Background: There has been limited evaluation of medication adherence, healthcare resource utilization (HCRU), and healthcare costs over time in patients with osteoarthritis (OA), and stratification by pain severity level has not been reported. Assessing such longitudinal changes may be useful to patients and healthcare providers for tracking disease progression, informing treatment options, and employing strategies to optimize patient outcomes. Objectives: To characterize treatment patterns, HCRU, and costs over time in patients with moderate to severe (MTS) OA pain in the United States. Methods: We conducted a retrospective claims analysis, using IBM® MarketScan® databases, from 2013-2018. Eligible patients were aged ≥45 years with ≥12 months pre-index (baseline) and ≥24 months (follow-up) of continuous enrollment; index date was defined as a physician diagnosis of hip or knee OA. An algorithm was employed to identify MTS OA pain patients, who were propensity score matched with patients having non-MTS OA pain. Data were summarized using descriptive statistics and univariate analyses. Results: After propensity score matching, the overall OA pain cohorts consisted of 186 374 patients each: 61% were female, mean age was 63 years, and two-thirds (65.6%) were of working age (45-65 years). Sleep-related conditions, anxiety, and depression were significantly higher in the MTS OA pain cohort vs non-MTS (P<0.001). At baseline and 12- and 24-month follow-ups, receipt of prescription pain medications, HCRU, and direct medical costs were significantly higher in the MTS OA pain cohort . Medication adherence was significantly higher in the MTS OA pain cohort for all medication classes except analgesics/antipyretics, which were significantly lower vs the non-MTS OA pain cohort . Conclusions: The burden of MTS OA pain is substantial, with patterns that show increasing medication use, HCRU, and costs vs non-MTS OA pain patients over time. Understanding the heterogeneity within the OA population may allow us to further appreciate the true burden of illness for patients in pain. Osteoarthritis (OA) is a chronic joint disease involving the cartilage and surrounding tissues that most commonly affects the hands, hips, and knees.Numerous guidelines have been published regarding the nonpharmacological and pharmacological management of OA. The 2019 American College of Rheumatology guidelines for management of OA emphasize optimizing benefit-risk outcomes for each patient, and recommend a multimodal approach based on efficacy, safety, tolerability, patient preference, and appropriateness of pharmacologic treatments.Regardless of published treatment guidelines and available pharmacologic options for the symptomatic treatment of OA, the current standard of care may be inadequate since patients often continue to experience unsatisfactory pain levels despite treatment.The economic impact of OA has been shown to include both direct medical costs and indirect costs associated with patient treatment expenses as well as lost productivity.Longitudinal studies of OA-related treatment patterns have been   reported.The aim of this study was to examine clinical comorbidities and changes in treatment patterns, medication adherence, HCRU, and healthcare costs over 12- and 24-month follow-up periods in patients with moderate to severe (MTS) OA pain, compared with a matched cohort of patients with non-MTS OA pain using a large, geographically dispersed patient population.Data for this retrospective cohort study were from the IBM® MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits claims databasesSupplemental Table 1). Patients <45 years were excluded due to the smaller number of patients in this age cohort and the different presentation of OA in these younger population . Patients with a diagnosis of neoplasm-related pain (ICD-9 338.3 or ICD-10 G89.3) were excluded. Patients with OA were required to have at least 3 years of continuous pharmaceutical and medical benefit enrollment, including 12 months pre-index (baseline) and 24 months post-index (follow-up).This analysis included data from patients aged ≥45 years who had a diagnosis of hip OA, knee OA, or unspecified OA, plus a diagnosis of pain in the hip or knee within 3 months after the first OA diagnosis within the study period (index date), per International Statistical Classification of Diseases and Related Health Problems (ICD) diagnostic codes  within the 12-month post-index period; (3) prescriptions for ≥2 different topical or oral NSAIDs within 3 months post-index; (4) prescriptions for ≥2 different opioids within 3 months post-index; or (5) an emergency room (ER) visit for hip and/or knee OA within 12 months post-index, followed by a primary care physician visit within 14 days of the ER visit. This definition came from a case-selection algorithm that was based on a targeted review of the published literature, treatment guidelines, professional organizations, and expert opinion.Patients were classified as having MTS OA pain if they met at least one of the following criteria: (1) a visit to a rheumatology, orthopedic, or pain management specialist within 3 months post-index; (2) a surgical or nonsurgical invasive procedure relating to OA treatment   1:1 with the non-MTS OA pain cohort on baseline age; gender; health plan type; region; obesity; anxiety; depression; Charlson Comorbidity Index (CCI)Medication was defined at the class level using NDC codes from the claims, and medication adherence was defined as proportion of days covered (PDC) and was calculated as the number of days covered in the period by a prescription/drug class divided by the number of days in the period.t tests and chi-square tests for continuous and categorical variables, respectively. Comparisons from baseline in medication use at 12 and 24 months were conducted using chi-square tests to generate P values with patient-level data. Statistical significance was defined as P<0.05. All analyses were conducted using Statistical Analysis System® version 9.4 or higher .Data were summarized for PSM cohorts using descriptive statistics, including means with standard differences for continuous variables, and counts and proportions for categorical variables. Differences in demographic and clinical characteristics were evaluated using Supplemental Figure 1). Among these patients, 546 254 met the inclusion criteria, of whom 342 019 (62.6%) were identified as having MTS OA pain and 204 235 (37.3%) were identified having non-MTS OA pain. PSM resulted in 186 374 patients in each cohort and, as shown in From January 2013 to December 2018, there were 91 019 047 patients enrolled in the IBM® MarketScan® Commercial Claims and Encounters and MDCR claims databases (P<0.0001), and the distribution of scores, which was significantly different between the cohorts (P<0.0001), indicated a trend toward a greater comorbidity burden in the MTS OA pain cohort (P<0.0001). However, a significantly lower proportion of patients with MTS OA pain had cerebrovascular disease than patients with non-MTS OA pain . The MTS OA pain cohort had a significantly higher prevalence of prespecified comorbidities overall compared with the non-MTS OA pain cohort , including sleep-related conditions, obesity, depression, and anxiety .The mean CCI score was significantly higher in the MTS OA pain cohort compared with non-MTS OA pain . Furthermore, all evaluated medications  were prescribed to significantly higher proportions of patients with MTS OA pain vs non-MTS OA pain at baseline. Of these medications, the most prescribed in the MTS vs non-MTS OA pain cohorts were nontramadol opioids (41.2% vs 28.6%), NSAIDs/COX-2 inhibitors (39.5% vs 32.3%), antidepressants (28.3% vs 21.7%), benzodiazepines (23.3% vs 17.9%), and anticonvulsants (21.9% vs 16.8) , except for antidepressants . In contrast, the MTS OA pain cohort had significantly lower antidepressant use (21.2%) at 24 months compared with the non-MTS cohort (26.0%) (P<0.0001).Examination of changes from baseline to the 24-month follow-up revealed generally similar patterns for patients with MTS OA pain as that at 12 months, although not all differences between cohorts were statistically significant. Significantly higher changes in the MTS pain cohort were observed, in decreasing order, for IA corticosteroid/HA injections, tramadol, analgesics/antipyretics, anticonvulsants, nontramadol opioids, and anxiolytics/sedatives/hypnotics , except for analgesics/antipyretics, in which patients with MTS OA pain had significantly lower PDC compared with patients with non-MTS OA pain . The largest differences in PDC between the 2 cohorts were observed for non-tramadol opioids: 37% in the MTS cohort vs 7% in the non-MTS cohort at 12 months and 34% vs 7%, respectively, at 24 months (both P<0.001).Medication adherence, as measured by PDC, was highest at the 12- and 24-month follow-ups for antidepressants in both OA pain cohorts (78%-84%), followed by anticonvulsants (58%-68%) and anxiolytics/sedatives/hypnotics (33%-62%) . At bothP<0.0001; P<0.0001). Length of hospital stay was significantly longer at 12 and 24 months for the MTS cohort compared with the non-MTS cohort, as were hospital readmissions (both P<0.0001). Hospital readmissions increased in the MTS cohort from 1236 patients (0.7%) at baseline to 2509 (1.4%) and 4262 (2.3%) patients at the 12- and 24-month follow-ups, respectively. Increases were also observed for the non-MTS OA pain cohort, although to a lesser extent (P<0.0001). In patients with MTS OA pain, the mean (SD) of filled prescriptions increased from 28.7 (26.8) at baseline to 32.2 (28.2) at 12 months and to 63.9 (55.6) at 24 months. A similar pattern of increase over time was observed for patients with non-MTS OA pain but to a lesser extent than patients with MTS OA pain  visits for baseline and 12- and 24-month follow-up periods  (P<0.0001). The total costs in the MTS OA pain cohort were higher than non-MTS OA pain by 19% at baseline, 64% at 12 months, and 53% at 24 months.The patients with MTS OA pain had significantly higher mean total healthcare costs overall and for the individual cost components of outpatient, inpatient, and pharmacy categories compared with patients with non-MTS OA at baseline and the 12- and 24-month follow-ups  . Total mAcross all time periods and cohorts, total costs were primarily driven by outpatient costs. At baseline, outpatient costs accounted for the majority of costs (55%) for both OA pain cohorts, as shown in For both the 12- and 24-month follow-up periods, outpatient costs continued to be the main driver of total healthcare costs in both cohorts, although the proportion relative to total costs decreased over time in patients with MTS OA pain but increased in the non-MTS cohort. Furthermore, inpatient costs, relative to total costs, increased over time in patients with MTS OA pain, whereas pharmacy costs decreased . There wThis study contributes important longitudinal information on the clinical and economic burden of OA, by pain severity level, spanning 24 months of follow-up post-OA diagnosis. It relies on a unique algorithm that allows healthcare researchers to identify patients with more severe OA pain while utilizing administrative claims data to track resource utilization and costs. Mean age in the PSM cohorts was 63 years, with approximately two-thirds of patients of working age and enrolled in commercial plans. Patients with MTS OA pain in our study had a significantly greater comorbidity burden compared with patients with non-MTS pain, including sleep disturbance, insomnia, depression, and anxiety, not unlike what has been reported in other OA studies using cross-sectional survey data in patients with increasing pain severity or pain interference with activities (PIA).P<0.0001), which is approximately half the proportions in the current study, but may not be unexpected as their study was based on patient self-report rather than administrative claims. In their study, non-tramadol opioids and NSAIDs were the most prevalent classes prescribed among MTS OA pain respondents (18% each cohort). Nalamachu et alPrescription pain medication use for OA showed a similar pattern to comorbidities, with significantly increased use of OA medications in patients with MTS OA pain relative to patients with non-MTS OA pain. Although the high prescribing of OA pain medications at baseline may be related to treatment of conditions other than OA, it is also possible that the patient was being treated for OA in the absence of an OA diagnosis during the baseline period. In patients with MTS OA pain, baseline prescribing was highest for nontramadol opioids (41.2%) followed by NSAIDs/ COX-2 inhibitors (39.5%). The use of NSAIDs is in line with current treatment guidelines for OA. The high use of non- tramadol opioids contrasts with the conditional recommendation to start tramadol if an opioid is necessary, and only choose non-tramadol opioids when all other treatment options have failed.A unique aspect of this study is that it provides insights into the current real-world prescribing of pain medications for MTS OA by following patients for 2 years. Significantly greater pain medication use was observed for patients with MTS OA pain compared with non-MTS at 12 months for all pain medication types, except antidepressants. This trend was also observed at 24 months in which all medication types except NSAID/COX-2 inhibitors, benzodiazepines, and muscle relaxants were significantly greater in the MTS OA pain cohort. Although 2 studies reported on the change in OA pain medications over time, neither stratified patients by OA pain severity.Our study showed significantly greater adherence, measured by PDC, to prescription OA pain medications in patients with MTS OA pain vs non-MTS for all medication types. Although PDC at the 12- and 24-month follow-ups was highest for antidepressants, anticonvulsants, and anxiolytics/sedatives/hypnotics in both OA cohorts, a PDC ≥80%, defined as the threshold for being considered adherent, was only observed with antidepressants across both OA pain severity cohorts. Using PDC as a proxy for adherence, this is not surprising given antidepressants are also used for symptoms beyond OA pain where high adherence is often observed. Pain medications, on the other hand, are often used as needed, and it may be possible that the lower PDCs observed in this study represent numerically lower yet appropriate rates of adherence. PDC is a useful measure in that, regardless of as-needed or scheduled use, it informs the level of utilization of a particular medication or class of medications. No studies of medication adherence were identified in OA, although several studies reported suboptimal treatment adherence in patients with other rheumatic diseases.P<0.01). Lastly, Wei et alHCRU was significantly greater for patients with MTS OA pain compared with non-MTS for inpatient hospitalizations, readmissions, outpatient, ER, and rehabilitation and PT visits. Somewhat similar findings were observed by Schepman et al,The economic burden of OA, especially in patients with MTS OA pain, is substantial. Our findings showed significantly higher costs in the MTS OA pain cohort at baseline and at both 12- and 24-month follow-ups compared with the non-MTS cohort, with increasing costs for each of the cohorts over time. In 2 published studies, higher healthcare costs were significantly associated with increasing PIAIn the current study, 63% of the patients with OA were categorized as having MTS OA pain. This proportion is similar to the 65% reported by Schepman et alSeveral study limitations should be considered. Although providing a wealth of clinical and economic information, claims data are limited in that medication use cannot be attributed to a specific disease, so pain medications prescribed within 30 days of index may not have been for OA. Claims data also do not capture information on patients change of healthcare insurance or if they have multiple insurance plans at the same time. Some prescription pain medications commonly used to treat OA also treat a number of other illnesses including depression, anxiety, and epilepsy. Given that patients with OA, especially those with more advanced disease, have a high comorbidity burden, these medications could be prescribed for other underlying conditions. Despite the strengths of our approach , there is an overlap of certain variables included in the definition of the cohorts and the outcomes analyzed. However, as the goal was to describe overall utilization, this study used a narrow timeline to define the variables included in the definition of the cohorts the length in time for the outcomes. Claims data also do not capture information on nonpharmacologic therapies and over-the-counter medications used to treat OA pain, nor are indirect costs, such as those related to lost productivity at work, absenteeism, and caregiver burden, captured. Therefore, the total costs reported in our population are likely underestimated. Although the sample size in our study was robust, patients were required to be continuously enrolled for 3 years in a health plan. Such patients may differ from other plan members; hence, generalizability beyond this commercially insured population may be limited. These results are not representative of all patients with OA. This study included only commercial insured patients with private or Medicare plus supplemental insurance that were seeking medical care. Generalizability may have been impacted when we applied PSM, as very healthy and very severe patients would have been excluded from the final cohorts. Claims data, however, are a rich source of information and, when used alongside other methodologies, expand our understanding of the clinical and economic impact of patients with MTS OA pain.The clinical and economic burden observed in this MTS OA population suggests a high unmet need that may require development of novel therapies or strategies to treat OA pain and improved healthcare strategies to manage disease progression. Patients with OA do not represent a homogeneous population, and focusing on population subtypes such as pain severity will allow a more targeted and efficient approach to patient management. Further research is warranted to examine the factors contributing to the substantial burden in this more severe OA pain population.The study was sponsored by Pfizer and Eli Lilly and Company. The findings of this manuscript have been presented at The International Osteoporosis Foundation (IOF) and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) 2020 Virtual World Congress (WCO-IOF-ESCEO); August 20-22, 2020, and at PAINWeek 2020 Virtual Meeting; September 11-13, 2020. The following authors are employees of Pfizer with stock and/or stock options: PS, ST, CB, DM, and BE. RLR is an employee and stockholder of Eli Lilly and Company. RNH received consulting fees associated with this study from Pfizer and Eli Lilly and Company. The authors report no conflicts of interest in this work.


To investigate the relief of low back pain after hip arthroplasty in patients with hip joint and spinal degenerative diseases, and to discuss the effects of unilateral and bilateral hip surgery on the relief of low back pain.via a posterolateral approach and also suffered from lumbar degenerative diseases in the period of 2009 to 2019. The inclusion criteria were: (i) patients who had been diagnosed with severe hip degenerative disease and also been diagnosed with lumbar degenerative disease; (ii) patients who had undergone THA surgery; and (iii) patients who were retrospectively recruited. The exclusion criteria were: (i) patients who had undergone lumbar fusion or internal fixation surgery; or (ii) patients who had vascular claudication, history of major trauma, diabetic polyneuropathy, lumbar and pelvic infections, tumor diseases; (iii) or patients who had undergone THA because of femoral neck fracture or ankylosing spondylitis. The improvement of hip joint function and the relief of low back pain (LBP) were studied, and the effect of unilateral and bilateral THA on the relief of LBP were discussed. Hip pain and function were evaluated by the Harris Hip Score (HHS), LBP was evaluated by Visual Analog Scale (VAS), and lumbar function was evaluated by the Japanese Orthopaedic Association (JOA) scoring system.In this retrospective study, we followed 153 patients  who had undergone total hip arthroplasty (THA) The average follow‐up time was 44.3 months (24–108 months). All patients recovered smoothly without complications. The LBP VAS of 153 patients decreased from 4.13 ± 1.37 preoperatively to 1.90 ± 1.44 postoperatively. The average HHS increased from 45.33 ± 13.23 preoperatively to 86.44 ± 7.59 postoperatively at the latest follow‐up. According to Japanese Orthopaedic Association scoring system, the proportion of patients with good response to treatment in these 153 patients reached 93.46%. LBP VAS decreased from 4.18 ± 1.38 preoperatively to 1.95 ± 1.49 postoperatively in unilateral group and from 3.94 ± 1.32 preoperatively to 1.73 ± 1.23 postoperatively in bilateral group, respectively. There were only nine patients with persistent or aggravated LBP after operation. Among them, six patients underwent subsequent lumbar surgery (five patients had pain relieved after reoperation and one patient had not) and the other three patients chose conservative treatment for pain.THA can relieve LBP while relieving hip pain and restoring hip function in patients with both hip and lumbar degenerative disease, thus possibly avoiding further spinal surgery. After THA, LBP in some patients will be effectively relieved, thus avoiding further spinal surgery. Therefore, the results of this study highlight the need to treat hip osteoarthritis first when patients have both hip disease  and lumbar degenerative disease. According to statistics, one in two patients with symptomatic hip joint degeneration suffers from low back pain (LBP)In people with pathological changes of the hips, pain distributions can include the groin, lateral hip, and posterior pelvis. However, the most common site of pain is in the buttocks, followed by thighs and groinsHowever, some of the symptoms of these two diseases (hip joint disease and lumbar degenerative disease) are the same, such as lower limb pain, pain around the knee joint, abnormal gait, and LBPOffierski and MacNabet al.et al.Previous studies indicated that low back pain in patients with hip osteoarthritis was relieved after THA and emphasized the need to treat hip osteoarthritis primarily. Ben‐Gallim However other studies have shown that patients with a history of THA have more back pain after low back surgery than patients with no history of total hip replacementSome scholars have reported the relief of low back pain in patients with hip osteoarthritis after total hip arthroplasty. However, knowledge about the relief of LBP in patients with degenerative changes in both hip and lumbar who first underwent THA surgery is limited and there is no study yet to analyze the effect of unilateral and bilateral THA on the relief of LBP. Therefore, the purpose of this study was: (i) to follow up a group of patients with hip joint disease and lumbar degenerative disease; (ii) to observe their hip joint pain relief and function recovery as well as LBP relief after THA; and (iii) to explore the effect of unilateral THA and bilateral THA on such patients.The inclusion criteria were: (i) patients who had been diagnosed with severe hip degenerative disease and also been diagnosed with lumbar degenerative disease ; (ii) patients who had undergone THA surgery; (iii) Harris Hip Score, Japanese Orthopaedic Association (JOA) score, and Visual Analog Scale were compared; (iv) patients who were retrospectively recruited.The exclusion criteria were: (i) patients who had undergone lumbar fusion or internal fixation surgery; or (ii) patients who had vascular claudication, history of major trauma, diabetic polyneuropathy, lumbar and pelvic infections, tumor diseases; (iii) or patients who had undergone THA because of femoral neck fracture or ankylosing spondylitis. Patients who met any of the exclusion criteria were excluded from the study.The subjects of this study were patients who received THA treatment in the orthopaedic department of our hospital from 2010 to 2019. Figure This study was a retrospective study. All subjects received and accepted informed consent before participating in the study, which was approved by the institutional review committee of our hospital.Hip joint diseases and lumbar degenerative diseases were diagnosed by experienced joint surgeons through imaging examination including X‐ray, computed tomography (CT), and magnetic resonance imaging (MRI) and also assessed by them in combination with the current symptoms.The surgical method is standard posterolateral approach for total hip arthroplasty.Because of spinal disease, all patients underwent THA under intravenous inhalation combined anesthesia. Patients were in the lateral position.via a posterolateral approach. After incision of the skin along the muscle fiber line, the tensor fasciae latae and gluteus maximus were divided, the external rotators and the joint capsular were incised.All procedures were performed Osteotomy along the femoral neck was performed to remove the femoral head, followed by removing the labrum, femoral head ligaments, and other adipose or fibrous tissue. Then, the acetabulum and femoral canal were carefully prepared.The acetabular cup and femoral stem were implanted by ensuring optimal position and orientation. Then, the hip joint was reset, and the incision was closed .We collected and analyzed the preoperative and postoperative Harris Hip Score (HHS), Japanese Orthopaedic Association (JOA) score, and low back pain (LBP) Visual Analog Scale (VAS) score of these patients. At the same time, in order to analyze the effect of unilateral and bilateral THA surgery on the relief of LBP, we divided the patients into unilateral THA surgery group and bilateral THA surgery group, and compared the difference between the two groups in follow‐up results.The in‐patient data of the patients such as height, weight, gender, age, phone number, and operation time were obtained from the hospital database. HHS was routinely evaluated before THA. For patients with lumbar diseases, JOA and LBP VAS were also evaluated. We also collected the results of the latest follow‐up. In the event that the patient underwent subsequent lumbar surgery because of the aggravation of lumbar pain or had reoperation for other reasons, only the score before reoperation was included in statistics.HHS was used to evaluate the hip joint function and pain relief before and after operation. The HHS score system mainly includes four aspects: pain, function, absence of deformity, and range of motion. The scoring standard took 100 points as the highest score (best possible outcome)JOA (0–29) scoring system was used to evaluate lumbar function before and after operation. It consisted of three parts: symptoms (9 points); signs including straight‐leg raise (6 points); and seven activities of daily living RR was used to evaluate the effective rate of low back pain relief. According to Recovery Rate (%) = (postoperative score − preoperative score)/(29 – preoperative score) × 100% in JOA scoring system, RR was calculated and divided into four groups: cured (RR = 100%); markedly effective (60% ≦ RR ≦ 99%); effective (25% ≦ RR ≦ 60%); and ineffective (RR ≦ 25%)VAS was used to evaluate the pain of the low back pre and post operation. It ranges from 0 to 10, where 0 represents no pain and 10 the worst possible paint‐test was used to analyze the preoperative scores and postoperative follow‐up results of the 153 patients. Independent t‐test was used to analyze the LBP VAS and HHS of unilateral and bilateral THA groups. A two‐tailed probability level of P < 0.05 was selected as the statistically significant level.The data was analyzed by a statistical software , and the quantitative data were expressed as mean ± standard deviation (SD). A According to the inclusion criteria and exclusion criteria, finally 160 patients met the criteria, among which seven patients died and were lost to follow‐up, and 153 patients were included in the study. The typical images of the patients were shown in Fig. P < 0.0001). The average HHS increased from 45.33 ± 13.23 preoperatively to 86.44 ± 7.59 postoperatively (P < 0.0001). According to the calculation method of RR in JOA scoring system, 8 cases were cured, 66 markedly effective, 61 effective, and 10 ineffective. The effective rate of low back pain relief was 93.46% ; HHS increased from 45.59 ± 13.59 preoperatively to 86.13 ± 8.07 postoperatively in unilateral group and from 44.39 ± 12.02 preoperatively to 87.58 ± 5.42 postoperatively in bilateral group, respectively (P < 0.0001). There was no significant difference in preoperative or postoperative HHS and LBP VAS between unilateral and bilateral groups (P > 0.05). However, interestingly, the patients who received unilateral THA had better relief of low back pain and recovery of lumbar function than those who received bilateral THA, and the difference was statistically significant  and the other three patients chose conservative treatment for pain. Their information is shown in Table P < 0.0001). At the same time, according to the RR calculation formula of the JOA scoring system, the proportion of patients with good treatment response to LBP reached 93.46%. Our results show that LBP has been relieved after THA, which is consistent with previous studiesIn this retrospective study we followed up 153 patients who were diagnosed with both hip joint disease and lumbar degenerative disease before THA. They all received THA in our hospital from 2010 to 2019. These operations were performed by three experienced joint surgeons. Through our follow‐up, it was found that the symptoms of LBP in these patients eased with the relief of hip pain and improvement of hip function after THA. Their average LBP VAS score decreased from preoperative 4.13 ± 1.37 to postoperative 1.90 ± 1.44  and spine disease as hip spine syndrome (HSS) in 1983et al. published a study on the intervention of patients with LBP and hip OA. In this study, the pain and function scores of 25 patients were evaluated before and after THA. All results showed a statistically significant improvement after THA. The authors concluded that THA relieved LBP and recommended hip surgery firstPrevious studies have shown that the surgical sequence may bring different effects to patientsCombined with our above follow‐up results, for diagnosis and surgical treatment of patients with hip joint disease and lumbar degenerative disease, we suggest focusing on symptoms. In patients with pathological changes of hips, the most common site of pain is in the buttocks, followed by thighs and groinThe following lumbar degenerative diseases need to be considered separately: lumbar disc herniation leading to nucleus pulposus falling out, cauda equina compression, lumbar spondylolisthesis leading to significant spinal canal stenosis. These patients are advised lumbar surgery first, but they also need to receive THA following the lumbar surgery, because the symptoms caused by hip joint diseases will not be relieved before THA.This study also has limitations. A main limitation is that we did not analyze the imaging data of spine and pelvis in these patients after THA, which may have helped us to further explore the LBP relief mechanism. The next step of our study plan is to follow them up for a long time to analyze the imaging data of their spine and pelvis. Secondly, this is a single‐center retrospective study, which has its inherent limitations. Thirdly, the sample size of the bilateral THA group is relatively small compared with the unilateral THA group. These limitations should be taken into consideration in interpreting our results and should be addressed in future studies.The results of this study highlight the need to treat hip osteoarthritis first when patients have both hip disease  and lumbar degenerative disease. After THA, LBP in some patients will be effectively relieved, thus avoiding further spinal surgery. Of course, for patients with cauda equina compression or severe lumbar lesions, more detailed and prudent surgical planning is needed.


Surgical treatment and conservative treatment is the options to improve pain, function, and range of motion following rotator cuff tear. In this study, we aimed to compare the effects of physiotherapy and corticosteroid injections on the function, pain, and range of motion in patients with full-thickness rotator cuff tearing separately and simultaneously.  A total of 96 patients were randomly assigned to the study and divided into 3 groups of 32 patients. DASH questionnaire and VAS criterion were completed by all three groups, and the range of motions of all groups was measured by a goniometer. Then, the first group underwent 12 sessions of physiotherapy twice a week for 6 weeks; the second group received 80 mg of methylprednisolone and 1 ml of lidocaine 2% in two stages, 21 days apart; and the third group received 80 mg of methylprednisolone and 1 ml of lidocaine 2%, and after 2 days, 6 sessions of physiotherapy twice a week for 3 weeks were prescribed. In the end, the questionnaire was filled out by the patient, and the range of emotions was assessed with a goniometer.  More than 80% of patients in each group were female. There was no significant difference between the gender and age distribution of the groups. The mean age in physiotherapy, steroid, and physiotherapy + steroid groups was 51.78 ± 7.37, 52.37 ± 6.61, and 50.87 ± 5.65, respectively. The combination of physiotherapy + steroid intervention was more effective in reducing VAS and DASH scores than physiotherapy or steroid injection alone. Goniometric findings showed that treatments that included the steroid injection approach (steroid injection and steroid + physiotherapy) had a more dramatic effect on improving the patients' range of motion than physiotherapy alone. IRCT20200102045987N1. Among the conservative approaches of treating full-thickness rotator cuff tear, a combination of steroid injection and physiotherapy is more effective significantly in comparison with either treatment alone. This trial is registered with  The shoulder is one of the largest joints and the most mobile and unstable joint in the body due to the shallow depth of the glenoid cavity. Therefore, the tendons and muscles around the joint including the rotator cuffs  play an important role in joint stability as well as joint movements . FurtherPain, weakness, and limited range of motion are the most common symptoms of complete rotator cuff rupture, which can impair the function and quality of life . LikewisThe prevalence and size of the ruptures increase with age, and the clinical success of the tendon repair decreases within the ruptures . In thisAlthough many studies have reported the results of complete rotator cuff rupture surgery, there are few studies on the effectiveness of conservative treatment. Likewise, conservative and physiotherapy treatments are diverse and choosing the best and most appropriate treatment for these patients requires further research.Therefore, due to the high prevalence and functional disability caused by rotator cuff tearing, disagreement about the appropriate treatment method and the limited evidence regarding the role of physiotherapy and exercise programs in reducing pain and disability of these patients, and lack of sufficient objective evidence of complete recovery of patients following surgery, a randomized clinical trial was needed to reduce the complications, pain, and costs of surgical treatment and determine the effects of physiotherapy and corticosteroid injections (CSI) in these patients.Numerous studies have been performed in recent years on the effects of physiotherapy and CSI in patients with other pathologies of the rotator cuff muscles such as impingement syndrome and frozen shoulder, which are pathologically different from the complete tendon rupture. In the present study, the separate and combined effect of physiotherapy and CSI on motor function and pain in patients with complete rupture of the rotator cuff was investigated.In the present randomized clinical trial study, 96 patients  with a mean age of 51 years who had complete rotator cuff rupture in the period of February 2017 to November 2016 were identified and enrolled in the study.p1=0.63 (percentage of the effect of physiotherapy and CSI on motor function in patients with rotator cuff rupture) and p2=0.3 (percentage of the effect of physiotherapy on motor function of patients with rupture of the rotator cuff), the sample size was calculated using the following formula in the three intervention groups.According to the specific purpose of comparing the performance in the three groups under study, the opinion of the relevant experts and previous studies  and consTherefore, the first group (physiotherapy and CSI) of 32 people, the second group (physiotherapy) of 32, and the third group (CSI) of 32 were calculated.Inclusion criteria were patients with an age range of 30 to 70 years who were diagnosed with complete rotator cuff degenerative rupture with MRI and clinical examination and were consciously and cooperatively willing to participate in the study. Exclusion criteria were any concomitant shoulder disease such as infection, fracture, and tumor as well as trauma during treatment and therapeutic intervention by other people. Patients were referred to the orthopedic clinic and assessed after signing the informed consent. The variables studied were pain and active range of motion of patients. The severity of pain was evaluated based on the visual pain scale (VAS), and the active range of motion was assessed by goniometer and disabilities of the arm, shoulder, and hand (DASH) questionnaire.The DASH questionnaire has 30 questions, of which 23 are about functional limitations in work, play, and interaction and examine the inadequacy of the upper extremity in performing functional activities, and 7 questions are about the severity of symptoms such as pain and weakness in impairing a person's functional ability. Likewise, the questionnaire is scored using a Likert scale with a range of 1 to 5 for each question. Score 1 indicates the absence of difficulty or limitation in the activities in question, and score 5 indicates the high intensity of the constraint. According to the instructions to convert the scores resulting from the questionnaire to standard scores in the range of 0 to 100 with the standard deviation of 50 ± 10, the raw scores obtained from each questionnaire are included in the following formula:Therefore, the overall score of this questionnaire is between zero and 100, and the higher scores indicate a higher level of disability.  FurthermIn addition to the 30 questions in this questionnaire, there are two series of questions with four items that are optional to answer and are called sports/arts DASH and work DASH and are scored similarly above. This part is not used in the present study. Mousavi et al.  preparedVisual pain scale (VAS) is the pain ruler that contains a horizontal line that is scaled from zero to 10; zero indicates absolutely no pain, and 10 signs the unbearable and worst pain .After the initial evaluation, the patients were randomly divided into 3 groups of 32 patients with block static method, so that based on 9-person blocks (AABBCC), all its subitems were calculated and randomly assigned to each intervention group.The first group underwent 12 sessions of physiotherapy in the form of massage, rotator cuff and scapular muscle stretching exercises, strengthening exercises and modalities including laser, transcutaneous electrical nerve stimulation (TENS), and ultrasound (US) twice a week for 6 weeks with a duration of 45 minutes per session including 30 minutes of electrotherapy and 15 minutes of manual therapy training. Normal tense current with a frequency of 120 Hertz, a pulse width of 120 microseconds in 15 minutes and current with a frequency of 50 Hertz, a pulse width of 350 microseconds, an 8 second contraction time, and a 2 second rest time for 10 minutes were used. Ultrasound with 1 to 2 watts per frequency of 3 MHz continuously and intensity of 5 cm square in 5 minutes was performed by a specialized rehabilitation physiotherapist. The first stage included the first 4 sessions to achieve shoulder movements, especially internal and external rotation equal to the opposite side and arm abduction less than 90°; with Cadman pendulum exercises and passive range of motion exercises, bending the shoulder, straightening the shoulder, and internal and external rotation were started. Capsule stretching exercises for the anterior, posterior, and inferior capsules were taught to patients using the contralateral arm and gradually moved toward active range-of-motion exercises such as wall walking. All inactive exercises at this stage were performed up to the maximum range of motion that did not aggravate the patient's pain, with the aim of controlling pain and creating shoulder movements below 90° and elbow movements.The second phase consisted of 4 second sessions performed with the aim of improving the strength, power, and endurance of the shoulder set. Pain control methods such as the first step were also performed in this step. The goal of the shoulder movements at this stage was to equalize the active range of motion of the affected shoulder joint with the opposite shoulder in all movement plates. For this purpose, exercises included passive range of motion, capsular stretching, and auxiliary-active movement exercises; then, the range-of-motion exercises were performed. To gain muscle strength, we performed the exercises twice a week, with 8 to 12 repetitions for three periods. Exercises included strengthening the remaining rotator cuff muscles, starting closed-chain isometric reinforcement , and progressing to open-chain strengthening.The third step was performed in the third 4 sessions with the aim of improving neuromuscular control and shoulder depth sense, preparing for a gradual return to functional activities. At the end of the sessions, motor function and pain according to DASH and VAS questionnaires and measurements with a goniometer  were evaluated.The second group was injected with 8 mg of methylprednisolone and 1 ml of 2% lidocaine with a posterior approach in the subacromial region in two stages 21 days apart. Two weeks after the second injection, the patient completed a questionnaire, and functional assessments were examined with a goniometer.The third group was injected with 8 mg of methylprednisolone and 1 ml of lidocaine 2% and, two days later, underwent 6 sessions of physiotherapy by a rehabilitation specialist twice a week for 3 weeks. The duration of each session was 45 minutes, including 30 minutes of electrotherapy and 15 minutes of manual therapy training; after 6 sessions of physiotherapy at the end of the third week, the injection was performed, and the other 6 sessions of physiotherapy twice a week for 2 weeks were performed with a duration of 45 minutes per session. (The steps of physiotherapy were the same as the first group.)All groups were instructed not to use NSAIDs or herbal and home remedies either orally or systemically or topically during the study. At the end of the sessions, function and pain were assessed according to the DASH and VAS questionnaires and goniometer measurement. At the end of the study, the data before and after the intervention of all three groups were compared.IRCT20200102045987N1. Quality control of verification and screening of adherence to protocols were performed on a regular basis by the trial coordinators. This research has been approved by the IRB of the authors' affiliated institutions. One-way analysis of variance within the subjects and Friedman test were used to investigate the relationship between separate and combined physiotherapy treatment and CSI and the studied variables. Statistical analysis was performed using SPSS software version 23. Alpha less than 0.05 was considered significant.Ethical considerations were applied in accordance with the approval of the ethics committee of Dezful University of Medical Sciences with the code number IR.DUMS.REC.1398.045. All the patients who agreed to participate in the trial provided written informed consent. Likewise, the patients' personal information was also preserved. The study protocol, including the statistical analysis plan, is available at fa.irct.ir with the code number p=0.789). The gender frequency distribution of patients in different groups was summarized in p=0.658).In this study, 32 patients in each treatment group were present. More than 80% of the patients in each group were female. The chi-square test shows that there is no significant difference between the gender distribution of groups , but this increase was little. The ANOVA test also showed that there was no difference in the extension angle of patients before and after the intervention. Therefore, the interventions performed did not change the extension angle clinically and significantly .Paired samples Management of rotator cuff complete rapture is a dilemma due to the controversial opinion among various surgical and nonsurgical treatment modalities. Nowadays with respect to surgical complications , there is an increasing trend for shifting from operative techniques to more conservative, nonoperative, and less invasive methods . LikewisThere are also many controversies among the choice of the optimal and most effective nonoperative managements including ice, simple exercises, medications, and progress to more intensive physical therapy, hyaluronic acid injections, CSI, biological augmentation with platelet-derived products (PRP), marrow stimulation, and so on . TherefoIn the present study, despite the significant decrease in VAS and DASH scores in all three groups, no significant differences were observed between the two physiotherapy treatment approaches and CSI in the VAS and DASH scores. Instead, people who received both treatments showed significantly lower VAS as well as DASH scores than the other two groups. Regarding this issue, there are some studies that reported similar aforementioned results and recommended the combination of CSI and physical therapy in comparison with physical therapy or CSI alone , 22. BurAs to the ROM evaluation, in the present study, it was observed that therapies containing the steroid injection approach (steroid injection and steroids + physiotherapy) had a more dramatic effect on improving the patients' ROM than physiotherapy alone. Similar results were reported by Boudreault et al., reporting that corticosteroid injection had a significant effect on the range of motion of the shoulder in abduction. Conversely, Burger et al. and Mehtap et al. did not report a significant difference between the two treatment approaches, which is inconsistent with the present study. This may be due to the fact that in the Burger et al.'s study, the subjects were the patients with rotator cuff syndrome, and in the Mehtap et al.‘s study, the patients with shoulder pain were evaluated, but the present study was performed on patients with complete rotator cuff rupture. To sum up, everything that has been stated so far, the effect of combined treatment (corticosteroids + physiotherapy) can be far better than any of the treatments alone in the range of motion and performance of individuals.Despite many positive considerations, this study had few limitations. No program was designed for long-term follow-up of patients. Furthermore, there was no control group to compare the effect of any interventions with no treatment. Likewise, although the patients were instructed not to use NSAIDs or herbal and home remedies either orally or systemically or topically during the study, we cannot be sure about it. Because we cannot follow the patients when they are out of the clinic.Among the conservative approaches to complete rotator cuff rupture, a combination of steroid injection and physiotherapy can be more effective than either approach alone in both reducing pain and improving shoulder function and range of motions.


Nasal packing is a common procedure used to ensure haemostasis after nasal surgery.A prospective, randomized, controlled and double-blinded study was conducted on 80 consecutive subjects to investigate whether using Nasal Dressing Sponge® (NDS) instead of simple Merocel® might improve patients’ postoperative experience of nasal packing.During the stay of the tampons no differences were noticed between the two groups as regards the postoperative pain. When it comes to pain during the packing removal, patients complained of worse symptoms in the side packed with Merocel. There was no bleeding after the removal of Merocel, whereas 5,6% patients were subject to some bleeding when NDS was removed.Merocel and NDS gave similar results regarding haemostatic activity. Nasal Dressing Sponge could decrease pain during the removal of the nasal pack, while it could be associated to a bigger incidence of mild bleeding after removing the pack. Nasal packing is a common procedure used after endoscopic sinus surgery (ESS) and septoplasty to prevent postoperative complications -4. A nasHowever, despite its post-operative advantages, nasal packing is often remembered as a bad experience by patients mainly because of pain during the removal of packing. Through this procedure, the pack might cause trauma to the nasal mucosa resulting in altered mucuciliary clearance, bleeding, increased crusting, inflammation and synechia formation . MoreoveA prospective, randomized, controlled and double-blinded study was conducted by the department of Otorinolaringoiatria of the University of Palermo on 80 consecutive subjects (ranging from 19 to 61 years of age) who underwent endoscopic sinus surgery and/or septoplasty. The study protocol was explained to patients, and written informed consent was obtained from each subject. The study design was approved by the Human Research Ethics Committee of Palermo University.Patients with a history of nasal surgery, sinonasal infections, sinonasal malignancy, bleeding disorders, anticoagulant therapy, any chronic comorbidity, or aged under 18 years or over 65 years were excluded.All cases were performed by one surgeon. All the procedure was performed under general anesthesia with total intravenous anesthesia (TIVA).Septoplasty was performed by means of a right hemitransfix incision and subperichondral dissection; all patients underwent radiofrequency decongestion of turbinate. The patient who underwent endoscopic sinus surgery (ESS), in 40 cases underwent bilateral medial antrostomy, anterior and posterior ethmoidectomy. A bilateral enlargement of the sphenoid sinus ostium was performed in the other 14 patients.® is a kind of foam pack made of polyvinyl acetal (PVA) and is packaged in a compressed, dehydrated state to allow ease of insertion. It requires rehydration with saline to activate it  ranging from 0 (no symptoms) to 10 (the most severe symptoms) was used to determine discomfort and pain. After surgery, the patients were subjected to nasal packing by an operator other than the surgeon: a random side was packedwith Merocel® and the other side with Nasal Dressing Sponge ®.All packings were removed 72h after surgery by one of the training assistant and again the patient was asked to make a mark on a visual analogue scale to represent the pain each pack caused on removal. Merocelivate it . Nasal dBleeding during packing removal was graded as follows: 0, no bleeding; 1, mild bleeding (controlled spontaneously without any intervention); 2, moderate bleeding (controlled by the insertion of ephedrine-soaked cottonoids); and 3, severe bleeding (controlled by repacking or reintervention). The patients were followed up weekly for 4 weeks after surgery. At each follow-up visit, nasal endoscopy was performed to look for inflammation, crusting, adhesion and sinechiae. Statistical analysis was conducted using the Matlab® computer programme; χ2 test, odds ratio, and/or Fisher Exact test were used, following standard application conditions. Significance was set at 0.05.Eighty subjects, 47 male and 33 females, ranging from 19 to 60 years of age (mean age = 42.97±12.28) were recruited. 54 patients suffered from chronic rhinosinusitis with nasal polyps (CRSwNP) and nasal septum deviation (NSD), 26 just from septal deviation and inferior turbinate hypertrophy. 26 patients  underwent septoplasty, 54 patients  underwent ESS and septoplasty. After surgery 56 patients underwent right nasal packing with Merocel and left nasal packingwith Nasal Dressing Sponge ® (NDS), while 24 patients underwent left nasal packing with Merocel and right with NDS. About the postoperative pain no difference between the two groups were noted at 1 hour, 6 hours and 1 day .Regarding pain during the packing removal, patients complain of the worse status of the side packed with Merocel (VAS 5.80 ±2.86) in comparison with the side packed with NDS (VAS 2.90 ±1.75) (P=0.0001) .After packing removal no bleeding was observed in patients treated with Merocel while 6 patients  suffered from grade 1 bleeding when NDS was removed (P=0.0093). No grade 2 and 3 bleeding were observed.An interesting fact is that, in general, a greater pain was shown during the removal of the swabs, respectively, both Merocel and NSD following septoplasty compared to those subjected to septoplasty and ESS. This could be explained in the light of a greater integrity of the mucosa and because of the pain perception during the removal of tampons in septoplasty.Nasal packing is a procedure commonly used after ESS and septoplasty ,2. It coPostoperative pain is considered to be the most common morbidity associated with packings used in septoplasty. In addition, nasal pack may result in significant mucosal injury and loss of ciliary function. Many attempts, such as shortening the duration of packing and developing new packing material, have been made to minimize the morbidity associated with packing materials.Some authors suggested that nasal pack could be avoided after septoplasty, but this protocol could be associated with more postoperative bleeding and subsequent formation of scars, synechiae, nasal obstruction and necessity of nasal packing ,11,12.Over the years, different types of nasal packing  have been proposed to allow better patients’ experience after surgery . ResearcUnlike all the other studies, in this instance the patient himself is packed with two different types of tampon in each nasal fossa, so, this dispels the bias related to the different perception of pain in individual patients. Merocel is a kind of foam pack made of polyvinyl acetal and is packaged in a compressed, dehydrated state to allow ease of insertion. It requires rehydration to activate it. The pores of the PVA swabs swell, causing hemostasis thanks to the retention of the clot and the pressure exerted on the walls of the nasal pits. However, the most important disadvantage of simple Merocel® is pain. This occurs during the insertion of the swab, if the patient is awake while the insertion in being carried out, during its stay in the nasal fossa and particularly, during the removal -14.Many studies have evidenced that when plain Merocel® in used, it adheres to the bleeding site, the incision site, and other raw areas over the septum. During its removal, the pack dislodges from the site of adherents, causing trauma to the nasal mucosa, which results in altered mucociliary clearance, bleeding, increased crusting, inflammation, and synechia formation ,14.According to some authors, these disadvantages may be overcome by using finger‐gloved Merocel® instead of simple Merocel® ,14.In our opinion, the simple finger of a glove to cover Merocel reduces some of these disadvantages related to adherence to the walls of the nasal cavities but, more significantly, it reduces the haemostatic and absorbent power of Merocel.For this reason, we decided to compare Merocel with a pad covered with a grid of "haemostatic material" which does not compromise its absorption characteristics. At the same time, it facilitates he removal procedures while safeguarding the integrity of the mucosa.In a study of Kaur et al,. 60 patients underwent nasal packing with gloved or ungloved Merocel after septoplasty. They reported less pain with gloved Merocel during pack insertion and removal and early normalization of saccharin transit time (STT) . On a prIn a study of 48 patients who underwent to ESS, gloved Merocel was superior to Silastic in terms of pain during the removal while no differences were noticed as to the incidence of synechiae and scarring and facial pain prior to removal and extent of discharge . Romano In a study of 60 patients Saedi et coll  compare A greater formation of crusts and synechiae was also found in the first cases of the study from the side buffered with coated pad. In fact, it was noticed that once the swab was extracted, the gelatinous coating remained at the level of the nasal fossa going to dehydration and promoting a greater formation of crusts and therefore of synechiae. We saw that by providing the suction of the residual gelatinous material at the level of the nasal fossa at the end of the removal, the formation of crusts and synechiae was significantly reduced with values superimposable to those evidenced in the use of Merocel.The current study was conducted to evaluate postoperative outcomes such as bleeding and pain in patients who underwent nasal packing Merocel or NDS after ESS and septoplasty. Our results suggest that Merocel and NDS had similar results regarding haemostatic activity. Nasal Dressing Sponge could decrease pain during the removal of the nasal pack, while it could be associated to a bigger incidence of mild bleeding after pack removal. Further studies are necessary to understand which type of protocol should be used after nasal surgery.


Somatosensory impairments and pain are common symptoms following stroke. However, the condition of perception and pain threshold for pressure stimuli and the factors that can influence this in individuals with stroke are still unclear. This study aimed to investigate the gender differences in pressure pain threshold (PPT) and positive somatosensory signs for pressure stimuli, and explore the effects of joint pain, motor function, and activities of daily living (ADL) on pain threshold in post-stroke patients.A cross-sectional study.A total of 60 participants with stroke were recruited, and their pain condition, motor functions, and ADL were evaluated by the Fugl-Meyer assessment of joint pain scale, motor function scale, and Barthel index, respectively. PPTs in eight tested points at the affected and unaffected sides were assessed.p < 0.05). Positive somatosensory signs for pressure stimuli, including hypoalgesia and hyperalgesia, were frequently found at the affected side, particularly in the extremity muscles, but such signs were not significantly influenced by gender (p > 0.05). More equal PPTs between both sides and relatively lower PPTs at the affected side in the trunk and medial gastrocnemius muscles (p < 0.05) were observed in patients with less pain, better motor functions, and ADL.Significant differences in PPTs were found between male and female patients in all measured muscles (Gender differences widely exist in post-stroke survivors either at the affected or unaffected side, which are multifactorial. Sensory loss and central and/or peripheral sensitization, such as hypoalgesia and hyperalgesia for pressure stimuli, caused by a brain lesion are common signs in male and female stroke patients. Moreover, patients who are in a better condition show a more symmetrical pain sensitivity between both sides in the trunk and in female lower extremities, indicating the bidirectional improvement of somatosensory abnormalities caused by a possible neural plasticity. All baseline data, including the characteristics of individual and stroke, Fugl-Meyer assessments, and Barthel Index, were assessed by one researcher and completed within 3 days prior to PPT tests.∗Power . The results were 19 for N1 and 39 for N2, and the actual power was 0.799. Finally, this study recruited 60 stroke survivors in the First Rehabilitation Hospital of Shanghai. All patients met the inclusion and exclusion criteria presented by our researchers. The inclusion criteria were as follows: (1) aged 18–90; (2) with stroke onset between 1 month and 10 years before baseline collection; (3) with unilateral stroke caused by brain ischemia or hemorrhage; (4) with good cognitive functions that can reliably respond to pressure pain; and (5) able to maintain a prone position until the completion of PPT tests. Exclusion criteria were as follows: (1) with severe cognitive impairments that might cause late and inconsistent response to pressure stimuli; (2) with diseases that might result in somatosensory abnormalities or pain; (3) with diseases that might lead to neurological symptoms, such as multiple sclerosis, Parkinson’s disease, diabetes, or chronic low back pain; and (4) using any medicine to relieve pain. This study was approved by the Human Ethics Committee of the First Rehabilitation Hospital of Shanghai (YK-2020-01-030). All participants who were willing to attend to this study gave their written informed consent before participation.According to a previous study that reported the gender differences of PPT in stroke patients , the sam2, which varied from 0 to 14 kgf. We selected 16 symmetrical points widely located at different bilateral parts of the body: 12 points on the bilateral muscle bellies of MD, BB (long head), RF, BF, TA, and MG; and 4 points on the bilateral ES muscle (2 cm from the midline at the L2 and L4 levels).Pressure pain threshold was defined as the amount of pressure applied to the skin surface, allowing pressure sensation to transform into pain perception . This st2 rubber disc of the equipment on the marked points until getting the response from the participants. For all symmetrical test points, the PPT assessment was started at the unaffected side. For each point, three repetitions of the PPT tests were applied and the interval between two repetitions ranged from 20 to 40 s.All participants were introduced to the PPT test prior to the real assessments and allowed to practice their response to the pressure pain applied on the forearm muscles at the unaffected side 3–8 times until they mastered it. Otherwise, the patient was excluded from this study. In addition, we marked these 16 test points using a black pen on the skin prior to testing. All participants were asked to stay in a supine position at the beginning with arms rested in bilateral sides of the trunk to complete the PPT tests at the bilateral MD, BB, RF, and TA muscles in turn. Then, patients had to transform into the prone position with the assistance of the assessor, if necessary, to finish the PPT assessments at the L2, L4, BF, and MG muscles in turn. During the assessment, the pressure was applied by the researcher slowly and stably through the 1 cmAny discomfort reported by the participants were tackled, and the participants could quit the study at any point during the whole process.U-test between different gender groups, respectively. Given the significant results of the Shapiro–Wilk tests (p < 0.05), non-parametric tests were selected to detect any difference in PPTs, and p-values less than 0.05 were considered as a statistically significant difference.Data were analyzed using the IBM SPSS Statistics version 26 . The baseline information, presented as frequencies and medians, was compared by the Chi-square and Mann–Whitney U-test was applied to compare PPTs between male and female patients. Considering that comparison between both sides is more sensitive to finding positive or negative somatosensory signs and 95% confidence intervals of relative reference data in healthy population for machinal pain threshold from 74 to 136% , we classified the data into three groups, namely, overall, male, and female groups. We divided the data into two subgroups according to median values of the Barthel index, Fugl-Meyer assessments of joint pain, and motor function in the three groups, respectively, to determine other factors. Consequently, we obtained the below- and above-median subgroups. The Mann–Whitney 2, respectively. All patients had a right dominant hand, and about half of them  had a right affected side. Moreover, there were gender differences in the frequencies of smoking and drinking while other baseline information were not significantly different between the male and female groups. Except for joint pain condition assessed by the Fugl-Meyer subscale, a total of 10 (16.67%) participants reported shoulder pain and 5 (8.33%) reported foot pain. None of them reported the pain influencing sleep.The demographics and characteristics of all 60 patients  are summarized in p-values less than 0.01 in the MD, BB, RF, BF, and TA muscles and less than 0.05 in the L2 (ES), L4 (ES), and MG muscles at both sides. Furthermore, men showed higher PPTs than women in all muscles in this study.All data of PPT values are presented as median and inter quartile range (Q1–Q3) in p > 0.05).According to the threshold ratios, relative abnormalities at the affected side and its percentage are presented in p < 0.05) are presented in All results from independent comparisons between the below- and above-median subgroups based on clinically functional assessments are shown in the This study investigated the gender differences in mechanical pain sensitivity and somatosensory abnormalities for pressure stimuli and other factors for pain threshold in stroke patients. We found that the female participants showed a higher mechanical pain sensitivity than male participants at the affected and unaffected sides in the large muscles all over the body. The affected side showed somatosensory abnormalities that were related to hypoalgesia and hyperalgesia, and the positive sign was not affected by gender. Furthermore, stroke patients with less pain, greater motor functions, and ADL had different changes of absolute pain threshold in different muscles, reduced relative pain threshold, and more symmetrical mechanical pain thresholds between the two sides in the trunk and medial gastrocnemius muscles.Female patients showed a significantly higher mechanical pain sensitivity than male patients in all the tested muscles at both sides. This gender difference has been reported in the healthy population , people With regard to pressure perception in this study, hypoalgesia and hyperalgesia existed in widespread muscles in post-stroke patients. In addition, the prevalence of hyperalgesia was normally lower than hypoalgesia, particularly in the BB, RF, TA, and MG muscles, which was similar to a study suggesting that the distal extremities might suffer from a more serious post-stroke sensory impairment than the proximal shoulder girdle . These pNo difference in mechanical pain threshold was found between less and more pain subgroups based on the joint pain subscale of Fugl-Meyer among the female, male, and overall groups. Although findings from two studies supported that mechanical pain thresholds were approximately equal between painful and pain-free stroke patients , more stBased on the motor function and ADL, an increase of mechanical pain tolerance in male trunk muscles but a decrease of pain tolerance in female calf muscles was found in patients with a better condition. The trends of absolute pain threshold in the different muscles were conflicting. However, the trends of relative pain sensitivity were the same in the trunk and calf muscles, which were decreased relative mechanical pain sensitivity at the affected side in patients with a better motor function or higher ADL. At the same time, the difference value between the PPTs at the two sides in these muscles was significantly reduced in these patients. These findings suggested that stroke patients with higher abilities of motor and daily activities appeared with more symmetrical pain thresholds between the two body sides.From the perspectives of joint pain, motor function, and ADL, patients in better conditions showed more symmetrical PPTs between the two sides than those in worse conditions. In the presence of hypoalgesia and hyperalgesia, this finding suggested that the recovery of joint pain, functions, and ADL is associated with the bidirectional improvement of pain sensitivity in stroke patients. Firstly, for the recovery of hyperalgesia, the good motor functions and ADL, indicating more physical activities, could reduce pain sensitivity based on the finding of exercise-induced hypoalgesia . ReciproThis study has some limitations. First, the sample size was small, particularly the number of the female subgroup. Second, the participants recruited were mostly in good functional and psychological conditions to ensure the reliability of the response to pressure pain. Therefore, the clinical assessment results of these participants were concentrated in a high level, which might affect the results of between-group comparison. For example, non-parametric analyses might miss some important values. In addition, although we compared PPTs in all muscles between ischemic and hemorrhagic stroke patients, no difference was detected. Considering that the symptoms of somatosensory deficits seemed to be different based on the affected region of brain lesion , a detaiMechanical pain sensitivity in post-stroke survivors is associated with gender, motor functions, ADL, and pain conditions. The somatosensory deficits are individualized and multifactorial, and neglect of these abnormalities in the management plan may inhibit the recovery of mobility and pain. Therefore, physiotherapists must pay more attention to and take some specific therapy for specific somatosensory impairments, including pressure perception loss, hypoalgesia, and hyperalgesia for pressure stimuli, in post-stroke patients to prevent worse pain and motor conditions. Additionally, motor therapy combined with sensory training may positively impact somatosensory impairments through neural plasticity, thereby improving symptoms of hypoalgesia and hyperalgesia. Further studies with a larger sample size, stricter recruitment criteria, and quantitative measurements are required to explore the changes of various pain thresholds and their correlation with brain activities in patients with different types of stroke, thereby providing evidence for the clinical application of this management plan.In conclusion, female stroke patients show a higher mechanical pain sensitivity than male stroke patients in large muscles all over the body, which may be caused by biological, psychological, or/and sociological factors, and the abnormalities for pressure perception in stroke patients are widespread and multifactorial but not significantly affected by gender. Hypoalgesia and hyperalgesia for pressure stimuli are common symptoms found at the affected side of patients, particularly in the upper and lower extremity muscles, which can be due to a brain lesion or followed central and/or peripheral sensitization or both. Furthermore, in this study, patients with less pain, better motor functions, and ADL showed a relatively decreased pain tolerance at the affected side and more symmetrical pain sensitivity between the two sides in the female medial gastrocnemius muscles and the female and male trunk muscles, which might indicate that good pain condition and functions were associated with a bidirectional improvement of pain threshold abnormalities because of neural plasticity, meaning the simultaneous recovery of hypoalgesia and hyperalgesia.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Human Ethics Committee of The First Rehabilitation Hospital of Shanghai (YK-2020-01-030). The patients/participants provided their written informed consent to participate in this study.J-FR and X-QW: conceptualization. Y-HZ, Y-CW, G-WH, X-QD, X-HS, and HY: investigation. Y-HZ, G-WH, X-QD, X-HS, and HY: data curation and analysis. Y-CW and Y-HZ: validation and writing—original draft preparation. Y-HZ and X-QW: writing—review and editing. X-QW: supervision. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To explore the safety of total knee arthroplasty (TKA) in the treatment of knee osteoarthritis (KOA) and its impact on patients' postoperative pain and quality of life.  A total of 60 KOA patients admitted to our hospital from January 2019 to January 2020 were selected as the research objects. The knee joint scores (HSS) before and after TKA were compared, and the patients' quality of life was evaluated using the Osteoarthritis Index of Western Ontario and McMaster University (WOMAC). At the same time, the number of patients with complications was recorded, and the efficacy of TKA was comprehensively analyzed. P < 0.05), the postoperative pain score increased with time, and the pain gradually decreased. The postoperative WOMAC score was significantly lower than the preoperative score (P < 0.001), and the score at 6 months after surgery was significantly lower than that at 3 months after surgery (P < 0.001). There were no complications such as severe prosthesis fracture, secondary sepsis, and patellar tendon rupture, and the total incidence of complications was 11.7%. The effective rate of treatment at 6 months after operation was 98.3%, which was significantly higher than that at 3 months after operation (P < 0.05).  The postoperative HSS score was significantly higher than the preoperative score ( Total knee arthroplasty can improve the knee joint function of patients with knee osteoarthritis, with low postoperative pain, low complication rate, and good quality of life for patients. It is worthy of promotion and application. In recent years, more people suffer from knee osteoarthritis (KOA) all around the world with the growing population of old people, and this disease will lead to physiologic dysfunction in knee joints. The patients not only suffer from pain and swelling of joints but also face the risk of completely losing the knee function, so the interventional therapy should be carried out as soon as possible to ensure their life and health –3. At pr60 cases with KOA admitted to our hospital from January 2019 to January 2020 were selected as the research objects, with the general data of patients given in The inclusion criteria for the patients of this study were as follows: the patients or their family members were fully aware of the research process and signed the informed consent, the patients were diagnosed with KOA –11 by exThe exclusion criteria for the patients of this study were as follows: the patients with mental problems or who were unable to communicate with others, the patients who were suffering from other organic diseases, the patients who were not available for the follow-up, the patients with knee joint infection and other diseases, the patients with immune dysfunction, and the patients with old fracture of lower extremity.All patients underwent the treatment of TKA, with the specific procedures as follows. (1) The patients were given routine preoperative examination, were evaluated for their loading ability of lower limbs, were given dietary intervention, and were informed of the TKA surgery details, which would make the patients psychologically prepared. (2) The supine position was taken after the combined spinal-epidural anesthesia, and the disinfectant towel was draped under the affected limb after cleaning and disinfection of the affected limb, and then, tourniquet was used after blood evacuation. (3) The vertical incision was made at the anterior of the affected knee joint, and the patients' skin, fascia, and joint cavity were incised successively. Then, the patella was opened to remove the proliferative synovial tissue, resect medial and lateral meniscus, and resect anterior cruciate ligament. (4) The distal standard osteotomy was performed after the distal femoral osteotomy locator was installed, and then, tibial plateau was exposed, and the proximal osteotomy was performed taking lateral tibial plateau as reference. The lateral femoral osteotomy locator was installed after confirming the extension gap, and the testing membrane was installed after the anterior and posterior osteotomies were performed. The installation of knee joints was observed.0), 3 months after surgery (T1), 6 months after surgery (T2), 12 months after surgery (T3), and 24 months after surgery (T4) were the time nodes for comparison, and higher scores referred to better recovery of knee joints [The knee joint scores (HSS): pain, function and activity, strength of joint motion, muscle strength, flexion deformity, and stability were utilized as assessment items. Before surgery (T0), 3 months after surgery (T1), and 6 months after surgery (T2) were the time nodes for comparison [The Western Ontario and McMaster University (WOMAC) scores: WOMAC scores could completely evaluate the patients' joint pain, joint motion, and improvement of physical signs and lower WOMAC scores referred to better quality of life. Before surgery  and 6 months after surgery (T2) were the time nodes for comparison [The curative effect of TKA: if the physical signs of the affected knee joints basically disappeared and the WOMAC scores decreased by more than 95%, the patients were considered to be cured. If the physical signs of the affected knee joints were significantly improved and the WOMAC scores decreased by 70%–95%, it was considered significantly effective. If the physical signs of the affected knee joints were improved and the WOMAC scores decreased by 30%–70%, it was considered effective. If the criteria mentioned above were not met, it was considered ineffective. 3 months after surgery . This study included count data and measurement data and used the P < 0.05), and the pain scores of patients increased with time, which indicated that patients' pain was alleviated gradually, as shown in Figures The HSS scores after surgery were significantly higher than the score before surgery (P < 0.001), and the score at 6 months after surgery was significantly lower than that at 3 months after surgery, as shown in The WOMAC scores after surgery were significantly lower than the score before surgery , as given in The effective rate of treatment of patients at 6 months after surgery (98.3%) was significantly higher than that at 3 months after surgery (P < 0.001), and the effective rate of treatment of patients at 6 months after surgery was 98.3%, indicating that TKA has a high value in improving the comprehensive condition of patients, accelerating their recovery after TKA, and significantly improving their quality of life. In the study of scholar Ackerman I.N, 121 cases with KOA who underwent TKA were followed up, and it was found that the WOMAC score at 3 months after surgery was (34.9 ± 5.2), while the score at 6 months after surgery was (26.4 ± 4.5), both of which were significantly lower than that before surgery (P < 0.001) [This study concluded that WOMAC scores of patients after surgery were significantly lower than the score before surgery (< 0.001) –19, indiFurthermore, the complications such as severe prosthesis fracture, secondary sepsis, and patellar tendon rupture were not found in patients involved in this study, with the total incidence of complications of 11.7%, indicating that the safety of TKA is excellent. However, this study has a small sample quantity, and more samples are required in future studies for exploring the safety of TKA.In conclusion, TKA can obviously improve the knee joint function and relieve pain of patients with KOA, with low incidence of complications and good quality of life of patients, which is worthy of further promotion and application.P < 0.05), and the postoperative pain scores increased with time, indicating that the patients' pain was alleviated gradually. This is because TKA can reduce the release frequency of proinflammatory cytokines in patients, especially tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β), which are closely related to the integrity of the articular cartilage tissue. These proinflammatory cytokines are important factors leading to KOA. TNF-α can increase secretion of matrix metalloproteinase-1, so as to speed up the release frequency of vascular endothelial growth factor and promote proliferation of endothelial cells, while IL-1β can further stimulate the activity of TNF-α and significantly increase secretion of the proinflammatory cytokines. TNF-α and IL-1β in combination can damage the knee joint function and enhance the sensitivity of pain receptor in patients. The pain receptor transmits the pain signal to sensory neuron till the sensory centre of cerebral cortex and makes patients feel more painful [α and IL-1β in patients, so as to reduce the inflammatory transmitter produced by chondrocytes, with less pain and better recovery effect of knee joints [Pain and dysfunction in knee joints are the main clinical manifestations of patients with KOA, and the purpose of treatment should be relieving pain and improving the knee joint function, so as to improve the quality of life of patients –23. This painful –27. The e joints .


This study aims to describe the neurological disorders associated with N2O. We conducted across-sectional study that enrolled patients with nitrous oxide toxicity admitted to Vietnam Poison Control Center, Bach Mai Hospital, Hanoi, Vietnam from June 2018 to July 2019. The questionnaire included demographic characteristics, characteristics of using N2O, signs and clinical symptoms, neuroimaging findings, injury on electromyography (EMG) and the Total Neuropathy Score clinical version (TNSc) criteria. A total of 47 participants were included with mean age: 24.38 ± 6.20 years. The number of balloons used per week was 130.59 ± 117.43. The mean duration of N2O exposure was 8.79 ± 7.1 months. Multivariate linear logistic regression revealed that the number of N2O balloons used per week was significantly associated with TNSc point . We found that myeloneuropathy and peripheral neuropathy were the main neurological disorders related to N2O abuse, which should improve the awareness of the appearance of neurological disorders associated with N2O abuse.Nitrous oxide (N The mos2O abuse, but there are few studies relating to neurological disorders being caused by the recreational use of N2O in Vietnam. Therefore, we have undertaken this study to describe the neurological disorders associated with N2O abuse among recreational users in Vietnam.Although supplying nitrous oxide for recreational purposes is illegal in some countries, its widespread use in the food industry makes its control almost impossible . Current2O toxicity who were admitted to the Vietnam Poison Control Center, Bach Mai Hospital, Hanoi, Vietnam from June 2018 to July 2019. This center is a referral government hospital and is the only poison control center (PCC) in the north of Vietnam.We conducted a cross-sectional study on inpatients with NThe patients received a clinical evaluation that included a medical history evaluation, a physical examination, and a neurologic examination to test for levels of vitamin B12 and homocysteine. All patients received electromyography (EMG) and magnetic resonance imaging (MRI).2O; (2) the presence of mental and neurological disorders; (3) a motor function disorder; and (4) subclinical characteristics, including increased homocysteine levels or abnormal results on EMG and MRI.Patients were included if they met criteria 1 and one of criteria 2, 3, and 4: (1) using N2O toxicity after an observation period; (2) a history of neurological diseases before using N2O; (3) a refusal to participate in the study.Patients were excluded from the study if they had at least one of the following criteria: (1) a lack of signs or symptoms of NA total of 47 patients were enrolled in the study.After obtaining consent, data were collected using a pre-designed and structured questionnaire by interviewing patients and their families, and by conducting a clinical evaluation at the time of admission. The questionnaire included the following:2O: history of inhaled N2O , N2O exposure time (months), number of balloons used per week , symptom onset (months) and place of using N2O.Characteristics of using NSigns and clinical symptoms: neurologic symptoms , vibration sensory impairment, weakness, dizziness/headache, decreased/loss of a deep tendon reflex , decreased/loss of upper limb’s deep tendon reflex, decreased/loss of lower limb’s deep tendon reflex, decreased/loss of upper muscle power, decreased/loss of lower muscle power, Lhermitte’s sign, Romberg’s sign, memory impairment (patient self-reported and interviewed their families), autonomic dysfunction , Babinski’s sign, psychiatric symptoms , and other symptoms .Neuroimaging results: MRI injury of the spinal cord , number of injury spinal segments on MRI (≤7 and >7), and spinal MRI changes (T1W and T2W).Injury on EMG of the upper limbs  and injury on EMG lower limbs , based on electromyography and nerve conduction studies, was performed by neurologists.Blood tests: hemoglobin , vitamin B12  and homocysteine .Urine drug screening was used to evaluate drug abuse in patients.Chemotherapy-induced peripheral neurotoxicity condition was diagnosed using the total neuropathy score clinical version (TNSc) criteria. The criteria included 7 domains  with 0–4 scored for each. Total scores ranged from 0 to 28 points. Total scores from 1–7 points were mild level, 8–14 points were moderate, 15–21 points were severe, and over 21 points were very severe [All of the data were recorded and analyzed using the Statistical Package for the Social Sciences , version 22.0. Descriptive statistics for the participant characteristics were presented as mean +/− SD for the continuous variables and frequency/percentages for the categorical variables.p-value and 95% confident intervals. A p-value of less than 0.05 was recognized as statistically significant.Multivariate linear logistic regression was used to identify associated factors with TNSc score. Standardized beta coefficients were presented along with the The study was approved by the Ethics Committee of Bach Mai Hospital. Written in-formed consent was obtained from all participants. For patients who were not of legal age to sign on their own behalf, written informed consent was obtained from their guardians. The questionnaire did not record private information, nor was any content that would be harmful to the participants. The results of the research were used only for study purposes. We can confirm that our study also complied with the Declaration of Helsinki.2O abuse occurred most frequently among adults (mean age of 24.38 ± 6.20 years). The number of balloons used per week were 130.59 ± 117.43. The mean duration of N2O exposure was 8.79 ± 7.1 months and the mean time from the last N2O exposure to the onset of symptoms was 8.46 ± 6.96 days  with reduced pin sensation (100%) and weakness (lower limb superiority). Moreover, vibration sense impairment was also found among a considerable number of patients (74.47%). Tendon reflex abnormalities were also found; 85.1% showed a decreased/loss of lower deep tendon reflex, and 78.7% showed a positive Romberg’s sign. .Psychiatric symptoms were insomnia  and depression , while no patient presented with the symptom of hallucinations. Memory impairment, urinary incontinence, digestive disorder, and sexual dysfunction were found in 31.9%, 6.4%, 4.3%, and 2.1 % of the participants, respectively. The mean total neuropathy score was 12.61 ± 4.17, which indicated a moderate level of severity .The main abnormal findings in the blood tests were vitamin B12 deficiency in 40.4% of the patients, hyper-homocysteine in 85.1% of the patients, and anemia in 12.8% .The cervical spinal cord was more frequently impaired than other areas of the spinal cord; 27 patients of the 47 (57.4%) showed lesions in the cervical spinal cord, 4 patients (8.5%) showed lesions in the thoracic spinal cord, and 1 patient showed lesions in both the cervical and thoracic spinal cord .A total of 31 patients had MRI changes in the spine; 22 (71%) had T2 hyperintensity of posterior column, while 100% of the damage on T1W was linked to hypointensity or isointensity. The majority of patients with abnormal MRI findings showed lesions with less than seven spinal segments  .Electromyography showed both myelin and axon impairment in all of the patients. Myelin impairment was the typical electromyography finding (93.6%) and was more prominent in the lower limbs .2O balloons used per week was significantly associated with the TNSc score   .2O abuse. Less common neurological signs and symptoms at the time of presentation include memory impairment, bowel and bladder dysfunction, sexual dysfunction, dizzy/headache, Lhermitte’s sign, and psychiatric symptoms. All lesions found were hyperintense on T2W and located in the posterior column. Myelin impairment was the typical electromyography finding. Our findings are similar to those reported in other studies [The study showed that sensory deficits, reduced pin sensation, vibration sense impairment and distal limb weakness, Romberg’s sign, and decreased deep tendon reflex were the most common clinical symptoms of neurological disorders related to N studies ,10,11,122O’s neurotoxic effects [2O abuse is its interference with vitamin B12 metabolism [2O irreversibly inactivates vitamin B12 by oxidizing its cobalt moiety from the Co1+ to the Co3+ valence state, leading to demyelination in the central and peripheral nervous system [2O abuse in our study was higher (40%) than that of subjects of the same age in other studies [2O intoxication.A variety of mechanisms are responsible for N effects . The maitabolism . Vitamins system . Vitamins system . The pre studies . Scalabr studies . They de studies , is the 2O itself can produce neurotoxicity by inhibiting the synthesis and release of xanthine and monoamine , thus affecting the cytokine balance and inducing cerebral hypoxia and acidosis [2O inhalation, resulting in psychosis.In addition, Nacidosis . This ca2O-related neurological disorders are generally associated with intensive and long-term use [2O balloons used per week was a significant factor associated with the increase in the TNSc point. This is consistent with the results of a study of 16,239 individuals who had used nitrous oxide in the last 12 months: the greater the dose per session, the greater the predicted probability of reporting paraesthesia [The literature suggests that Nterm use . Our stuesthesia .2O abuse. Participants may be less forthcoming about their amount and duration of use. We also did not determine the exact amount of N2O in each balloon. Second, this study used a small sample. We recommend that further studies should be conducted with a larger sample size and in multiple hospitals.There are some limitations to this study. First, it is difficult to truly and accurately quantify the degree of NThis study has several implications. While the majority of research in the world is retrospective, our research design has overcome the shortcomings with a predetermined protocol. Nitrous oxide-induced neuropathy in the study was comprehensively evaluated through clinical examination and blood tests, as well as functional exploration.2O abuse, which should improve the awareness of the appearance of neurological disorders associated with N2O abuse.In conclusion, we found that myeloneuropathy and peripheral neuropathy were the main types of neurological disorders related to N