRL group (p<0.05), but in the LPIL group, a negligible increase in pain occurred . Figure p<0.05). On the other hand, there was a significant reduction in painful symptoms after 6 hours of intervention in both laser groups (p<0.05), which continued until T2 time point in the LPRL group . The variations of VAS scores on day 3 are demonstrated in figure p<0.05) with the exception of LPRL group between T1-T2 time points (p>0.05). The LPRL group was the only one that completed the study period with a pain value near zero , so one way analysis of variance (ANOVA) was run to compare pain intensity among the study groups at each treatment interval. The results showed that the pretreatment pain (T0) was not significantly different among the groups (p=0.509), but at both 6 (T1) and 12 (T2) hours after intervention, significant between-group differences were found (p<0.001). Tukey pairwise comparison test revealed that at both T1 and T2, pain was significantly lower in the alvogyl group compared to the red and infrared laser groups (p<0.05). At T1, the two laser groups were not significantly different from each other, but at T2, pain was significantly lower in the red compared to the infrared laser group . Pair wise comparisons indicated that at T0, pain was significantly lower in the alvogyl group than the red laser group, which in turn showed significantly lower pain than the infrared laser group (p<0.01). At T1, the mean VAS was significantly lower in the alvogyl than both laser groups (p<0.01), which were not significantly different from each other. At T2, the VAS became significantly lower in the red laser group than the other groups, and it was significantly lower in the alvogyl group than the infrared laser group . The Mann Whitney U test indicated that at T0, T1 and T2, pain intensity in the red laser group was significantly lower than both the alvogyl and infrared laser groups, and in the alvogyl group, it was significantly lower than the infrared laser group  after 6 hours, while between 6 and 12 hours of intervention, it decreased from 2.45 to 2.25 (8 % improvement). On the second day, the degree of pain increased 4% and 18% after 6 hours and between 6 and 12 hours of initial examination, respectively. Although pain worsening was small in the alvogyl group on day 2, it reached statistical significance between T1-T2 and T0-T2 time points. On the third day, the mean VAS significantly decreased after refreshing the dressing, so that pain improved 74% within the first 6 hours and about 53% between 6 and 12 hours of intervention. The effectiveness of dressings containing eugenol in management of patients with postoperative pain has been reported in previous studies  after 6 hours of intervention, and from 5.35 to 4.42 (17% improvement) between 6 and 12 hours later. On day 2, VAS improved 41% and 47% after 6 hours and between 6 and 12 hours of laser therapy, respectively. The VAS scores on day 3 were near zero and were the lowest among the study groups.LLLT was performed with an 810 nm infrared laser in the third group of this experiment. On the first day, pain decreased 38% (VAS reduction from 8.11 to 5.05 degree) after the first 6 hours of laser application, while between 6 and 12 hours later, not only pain reduction stopped but also there was 7% worsening in the pain experienced by the patients. The VAS improved 40% following 6 hours, and 5% between 6 and 12 hours of irradiation on day 2. The corresponding values were 57% and 45% on day 3. The total amount of reduction in VAS scores on days 1, 2 and 3 was 2.7, 3.1 and 4 degree, respectively, which means that the efficacy of the 810 nm diode laser increased over time.Comparison of pain intensity among the study groups revealed that on the first day, pain was significantly lower in the alvogyl group than the other groups at both 6 and 12 hours after intervention. This difference also existed at T0 and T1 time points on day 2, when significantly lower pain was experienced by the patients in the alvogyl group compared to the other groups. This can be attributed to the presence of the dressing that could fill the empty socket and in this way prevent from stimulation of denuded bone, which is one of the main factors producing pain. Furthermore, the dressing contains analgesic and local anesthetic factors that can act immediately and reduce patients’ pain. However, the presence of a dressing within the extraction socket could also be associated with delayed healing .The order of pain intensity changed after 12 hours of intervention on day 2, so that the mean VAS became significantly lower in the red laser group than the other groups. The significantly lower pain intensity in the LPRL group continued at all treatment intervals on day 3 compared to the LPIL and alvogyl groups. These results indicate that the alveogyl has a more immediate effect than LLLT on reducing pain of the patients affected with dry socket, but after 12 hours of intervention on day 2 and at all treatment intervals on day 3, the 660 nm laser became more efficacious than the alvogyl for pain reduction. This may be related to the fact that LLLT is not only capable to reduce pain and inflammation, but also can increase the rate and quality of wound healing ,15. The The infrared laser did not perform more effectively than the other groups at any of the treatment evaluations, but it caused a significant decrease in VAS scores during the 3-day treatment course, so that pain reached an acceptable value (VAS =1.2 degree) at the end of the experiment. It is possible that with repetitious use of this laser on the next days or with alteration in laser parameters, its efficacy would be improved, but further studies are warranted for verification.It should be noted that in the control  group, the socket was gently irrigated with normal saline solution before placing alvogyl in order to remove debris and bacteria. In the LLLT groups, however, socket irrigation was not performed in order to eliminate the need for local anesthesia and to accelerate the treatment process. Furthermore, since no material was inserted in the socket, irrigation seemed to be not obligatory. Treatment of dry socket is a time-consuming process for both the surgeon and patient, which may require several appointments for refreshing the dressing. We aimed to reach an effective approach that could be accomplished by a laser therapist or a dental assistant without the need to interact with routine activities in the dental office. It is possible, however, that socket irrigation before laser therapy would improve the treatment outcomes, but further studies are required to elucidate this issue.et al.  . In bothet al.  believedThe limitation of this study was the short follow-up period. Further studies with longer follow-ups are warranted to find the optimum parameters of low power lasers and to evaluate the combined effects of red and infrared lasers in reducing pain and accelerating the healing process in patients affected with dry socket.Under the conditions used in this study.1- The immediate effect of the alvogyl in reducing pain of the patients affected with dry socket was significantly greater than the low power red and infrared lasers, but after 12 hours of intervention on day 2 and at all treatment intervals on day 3, the 660 nm laser became more effective. Therefore, the low level red laser should be further investigated as an alternative to alvogyl in the management of AO.2- Although pain significantly decreased in the 810 nm laser group over time, its performance was not better than either the alvogyl or the 660 nm laser groups at any of the treatment intervals.


To examine whether function and pain outcomes of patients undergoing primary total knee arthroplasty (TKA) are changing over time.The Mayo Clinic Total Joint Registry provided data for time-trends in preoperative and 2-year post-operative activity limitation and pain in primary TKA patients from 1993-2005. We used chi-square test and analysis for variance, as appropriate. Multivariable-adjusted analyses were done using logistic regression.In a cohort of 7,229 patients who underwent primary TKA during 1993-2005, mean age was 68.4 years (standard deviation (SD), 9.8), mean BMI was 31.1  and 55% were women. Crude estimates showed that preoperative moderate-severe overall limitation were seen in 7.3% fewer patients and preoperative moderate-severe pain in 2.7% more patients in 2002-05, compared to 1992-95 (p < 0.001 for both). At 2-years, crude estimates indicated that compared to 1992-95, moderate-severe post-TKA overall limitation was seen in 4.7% more patients and moderate-severe post-TKA pain in 3.6% more patients in 2002-05, both statistically significant (p ≤ 0.018) and clinically meaningful. In multivariable-adjusted analyses that adjusted for age, sex, anxiety, depression, Deyo-Charlson index, body mass index and preoperative pain/limitation, patients had worse outcomes 2-year post-TKA in 2002-2005 compared to 1993-95 with an odds ratio ; p-value) of 1.34  for moderate-severe activity limitation and 1.79  for moderate-severe pain.Patient-reported function and pain outcomes after primary TKA have worsened over the study period 1993-95 to 2002-05. This time-trend is independent of changes in preoperative pain/limitation and certain patient characteristics.The online version of this article (doi:10.1186/1471-2474-15-440) contains supplementary material, which is available to authorized users. Total knee arthroplasty (TKA) is an extremely effective surgical treatment option for patients with end-stage refractory knee pain and associated functional disability. National Inpatient Sample (NIS) reported that 719,000 primary TKAs were performed in the U.S. in 2010 , leadingMany studies have focused on time-trends in utilization and specific in-hospital or immediate post-arthroplasty outcomes –9. To ouWe followed the recommendations from the Strengthening of Reporting in Observational studies in Epidemiology (STROBE) statement  to reporWe included all patients from the Mayo Clinic Total Joint Registry who had undergone primary TKA between 1993-2005 and had completed a preoperative and/or 2-year postoperative pain and function questionnaire. The Mayo Clinic Total Joint Registry captures data on all patients who undergo knee, hip or other joint arthroplasty. For TKA, data are captured using the Mayo Knee Survey that has construct validity and reproducibility . Mayo KnThe main predictor of interest was time-period, divided into 1993-1995, 1996-1998, 1999-2001 and 2002-2005. Given that our objective was to assess whether the pain and activity limitation had changed over time, we compared the prevalence of moderate-severe activity limitation and moderate-severe pain in the first period, i.e., 1993-95 to the last period, i.e., 2002-05. Since the entire study period (13 years) was not an exact multiple of 3, the last period consisted of 4-years.a priori , as previously [a priori, as previously [The main outcomes of interest were PROs, moderate-severe limitation of activities of daily living (ADL) and moderate-severe pain. For each of the 3 ADLs, walking, climbing stairs and getting out of a chair, patient responses were categorized into mild, moderate or severe limitation category, as previously , 19, 20.eviously , 18–21. eviously .We included several covariates  that are associated with pain/function after TKA –26, nameWe included several known confounders of function and pain outcomes to reduce confounding bias, but the cohort study design raises the possibility of residual confounding bias. We accounted for non-response bias, an expected limitation of this study, by presenting the non-responder characteristics and considering them in study interpretation. We did not perform any formal sample size calculations, since we anticipated >6,000 patients at both baseline and 2-year follow-up for our study, to provide adequate number of outcomes. Correlation of observations  was accounted for by using appropriate statistical methods.a priori, we compared the first and the last time-periods. The multivariable models were hierarchical and included the variables: (1) model 1: age and sex; (2) model 2: model 1+ medical comorbidity; (3) model 3: model 2 + anxiety + depression; (4) model 4: model 3 + medical comorbidity; (5) model 5: model 4 + preoperative pain/ADL limitation (in the respective model); (5) model 6: model 5 + BMI.We compared crude rates of moderate-severe ADL limitation and pain across the four pre-specified time periods using chi-square tests. We used univariate and multivariable-adjusted logistic regression models, using a generalized estimating equations (GEE) approach, to assess the association between the most recent time period  and moderate-severe ADL limitation/pain 2-years after primary TKA. This method adjusted for the correlation between observations on the same subject due to both knees having been replaced. As specified Subgroup analyses were done by examining multivariable-adjusted model 5 in patient subpopulations of: (1) age, <65 vs. ≥65; (2) psychological morbidity, defined as presence of anxiety and/or depression (none vs. any); (3) BMI, <30 vs. ≥30; and (4) Deyo-Charlson index (zero vs. one or higher). Odds ratios (OR), 95% confidence intervals (CI) and p-values were calculated. A p-value <0.05 was considered statistically significant.7,229 patients underwent primary TKA at our institution 1993-2005 and completed baseline preoperative assessments and 7,139 patients who completed 2-year assessments , with a lower proportion of patients with moderate or severe activity limitations in the more recent period compared to the earlier time-period, except for stair climbing Table . AdditioCompared to 1992-95, moderate-severe post-TKA overall ADL limitation was seen in 4.7% more patients and moderate-severe post-TKA pain in 3.6% more patients in 2002-05, both statistically significant  and 3.6% (5% vs. 8.6%), statistically significant and clinically meaningful. These findings add to the current knowledge in post-arthroplasty PROs. We are not aware of any other study of time-trends in PROs after primary TKA.Our study addressed our first hypothesis, i.e., time-trends in post-TKA function and pain outcomes, which contrary to our expectation, actually worsened over time. Medical , 28, 29 So, why in the face of lower proportion of patients with moderate-severe ADL limitation  preoperatively, are postoperative pain and function outcomes worsening over time? Since our final models were adjusted for preoperative status and various other important factors, the time-trends in post-operative pain and function are in fact independent of changes in preoperative pain and function, respectively. We think that the increase in odds of moderate-severe ADL limitation over time may be related to shorter inpatient stay and a lower proportion discharged to home over time , both ofFuture studies need to examine whether other factors such as psychological distress (e.g. post-traumatic stress disorder), coping strategies, family support, pain medication use in the postoperative period and/or type of rehabilitation, can explain the worsening pain and function outcomes after primary TKA over time. We used a diagnostic code, not a questionnaire, for depression/anxiety and therefore we may have missed subclinical or undiagnosed disease. Severity of depression or anxiety was not measured in our study, which may also contribute to worsening of persistent pain/functional limitation post-TKA. Over time, TKA has been made available to a wider patient population, some of whom may have been excluded previously, due to an unfavorable patient profile, not likely to benefit optimally from TKA. Worsening in other patient characteristics  over time not measured in our study may also be contributing to worsening outcomes over time.Our subgroup analyses provided important insights. We hypothesized that post-TKA pain and function outcomes would improve over time in the oldest, and in those with lower comorbidity and lower BMI. We noted worse pain and function outcomes in 2002-05 compared to 1993-95 in the patients 65 years and older and those without psychological comorbidity. This was contrary to our expectations, since we hypothesized that patients with psychological comorbidity and those in the younger age group  might be the ones at highest risk of worsening PRO outcomes over time. These associations were also independent of sex, preoperative pain/function, BMI and preoperative comorbidity. To our knowledge, this is the first study to report these findings. Another novel finding was that pain outcomes in the 2002-05 were worse compared to 1993-95 in patients with Deyo-Charlson index of one or more or BMI ≥30. Thus, our study identified specific patient populations who demonstrate worsening PRO outcomes post-TKA. Patients with these characteristics should be the focus of the future studies to investigate the reasons for worsening PROs over time and design strategies to improve PROs.Study findings must be interpreted considering the study limitations. Non-response may have biased our results. Non-responders to 2-year survey were more likely than responders to have slightly higher co-morbidity, higher ASA class, greater distance to the medical center and were younger. However, the direction of bias is unclear since it’s not known how the patient characteristics associated with non-response might have impacted these time-trends. This is single center study and generalizability to other settings may be challenging. The similarity of our cohort to other published cohorts –41 as weIn conclusion, we found that post-TKA PRO outcomes 2 years after primary TKA had worsened from 1993-95 to 2002-05. In particular, the odds of moderate-severe ADL limitation and pain were higher in the most recent time-period. Time-related worsening of pain and ADL outcomes was independent of pre-operative ADL limitation and pain and other factors associated with post-TKA pain and functional limitation. The increase in odds was noted in particular in patients with older age, no psychological morbidity, obesity and higher medical comorbidity. Future studies are needed to identify the reasons for worsening pain and functional outcomes in general and in these groups of patients so that interventions can be targeted for improving post-arthroplasty outcomes.The Mayo Clinic Institutional Review Board approved this study and all investigations were conducted in conformity with ethical principles of research.JAS is supported by grants from the Agency for Health Quality and Research Center for Education and Research on Therapeutics (AHRQ CERTs) U19 HS021110, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) P50 AR060772 and U34 AR062891, National Institute of Aging (NIA) U01 AG018947, and National Cancer Institute (NCI) U10 CA149950, and research contract CE-1304-6631 from Patient Centered Outcomes Research Institute (PCORI). JAS is also supported by the resources and the use of facilities at the VA Medical Center at Birmingham, Alabama, USA.The funding sources played no role in development of the study protocol, data analyses or interpretation, preparation of the manuscript or the decision to submit it.Additional file 1:Time trends in unadjusted rates of preoperative pain and activity limitation.(DOCX 69 KB)