P-values were < 0.005). Moreover, a linear regression model showed that the serum OPN concentration was correlated with pain intensity in patients with PHN (P = 0.03). There was no significant difference between the serum concentration of soluble epidermal growth factor receptors, sErbB3, soluble AXL, tenascin, and soluble neuropilin-1 in patients with acute and subacute pain and that of healthy controls. The results of this study provided new valuable insights into our understanding of angiogenic factors that may contribute to as mechanistic biomarkers of pain, and reveal the pathophysiological mechanism of pain.Screening serum biomarkers for acute and subacute pain is important for precise pain management. This study aimed to examine serum levels of angiogenic factors in patients with acute and subacute pain as potential biomarkers. Serum samples were collected from 12 healthy controls, 20 patients with postherpetic neuralgia (PHN), 4 with low back pain (LBP), and 1 with trigeminal neuralgia (TN). Pain intensity in these patients was evaluated using the visual analog scale (VAS). The serum concentrations of 11 angiogenic biomarkers were examined by Milliplex Map Human Angiogenesis Magnetic Bead Panel 2. The pain assessment from VAS showed that all patients showed moderate and severe pain. Among 11 angiogenic factors, osteopontin (OPN), thrombospondin-2 (TSP-2), soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1), soluble urokinase-type plasminogen activator receptor (suPAR), and soluble epidermal growth factor receptors (sErbB2) were up-regulated and soluble interleukin-6 receptor α (sIL-6Rα) were down-regulated in patients with pain compared to the healthy participants (all Clinical Trial Registration:www.chictr.org.cn, identifier ChiCTR2200061775. Pain may be conceived as a disease in conditions, such as fibromyalgia or non-specific low back pain (LBP) . More poAngiogenesis, which is the formation of new blood vessels from the endothelium of the existing vasculature, is a fundamental process that occurs in physiological and pathophysiological conditions . InsuffiWe examined the serum levels of 11 angiogenic factors in patients with PHN, LBP, or TN using the Millipore Milliplex Map Human Angiogenesis Magnetic Bead Panel 2 assay and evaluated the correlations of these factors with pain intensity in PHN patients. These 11 angiogenic factors included osteopontin (OPN), thrombospondin-2 (TSP-2), soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1), soluble urokinase-type plasminogen activator receptor (suPAR), soluble epidermal growth factor receptors (sEGFR/sHER1/sErbB1), soluble human epidermal growth factor receptor 2 (sEGFR2/sErbB2s/HER2), sErbB3 (sEGFR3/sHER3), soluble interleukin-6 receptor α (sIL-6Rα), soluble AXL (sAXL), tenascin C (TN-C), and soluble neuropilin-1 (sNRP-1). We will observe the expression levels of their homologous genes in the dorsal root ganglion (DRG), spinal cord, and the key parts of the sensory nervous system using a mouse neuropathic pain model in the next step.All the participants were recruited from the Tianjin Union Medical Centre, Tianjin, China. There were 20 patients with PHN, 4 with LBP, and 1 with TN. All the patients were diagnosed by clinically qualified doctors. Twelve age-matched healthy participants without pain-related diseases or conditions were enrolled from the physical examination center of the Tianjin Union Medical Centre. Baseline characteristics (age and sex) of the participants are listed in All the patients and healthy participants completed a visual analog scale (VAS) questionnaire for pain. The participants were asked to rate their current pain intensity on a VAS, ranging between “0–10.” A VAS of “0” represents “no pain”; “1–3” represents mild tolerable pain; “4–6” represents moderate tolerable pain and sleep was disturbed. A VAS pain score from of “7–10” represents intense intolerable pain and both sleep and diet were disturbed.Blood samples from the participants were collected into 10 mL sterile tubes containing no additives. The samples were immediately centrifuged at 1,000 × g for 10 min and sediment-free serum samples were obtained, aliquoted, and frozen at –80°C until further analysis.® 200™ and analyzed using the Bio-Plex Manager software. The equipment settings were provided in the instruction book. Results were expressed in nanogram per milliliter (ng/mL) for the serum levels.Serum concentrations of the 11 angiogenic factors  were measured by commercially available Milliplex Map Human Angiogenesis Magnetic Bead Panel 2 assay . The serum samples were diluted to 1:5 before use. All procedures were carried out according to manufacturer’s the instructions and all the samples were tested along with the quality controls and standard samples provided in the kit. After all steps were completed, the 96-well plate was placed onto Luminext-test.Serum levels of the angiogenic factors were evaluated using absolute concentration values. Data are reported as mean ± standard error of the mean (SEM). Comparisons of each angiogenic factor between the patients with pain and healthy controls was performed using the Student’s P < 0.05 considered as significant. Spearman’s order correlation was performed to examine the correlation and calculate the correlation coefficients.Correlations between the concentration of the angiogenic factors and pain intensity or duration in patients with PHN were determined using linear regression analysis. The F-test was used to determine statistical significance, with P < 0.05.All analyses were performed using Statistical Package for the Social Sciences . Statistical significance was set at Descriptive characteristics of the patients are shown in The mean ± S.E.M. levels of the serum angiogenic factors are shown in P = 0.03, The altered angiogenic factors including OPN, TSP-2, sPECAM-1, sHER2, suPAR, and sIL-6Rα in the PHN patients were further analyzed according to pain intensity and duration . We founThe objective of this study was to compare the levels of angiogenic factors in the sera of patients with pain and healthy controls. We found that higher levels of OPN, TSP-2, sPECAM-1, sErbB2, and suPAR and lower levels of sIL-6Rα were up-regulated and sIL-6Rα were down-regulated in those patients with pain compared to the healthy participants. Moreover, serum OPN levels were correlated with pain intensity in patients with PHN. These angiogenic factors may be involved in the pathogenesis of pain, and their soluble part in the blood can serve as biochemical indicators of acute or subacute pain.The biological functions of OPN are diverse as it can be beneficial for wound healing, bone homeostasis, and extracellular matrix function, and deleterious in cardiovascular diseases, cancer, diabetes, and kidney stone diseases . CirculaPlatelet endothelial cell adhesion molecule-1, also called CD31, is a 130-kDa protein belonging to the Ig superfamily; it has distinct variants and therefore different isoforms which allow diversity of PECAM-1 functions, including inflammation, angiogenesis and vascular development . SplicinErbB2 is a member of the EGFR family of receptor tyrosine kinases, which comprises ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4 . ErbB2 iInterleukin-6 is a key cytokine in many inflammatory and autoimmune diseases and IL-6, as well as IL-6 signaling, have been implicated in pain pathogenesis . The IL-Urokinase-type plasminogen activator receptor is a glycosyl-phosphatidylinositol-anchored membrane glycoprotein belonging to the plasminogen activator system . SolubleThrombospondin-2, a matricellular glycoprotein of the thrombospondin family, regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion, and extracellular matrix modeling . High TSWe found significant changes in OPN, TSP-2, sPECAM-1, sErbB2, suPAR, and sIL-6Rα levels in the serum of patients with pain. Moreover, the serum OPN concentration may indicate pain severity. The results from this study provide new valuable insights into our understanding of angiogenic factors that may contribute to mechanistic biomarkers of pain to reveal the pathophysiological mechanisms of acute and subacute pain.The present study showed significant changes in OPN, TSP-2, sPECAM-1, sErbB2, suPAR, and sIL-6Rα levels in the serum of patients with pain, especially with PHN. Moreover, the serum OPN concentration may indicate pain severity. Based on our findings, we hypothesized that elevated levels of circulating angiogenic factors contribute to the development of pain pathogenesis. Further studies should focus on their local effects and functions in the pain pathway, such as in the dorsal root ganglion and spinal cord, to determine their contribution to pain pathogenesis. To date, the expression of genes encoding these altered angiogenic factors has been found to be increased in the injured DRG in an experimental neuropathic pain model based on RNA-sequencing analysis . HoweverA limitation of our study was the study group selection. Healthy controls were chosen from among age-matched elderly individuals who may have various other diseases, which may have affected serum angiogenic factor concentrations. Another limitation of this study was the inadequate number of patients, especially those with LBP and TN. We recruited only one patient with TN; therefore, the data could not be statistically analyzed. Further large-scale studies are required to define the role of these markers in patients with pain.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethical Committee of Tianjin Union Medical Center. The patients/participants provided their written informed consent to participate in this study.XY and JZ: conceptualization. HW and YW: methodology. HW and ML: formal analysis. XY and CY: writing—original draft preparation. JZ and ZL: writing—review and editing. CY: visualization. XY: supervision. JZ and XY: project administration and funding acquisition. 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.


Intra-articular or peri-articular corticosteroid injections are often used for treatment of sacroiliac joint (SIJ) pain. However, response to these injections is variable and many patients require multiple injections for sustained benefit. In this study, we aim to identify patient-specific predictors of response or non-response to SIJ injections. Identification of these predictors would allow providers to better determine what treatment would be appropriate for a patient with SIJ pain. A retrospective review of 100 consecutive patient charts spanning a 2-year period at an academic multi-specialty pain center was conducted and a multivariate regression analysis was used to identify patient-specific predictors of response to SIJ injections. Our analysis identified that a history of depression and anxiety  and increased age  significantly reduced the odds of responding to injections. We also found that the associated NPRS score change for SIJ injection responders was less than the minimally clinically significant value of a 2-point differential, suggesting that reported changes in pain scores may not accurately represent a patient’s perception of success after SIJ injection. These findings warrant further investigation through a prospective study and can potentially influence clinical decision making and prognosis for patients receiving SIJ injections. SIJ pain is a common cause of chronic low back pain (CLBP) as an estimated 15–21% of all CLBP is due to dysfunction of the SIJ [The diagnosis of SIJ pain remains challenging as the characteristics of the pain can vary between patients. Pain referral patterns are very common and variable in SIJ pain due to the size and heterogeneity of the joint . The refInitial treatment of SIJ pain includes ice and physical therapy . PatientPrevious studies have investigated pain referral patterns and SIJ pain with varying results. The area 1cm inferomedial to the posterior inferior iliac spine (PSIS), which is commonly demonstrated to be painful in the “Fortin finger test”, was described to be specifically present in SIJ pain . PatientThis was a retrospective chart review of 100 consecutive patients at an academic multi-specialty pain center who received one or more SIJ injections under fluoroscopic guidance between 2015 and 2017. Patients were referred through their primary care physicians and had chronic (>3 months duration) pain. Inclusion criteria for the study were: age 18 years or older, had undergone sacroiliac joint injection(s) with a pre-procedure and post-procedure clinic visit documented in their medical records, and at least one of the six positive provocative SIJ exam tests described by Laslett et al.  [The primary outcome of this study was whether a patient responded to their first SIJ injection. A patient was classified as a “responder” if they self-reported a ≥50% improvement on a visual analogue scale after SIJ injection that lasted ≥2 weeks to distinguish between corticosteroid and local anesthetic. The 50% improvement threshold was based on prior literature identifying meaningful clinical improvement for SIJ injection . SecondaPain referral patterns have been studied previously in SIJ populations . The Opit-tests were used to compare primary and secondary outcome values for responders vs. non-responders listed in p ≤ 0.05 was considered statistically significant. The sample size of N = 100 was determined based on the suggested criteria of 10 participants per independent variable of interest for multivariate regression models [A multivariate logistic regression model to determine significant predictors for responsiveness to SIJ injections was performed. This statistical analysis was performed using SPSS Version 26 . This was a complete-case analysis. Model performance was assessed through the Nagelkerke R square of the logistic regression analysis. Two tailed independent student n models .p < 0.001). The change in NPRS between both groups was statistically significant as well (p = 0.034). The difference of mean age in a univariate analysis was statistically significant (p = 0.019); however, there was no statistical difference between the BMI of both groups in the univariate analysis.In total, 140 patient charts were reviewed and 40 patient charts were excluded, leaving 100 charts for data analysis. Of the 100 patient charts reviewed, 40 (40%) were identified as responders and 60(60%) as non-responders. Average ± SD time to first follow-up visit was 2.6 ± 2.4 months. The mean ± SD age of patients was 57 ± 14 for responders vs. 64 ± 16 for non-responders A. There 2 = 0.246). The model revealed that a history of depression and anxiety and increased age significantly reduced the odds of responding to injections. In particular, patients with a history of depression and anxiety concomitantly were 76.7% less likely to be responders, and each additional year of age increased the odds of failure by 5.4%. Gender, history of lumbar spine surgery, smoking status, pain referral pattern, Opioid Risk Tool scores, history of hypertension, and history of diabetes were not predictive of response to injection (p > 0.144). . This retrospective study aimed to identify patient-specific predictors of responsiveness to intra-articular SIJ corticosteroid injections. A history of depression and anxiety and increased age significantly reduced the odds of responding to injections.Previous studies have primarily focused on physical exam findings and pain location as predictors for SIJ pain, with varying results ,5,7. ManAge was associated with a decreased likelihood of responding to SIJ injections, which is consistent with other studies investigating SIJ and/or chronic low back pain and interventions ,18. IncrA history of depression and anxiety was associated with a reduced odds of responding to SIJ injections. This is consistent with previous studies suggesting psychosocial factors contribute to persistent pain in the spine . InteresOne unexpected finding was that despite responders subjectively reporting an improvement of greater than 50% pain reduction, the associated change in NPRS scores was not clinically significant (<2 point change) . ImportaThere are several limitations of the study. Due to its retrospective nature, the follow up time for return to clinic ranged widely. Given the wide range of follow up times, some patients may have had their follow-up clinic visit after the effect of their injection had worn off, leading to their reported % improvement to be falsely lower than if recorded earlier, or what could have been seen when the steroid effect was present. This study also focused on patients’ first SIJ injection and so long-term outcomes for patients who receive multiple SIJ injections were not addressed. The responder rate was 40%, which is consistent with other retrospective studies that have reported the % of people who improve after a single injection. Hawkins and Schofferman  noted thA retrospective chart review at an academic multi-specialty pain center revealed that a history of anxiety and depression and increased age significantly decreased responsiveness to initial SIJ injection. Additionally, the associated NPRS score change for patients who were classified as responders in our study was less than the minimally clinically significant value of a 2-point differential, suggesting patient perception of success after SIJ injection may not be accurately represented through changes in pain scores. A prospective study evaluating these patient-specific predictors with follow-up at set time periods is warranted.


Background and Objectives: Knee osteoarthritis (OA) is a frequent cause of pain, functional limitations, and a common reason for surgical treatment, such as joint replacement. Conservative therapies can reduce pain and improve function; thus, delaying or even preventing surgical intervention. Various individual conservative therapies show benefits, but combination therapies remain underexplored. The aim of this prospective case-study was to assess the effect of a conservative combination therapy in patients with painful varus knee OA. Materials and Methods: With strong inclusion and exclusion criteria, nine patients with painful varus knee OA (mean age 56 years (range 51–63 years) were selected and monitored over six months, using the following clinical outcome scores: pain visual analog scale (VAS), Western Ontario and McMaster Universities osteoarthritis index (WOMAC score), short-form–36 items (SF-36) quality of life score, and the sports frequency score. All patients received a standardized conservative trio-therapy with varus-reducing hindfoot shoe-insoles with a lateral hindfoot wedge, oral viscosupplementation, and physiotherapy for six months. Results: The pain was reduced significantly from initial VAS values of 5.4 points  to values of 0.6 points , at the end of treatment. After six months, seven out of nine patients reported no pain at all (VAS 0). The WOMAC score improved significantly, from initial values of 35  to values of 2 . The SF-36 score showed significant improvement after six months in all four domains of physical health (p < 0.01) and in two of the four domains of mental health (p < 0.05). The sports frequency score increased by at least one level in six out of nine patients after six months. Conclusions: The conservative trio-therapy in patients with varus knee OA showed positive initial clinical results: less pain, higher function, better quality of life, and higher sport activity. Further studies are required to evaluate the long-term effect. Symptomcal work ,5.Kellgren and Lawrence distinguished four stages : grade 0Several studies have shown that physiotherapy mitigates the symptoms of knee OA . ExercisAlthough it remains controversial, orally administered components of the extracellular matrix (viscosupplementation), in particular glucosamine sulfate and chondroitin sulfate, might relieve pain in joints of lower extremities, including knee ,11,12,13In case of varus deviation of the leg axes, shoe insoles with lateral hindfoot wedges can reduce the adduction moment, thereby relieving the medial compartment . A meta-There are plenty of other conservative therapies. While some, such as dry needling, have been shown to be not effective , others,Most previous studies described the effect of individual forms of therapy, but combinations remain underexplored. In this study, patients with varus knee OA were treated with a conservative trio-therapy, a combination of varus-reducing hindfoot shoe-insoles, oral viscosupplementation, and physiotherapy. We hypothesized that this conservative trio-therapy would reduce pain and improve measured scores in patients with varus knee OA.2, and lack of willingness to perform the conservative trio-therapy. With these strict inclusion and exclusion criteria, 80% of the patients had to be excluded from the study. For example, these common combinations had to be excluded: medial degeneration Grade IV, or medial degeneration with medial meniscus degeneration/tear, medial degeneration with patellofemoral OA, and others. In total 12 ‘absolute clean’ patients could be recruited.In this prospective case-study, all patients received the same trio-therapy and were followed for 6 months. Patients were recruited through referrals from general practitioners over a seven-month period. The inclusion criteria were unilateral or bilateral unicompartmental isolated medial varus knee OA with varus > 5° in orthoradiogram/lower limb radiography and Kellgren-Lawrence Grade II to III OA with-out any signs of lateral knee OA or patellofemoral OA in the MRI, age between 18 and 80 years, willingness to participate in the study, and signed patient’s informed consent. The exclusion criteria were unicompartmental medial varus knee OA with Kellgren-Lawrence Grade I or IV, varus knee OA with lateral or patellofemoral OA, valgus knee OA, patellofemoral OA, complete tri-compartmental knee OA, other diseases of the knee joint , age < 18 years and >80 years, hip OA, OA of the ankle joint or foot, other leg or spinal disorders, neuromuscular diseases, rheumatoid diseases, osteoporosis, obesity with BMI > 30 kg/mAll patients received a standardized trio-therapy with corrective shoe-insoles, oral viscosupplementation, and physiotherapy for six months.The orthopedic insoles were equipped with a varus-reducing lateral hindfoot wedge to reduce the leg’s varus, i.e., the knee axis’s lateralizing position; thus, relieving the knee OA medially. For each degree in varus, a correction of 1 mm wedge height was implemented in the lateral orthopedic insole. The insoles were all performed by the same orthopedic technician and fitted in flat mid-height shoes with hard soles. The patients were instructed to wear the shoe throughout the entire day.® Drink  once daily for the first three months. According to Swiss Alp Health recommendations, maintenance dosing during months four to six was two to three sachets per week. The ExtraCellMatrix ECM® Drink consisted of the following ingredients: collagen type I, II, III (10 g), glucosamine sulfate (1270 mg), chondroitin sulfate (500 mg), hyaluronic acid (100 mg), MSM (100 mg), L-lysine (400 mg), L-threonine (300 mg), rosehip, melon extract, edelweiss, gen-tian, agar–agar, paprika extract, minerals , and vitamins .Oral viscosupplementation: patients ingested one sachet (21.8 g) of ExtraCellMatrix ECMAll patients received physiotherapy twice a week for 30 min, over the entire period of six months. Uniform stretching hamstrings, quadriceps calf muscles, strength training of all periarticular knee muscles, and local anti-inflammatory measures to reduce pain and improve functionality, e.g., local lymphatic drainage, were prescribed. The exercises were adjusted to the patient, according to their pain tolerance.Patients were interviewed at the start of therapy and after three and six months. The level of pain was assessed with the visual analog scale (VAS) on a scale of 0 (no pain) to 10 (most severe pain) . FunctioQuality of life was assessed using the short form–36 items (SF-36) questionnaire, before starting therapy and after six months . This quPhysical sports activity was assessed with the sports frequency score  on all tp < 0.05, statistical power 0.8. A chi-square likely ratio test was used to assess the statistical significance of differences between the start and end of treatment. The significance level was set at α = 0.05. The results are depicted as average values with ± standard deviations and the range of minimum and maximum values. We also calculated minimal detectable changes (MDC) for a power of 0.8.A power calculation before the study started resulted in a minimum number of four patients for a VAS pain score  with the following average values: before intervention OA pain VAS 6, after trio-therapy VAS 2, standard deviation 2, statistical significance Of the 12 patients initially enrolled in the study, nine patients could be thoroughly examined and interviewed till the endpoint of six months follow-up. Two patients could not be reached after the first appointment and were, therefore, excluded from the data analysis. Another patient declined the conservative therapy after the first appointment and had surgery on the affected knee. The data of the three drop-out-patients were not used. Therefore, nine patients could be used in the study: seven women and two men, with a mean age of 56 years  and a mean varus deviation of 7° .p < 0.01. After six months of therapy, patients reported pain levels closed to the minimum value possible: VAS 0.6 ± 1.1  p < 0.01. Seven out of nine patients reported no pain at all (VAS 0) after six months. Most of the improvement was achieved within the first three months. The MDC of 2.5 was reached.All patients reported a reduction of pain in the affected knee . At the p < 0.05) after three months of therapy, and to 2 ± 4  after six months. Thus, the patients achieved better scores than the normal population in this age category [Patients had initial WOMAC scores of 35 ± 15  . During category . Five oup < 0.01). In contrast to the VAS results, the SF-36 showed complete freedom from pain in only two patients. It is important to note that the SF-36 questionnaire refers to the entire body and mental state, while in this study, the VAS only referred to the knee. It is, therefore, possible that the patients had other present problems besides the knee pain.The SF-36 questionnaire assessed quality of life before the start of therapy and after six months . All foup < 0.05). The two domains role-emotional and social functioning showed only minor non-significant changes (p > 0.05). The two domains bodily pain and general health did reach the MDC, the other six domains didn’t. In the four domains of mental health, the two domains, vitality and mental health showed significant improvements  is a common disease in the middle to old age. Patients with a substantial leg axis deviation  are frequently affected. Surgery or joint re-placement is usually necessary in the long term. Conservative therapies can relieve pain and improve function, at least temporarily and especially in the early stages. Although various conservative treatments are effective, the possibly enhanced benefits of combinatorial therapies are underexplored. In this prospective study, it was shown that a six-month conservative trio-therapy consisting of varus-reducing hindfoot shoe-insoles with a lateral wedge, oral viscosupplementation with ECM, and physiotherapy enormously improved pain, function, quality of life, and sports activity in patients with painful varus knee OA.The conservative trio-therapy achieved an average pain relief of 5 points  and an improved WOMAC functionality of 30 points . Seven out of nine patients even became entirely pain-free in the affected joint within six months. In six of the eight domains of the SF-36 questionnaire, there was a significant improvement in life quality. Physical activity also increased in six of the nine patients by at least one level on the sports frequency score.The success of the combined trio-therapy in this study was striking compared to previous studies using monotherapies. A meta-analysis of studies on physiotherapy alone showed a pain reduction of only 1 point on a scale of 0 to 10 points and improved functionality of only 10 points on a scale of 0 to 100 points . InsolesAssuming purely additive effects of the individual components, a pain reduction of 4 points could be expected for the conservative trio-therapy, based on the study data to date. This value is close to the observed results of the present study, of 5 points. Additive effects are compatible with the targeting of different pathophysiological aspects. Overall, the pain reduction and improved function were highly effective, suggesting this conservative combination therapy as the first choice treatment in varus knee OA.This study has limitations. The patient population of nine patients was small. Nevertheless, according to the power calculation, this was more than sufficient to answer the question. Furthermore, there was no control group in this prospective case-study, so that part of the improvement could have been based on the placebo effect. Therefore, it is not known how much of the changes can be attributed to the three forms of treatment together. Double-blinding is not possible for physiotherapy and insoles, so that the placebo effect cannot be determined precisely. Observations with flat insoles without side wedges suggest only a minimal placebo effect for insoles with lateral side wedges . A possiFurthermore, the study had a duration of only six months. Therefore, it is unclear how long the pain reduction lasts and how long a surgical intervention can be delayed compared to patients without a conservative trio-therapy. These questions should be clarified in future studies.The conservative trio-therapy with varus-reducing hindfoot shoe-insoles with a lateral wedge, oral viscosupplementation with ECM, and physiotherapy in patients with varus knee OA showed positive initial clinical results: less pain, higher function, better quality of life, and higher sport activity. Further studies are required to evaluate the long-term effect. If this trio-therapy should become established in daily clinical practice, it would provide a treatment option for most patients with varus knee OA.


Intense pain is one of the most important postoperative complaints after tonsillectomy. It is often described by patients as comparable to the pain that accompanies an acute tonsillitis. Although recurrent tonsillitis is the most frequent indication for surgery, many tonsillectomies are performed due to other indications and these patients may be unfamiliar with such pain.To verify whether individuals with recurrent tonsillitis experience different post-tonsillectomy pain intensity than those with other indications for surgery, with no history of episodes of acute tonsillitis.A total of 61 tonsillectomies were performed under general anesthesia, using a potassium titanyl phosphate (KTP) laser  and multiple ligations of blood vessels within the tonsillar beds. The patients received 37.5 mg Tramadoli hydrochloridum + 325 mg Paracetamol tablets for 10 days. Postoperative variables included the duration of hospital stay, postoperative hemorrhage and readmission rate. The patients reported pain intensity on consecutive days, pain duration, weight loss on postoperative day 10, character, intensity and duration of swallowing difficulties, and the need for additional doses of painkillers. Healing was also assessed. Capsular nerve fibers were histologically examined in the resected tonsils by immunostainings for general and sensory markers.Indications for the surgery were: recurrent acute tonsillitis (34 patients), no history of recurrent tonsillitis: focus tonsil (20) and intense malodour (7). Pain intensity on postoperative days 3–4 and incidence of readmissions due to dehydration were significantly higher in the group with no history of recurrent tonsillitis. No significant differences in relative densities of protein gene product (PGP) 9.5- and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers were observed.Patients with recurrent tonsillitis qualified for tonsillectomy reported lower pain intensity than those without recurrent tonsillitis and the pain scores were unrelated to nerve fibers density. Intense pain is one of the most important postoperative complaints after tonsillectomy, and in 20% of patients it becomes the reason for a hospital revisit, often due to subsequent dehydration.Postoperative pain after tonsillectomy is frequently described by patients as comparable to the pain that accompanies an episode of acute tonsillitis. Most of the patients qualified for tonsillectomy had experienced such pain numerous times before the surgery, since chronic tonsillitis, defined by American Academy of Otolaryngology – Head and Neck Surgery criteria, as chronic tonsillithiasis or recurrent acute tonsillitis ,18Inflammatory processes have been found to influence sensory innervation in various organs and tissues.In this study we set out to verify: (1) whether individuals with recurrent tonsillitis in anamnesis experience different post-tonsillectomy pain intensity than those with other indications for surgery and no history of recurrent tonsillitis, and (2) to determine whether densities of capsular nerve fibers in resected tonsils differ between these groups.Prior to examination, all the participants signed written informed consent for their participation in the study. The research plan was approved by the institutional research committee and the local medical ethics committee (75/KBL/OIL/2010). The tenets of the Helsinki declaration were followed.2/air 50% mixture and intermittent positive pressure ventilation. Intravenous 5.0–10.0 mg morphine and 50.0–100.0 mg ketoprofen were used for analgesia.The study sample size was estimated with the use of a minimum expected difference of pain scores of 2, an estimated standard deviation of the variable of 1.5 with a resulting standardized difference of 1.3, and a desired test power of 0.8. A total of 61 tonsillectomies were performed during the period of January 2013–March 2014. There were 33 female and 28 male patients, aged 20–40 years . This study did not analyze patients in whom tonsillectomy was performed due to upper airway obstruction secondary to tonsillar hypertrophy, as all these procedures were combined with laser-assisted uvulopalatoplasty. General anesthesia induction was achieved with 1.0–2.0 mg/kg fentanyl and 1.0–2.0 mg/kg propofol 0.6–1.0 mg/kg. Rocuronium was used as a muscle relaxant for endotracheal intubation. Anesthesia was maintained by sevoflurane in an OSurgery was performed with potassium titanyl phosphate laser . The laser power was set at 15 W. Multiple ligations  of blood vessels within tonsillar beds were applied. Difficult to access parts of the pillars, adjacent to the tongue base, were cauterized with the laser in order to prevent postoperative bleeding. Excised tonsils were submitted for histological examination.A single dose of intravenous steroids was administered at the time of surgery. Each patient received a single intravenous dose of 150.0 μg/kg (maximum dose 8.0 mg) dexamethasone sodium phosphate at the time of surgery, as well as three subsequent daily oral doses of 37.5 mg tramadol + 325.0 mg paracetamol, and in addition four daily 500.0 mg tablets of paracetamol for ten days. Further, up to one tablet of 50.0 mg tramadol daily was allowed. No allergy to the drugs was reported. All operations were carried out by a single surgeon. After surgery, the patients had at minimum an overnight hospital recovery.All the patients operated on during the study period were invited to participate in the prospective, observational, questionnaire based study, and they accepted the invitation. They were followed-up for three weeks.On postoperative days four and ten, the pharynx of each patient was examined to assess the healing process, rated on a five-point scale: 4 – redness and edema of vast regions of pharyngeal mucosa, including the uvula; 3 – edema of the uvula with or without redness and/or edema of anterior pillar mucosa; 2 – redness and edema of peritonsillar tissues excluding the uvula; 1 – redness of anterior pillar mucosa without edema; 0 – normal mucosa, without redness or edema.The participants were informed about the scientific significance of the reliability of the data they were supplying. None of the patients missed the follow-up.In order to verify whether the differences in pain intensity between the groups could result from changes of the tonsil innervation caused by repeated acute and subsequent chronic inflammation, histological examination of the densities of nerve fibers in the dissected tonsils was performed.l-lysine-coated slides.Both dissected tonsils were fixed overnight in 10% buffered formalin and then rinsed in phosphate buffered saline (PBS) and immersed in 25% sucrose solution. Regions of the tonsils containing the capsule were further processed. Tissue blocks were mounted in optimal cutting temperature (OCT) compound and snap-frozen. Ten-micrometer-thick cryosections were cut and thaw-mounted on poly-The sections were subjected to indirect immunofluorescence staining.The sections were examined using an Olympus BX-50  epifluorescence microscope equipped with appropriate filter set U-MNG for Cy3 visualization. Digital images were acquired by Olympus DP-71 camera. Relative densities of nerve fibers in distinct locations were semi-quantitatively evaluated in tissue sections by two independent observers. Arbitrary scoring for nerve fiber densities was defined: 0 – no fibers, 1 – single, 2 – sparse, 3 – numerous.No healthy (control) tonsils were examined, as the aim was to compare patients with potentially different postoperative pain intensities.U rank sum test was performed with Statistica version 5 software . Contingency tables were created and the chi-squared test was used to confirm differences in relative nerve fiber densities. Logistic regression was used to compare the incidence of readmission due to dehydration in both groups.To determine significant differences between the distributions of the participants’ age, pain intensities, maximum pain scores, mean day of return to a normal diet, intensity of swallowing difficulties, body weight, and number of additional doses of analgesics, the Mann–Whitney The indications for tonsillectomy allowed defining two groups of patients: (1) with a history of recurrent acute tonsillitis (34 participants), and (2) with no history of recurrent tonsillitis .The participants’ age and gender distribution did not differ between the groups. The length of hospital stay did not differ either. Differences in pain intensity on postoperative days one, two, and five to 13 were non-significant . Pain invs. one in the group with a history of recurrent tonsillitis required readmission due to dehydration .Serious postoperative complications did not occur. There was no major postoperative hemorrhage in either group that required surgical attention. Hemorrhage was considered an early one if it occurred within the first 24 postoperative hours and late when bleeding occurred after 24 h. Mild, spontaneously subsiding hemorrhage occurred in four patients, equally divided between the groups. All cases of postoperative hemorrhage occurred after 24 h from the surgery. Five patients in the group without a history of recurrent tonsillitis Overall densities of nerve fibers found in the tonsillar capsules were low. PGP 9.5-immunoreactive fibers were more numerous than CGRP-positive fibers . CGRP fiExternal validity of the findings was confirmed by the fact that all the patients gave consent to participation ; the examined groups of patients were coherent in terms of age and lack of co-morbidities, and that they reflected the demographic and socioeconomic characteristics of the general population treated in a community-based hospital. Also, the surgical technique was the same in all the participants.The data from this study demonstrate that post-tonsillectomy pain intensity recorded after KTP laser tonsillectomy on postoperative days three and four in patients with no history of recurrent tonsillitis was significantly higher than in those in whom recurrent tonsillitis was the indication for surgery. Also, the readmission rate due to dehydration was higher in the former group. So far, evidence concerning effects of indications for the surgery on post-tonsillectomy pain has not been reported.Logically, postoperative pain in patients tonsillectomized due to recurrent tonsillitis should be more intense than in the other group, as dissection of the tonsils from the surrounding scarred tissues could be associated with greater intra-operative trauma. Therefore, while planning the study, it was decided to use laser instead of performing cold steel surgery, in order to eliminate potential influence of forceful dissection of the tonsils in this group of patients on the results of the study. Thus, it was possible to eliminate factors relating to the surgical procedure itself from the analysis of post-tonsillectomy outcomes. This study did not confirm more intense pain in the group of patients with recurrent tonsillitis in anamnesis, most probably because laser enables easy dissection of the tonsils from their beds.Significant differences in reported pain intensity were observed on the days when post-tonsillectomy pain in most patients was most aggravated.Since no differences were established between the examined groups on histological examination, the observation that pain experienced by patients with no history of recurrent tonsillitis was significantly more intense could be explained by the fact that the patients with a history of recurrent acute tonsillitis were more familiar with this kind of pharyngeal pain, and therefore tolerated it better.Densities and distribution of nerve fibers within the tonsillar capsule and lymphatic tissue differed between individuals and anatomical regions of the tonsil, and the distribution was dependent on the tissue intersection plane. Hence, considerable differences in densities of nerve fibers were found locally in various examined tonsils. However, the observed overall differences were statistically non-significant.The strengths of this study include direct comparison of statistically significant groups of participants operated for the same symptoms using the same technique and with long-term follow-up. Weaknesses include the fact that there could be other factors determining differences in postoperative pain perception, not accounted for in the current study. Determining these factors would foster future research in this field. In addition, the scales used for swallowing difficulty and postoperative wound healing was not validated, and therefore subject to bias.Several important conclusions can be drawn from this study. The results obtained will assist in preoperative counseling of patients undergoing tonsillectomy regarding possible postoperative pain intensity and establishing improved follow-up protocols. Based on the obtained results, prior to surgery detailed medical history is collected from all candidates for tonsillectomy. If a patient has no history of recurrent tonsillitis, she/he is informed about increased probability of intense postoperative pain a few days after tonsillectomy, and analgesic dosage adjustment is advocated. These patients are also advised to stay in hospital longer, until their aggravated swallowing difficulties subside, as they are at risk of re-admission due to dehydration.Patients qualified for tonsillectomy due to recurrent tonsillitis report lower pain intensity than those with other indications for the surgery. Postoperative pain intensity was unrelated to nerve fiber density.The authors declare no conflicts of interest.


IntroductionWith recent developments in postoperative pain management after total knee replacement (TKR), the continuous femoral nerve block is becoming a common practice. The purpose of this study was to compare a femoral nerve block with time-tested epidural analgesia in a tertiary care setup in a developing country.MethodologyA randomized control trial took place at Shifa International Hospital (SIH), Islamabad, Pakistan. Sixty patients, aged 40 to 90 years old, 12 males and 48 females, who were undergoing unilateral TKR for osteoarthritis in American Society of Anesthesiologists (ASA) physical status classes I and II, weighing between 50 and 99 kg, and fully able to understand and respond to the numeric rating scale (NRS) were included in the study. While patients belonging to ASA physical status class ≥3, with chronic opiate therapy, having allergies to local anesthetics or equipment material, or with neuromuscular disease, were excluded from the study. Ethical approval was obtained, and patients were divided into two groups, with group A given epidural and group B given a femoral nerve block for pain management postop. Data were collected. The pain was recorded using the NRS at six, 12, and 24 hours postop.ResultsThe results for six hours and 12 hours were found to be significant. Patients in group A had a lower NRS rating postop as compared to group B and required a lesser amount of additional boluses for pain management. ConclusionThe femoral nerve block is inferior to epidural analgesia for pain management after unilateral TKR in the first 24 hours, with a greater need for extra boluses to relieve pain. Total knee replacement (TKR) is a commonly performed procedure, with up to one million TKRs performed per year in the US. It is expected to increase to 3.5 million per year in 2030 . This prAnalgesic options after TKR include pre-emptive analgesia, local infiltration, systemic analgesics , epidural analgesia, nerve blocks, and multimodal approaches . Among aIn 2017, Vishwanatha and Kalappa compared continuous femoral nerve blockade (CFNB) with epidural analgesia for postoperative pain relief in knee surgeries . All theAt our facility, only epidural analgesia has been used for postoperative pain relief for bilateral as well as unilateral TKR. Inspired by the above-mentioned studies, we carried out a randomized controlled trial to compare the efficacy of continuous femoral nerve block with continuous epidural analgesia for postoperative pain relief in the first 24 hours.This study was a randomized control trial (RCT). The trial was started after the approval from the Ethical Board of Shifa International Hospital and was conducted at Shifa International Hospital. It was conducted over a period of six months. Patients, aged 40 to 90 years, scheduled for unilateral TKR for osteoarthritis, belonging to the American Society of Anesthesiologists (ASA) physical status classes I and II, weighing between 50 and 99 kg, and fully able to understand and respond to the NRS were included in the study [Patients were divided into two groups using consecutive random sampling. The patients in group A, the epidural group, received combined spinal-epidural anesthesia in the L3-L4 interspace in the lateral decubitus position with the operative site on the dependent side. For surgery, spinal anesthesia with 2 ml of 0.75% bupivacaine and 20 ug of fentanyl was used. The patients in group B, the femoral nerve block group, received intrathecal anesthesia with the same drugs in the lateral decubitus position with the operative site on the dependent side. After turning supine, an ultrasound-guided femoral nerve block catheter was passed under aseptic conditions on the operative side. Surgery was completed under intrathecal anesthesia. In the post-anesthesia care unit (PACU), infusion of bupivacaine 0.187 % was started in both groups at 8-10 ml/hour through epidural and femoral catheters. The patient received an injection of paracetamol 1000 mg intravenous every six hours, an injection of ketorolac 30 mg every eight hours, and a capsule of pregabalin 25 mg every 12 hours regularly during the postoperative period. Injection tramadol 50 mg was given for rescue to the patients only if the pain score exceeded 4 on NRS every six hours with 25 mg of injection Gravinate. The pain was assessed at six, 12, and 24 hours by a pain fellow on duty using NRS and documented on the proforma along with the total number of rescue tramadol.The results were averaged (mean ± standard deviation) for continuous data as mentioned in the results section. The Mann-Whitney U-test was applied to find out the significant difference between the two independent groups. In the entire above test, P-value < 0.05 was accepted as indicating statistical significance. Data analysis was carried out using Statistical Product and Service Solutions .A sample size of 62 patients was recruited in the current study. This was done to avoid any untoward dropout because of the coronavirus disease 2019 (COVID-19) pandemic. Two patients dropped out. One patient was diagnosed as COVID positive and the second patient had financial issues. So 60 patients were treated, with a minimum age of 42 and maximum age of 81. The mean age of the total participants was 62.82 ± 8.25. Patients were equally divided into two groups (group A and group B) by consecutive random sampling. Each group contained 30 patients. Forty-eight females and 12 males were recruited for this study.Intergroup analysis was carried out using the Mann-Whitney U-test (non-parametric) Table . The resThis study shows that a continuous femoral nerve block is inferior to epidural analgesia at six and 12 hours after unilateral TKR in terms of analgesia. The benefits of epidural analgesia and surgical outcomes have been well-documented in the literature. Nowadays, specific pathways of care, including enhanced recovery after surgery (ERAS), have been introduced. It has been proposed that these pathways, along with multimodal analgesia, have reduced the length of hospital stay (LOS) for patients undergoing TKR . PeripheHowever, this study failed to prove that a femoral nerve block is equivalent in analgesic efficacy to epidural analgesia . This is fairly understandable when we look at the nerve supply of the knee joint. Innervation of the knee is complex, with contributions from both the lumbar and sacral plexuses. It follows Hilton's law, i.e. nerves supplying the muscles around a joint supply the joint as well . This meHowever, as the level of significance was set at 80%, the sample size was small. This limits the results of the study. Second, five patients in the femoral nerve block group were excluded from the study, further reducing the sample size. Third, operator expertise with an ultrasound-guided femoral nerve block can be a limitation of the study.This study shows that a femoral nerve block is inferior in efficacy to epidural analgesia for postoperative pain relief after unilateral TKR. The femoral nerve block leads to higher pain scores and greater opioid requirements postoperatively. Further research is needed to investigate whether combining it with sciatic nerve block or patient-controlled analgesia (PCA) morphine can improve pain scores or not. Until then, epidural analgesia should be continued as a routine postoperative pain management tool after unilateral TKR.


Low-back pain (LBP) is a major public health problem globally and its direct and indirect healthcare costs are growing rapidly. Virtual reality involving the use of video games or non-game applications are alternatives to conventional face-to-face physical therapy for LBP. The purpose of this study was to assess the cost-effectiveness of Back Extension-Virtual Reality Game (BE-VRG) compared to Clinic-based McKenzie therapy (CBMT) for chronic non-specific LBP in Nigeria.Patients with chronic non-specific LBP were randomised into either BE-VRG or CBMT group. Patients’ level of disability was assessed using Oswestry Disability Index (ODI) at week 4 and week 8. ODI was mapped to SF-6D to generate quality adjusted life years (QALYs) used for cost-effectiveness analysis. Resource use and costs were assessed based on rehabilitation services from a healthcare perspective. Cost-effectiveness analysis which included direct healthcare costs was conducted. Incremental cost per QALY was also calculated.n = 22; CBMT, n = 24) with the mean (±SD) age of 32.6 ± (11.5) years for BE-VRG and 48.8 ± (10.2) years for CBMT intervention completed in this study. The mean direct health costs per patient were USD100.67 and USD106.3 for BE-VRG and CBMT, respectively. The mean quality adjusted life years at week 4 and week 8 were ; CBMT, 0.0548 ± (0.002)); and ; CBMT; 0.114 ± (0.004)), respectively. Incremental cost-effectiveness ratio showed that BE-VRG arm was less costly and more effective than CBMT.Forty-six patients (BE-VRG, The findings of this study suggest that BE-VRG was cost saving for chronic non-specific LBP compared to CBMT. This evidence could guide policy makers, payers and clinicians in evaluating BE-VRG as a treatment option for people with chronic non-specific LBP. LBP is a major public health problem globally and typically classified as being specific or nonspecific. Nonspecific LBP refers to pain with unknown origin. In 2017, LBP was responsible for 577 million affected people and 64.9 million years lived with worldwide. In 2019, the personal and societal impact of LBP in the Netherlands were €4875 and €4315 per patient, respectively. Parallel to this, in 2004 indirect cost of US$ 7,400,000,000 due to LBP was spent at national level in United States of America. Musculoskeletal problems with complaints of back pain were also one in seven of all the recorded consultations in the United Kingdom in 2006. Therefore, LBP is not only a health problem but also a socioeconomic problem.Chronic low-back pain (LBP) is pain in the lower back persisting for at least 12 weeks. Non-surgical and non-pharmacological therapies such as physiotherapy interventions are the most widely used type of management strategies for LBP. Indeed, exercise therapy is arguably the cheapest physiotherapeutic intervention and one in which the patient has some measure of direct control. However, it remains inconclusive which type of exercise is better than the other, leading to a proliferation of exercise programmes with limited evidence on their effectiveness and cost-effectiveness. In some Western nations, one of the most frequently used and effective type of physiotherapy for patients with long-term LBP is the McKenzie exercise. A recent systematic review on the effectiveness of the McKenzie method in the management of patients with chronic low back pain reported that the McKenzie method is a successful treatment to reduce pain in the short term and in enhancing function in the long term. The implementation of McKenzie exercise may have some limitation in remote areas due to the lack of specialized training of patients to help themselves in their own time.14 Further, there is a scarcity of health services in the rural areas of Africa.16 The problem of distance and time to receive healthcare can be solved by using telerehabilitation. Telerehabilitation, a mobile phone based application, used to treat LBP patients. In addition to mobile phones patients with LBP could also use a virtual reality game (VRG). It involves the use of video games or non-game applications.A range of management strategies are recommended for LBP including surgery, pharmacological and non-pharmacological therapies. The failure to investigate the cost-effectiveness of BE-VRG may limit its potential in the management of LBP. Therefore, this study examined the cost-effectiveness of BE-VRG compared to a conventional face-to-face intervention for chronic non-specific LBP.Evidence suggests that Back Extension-Virtual Reality Game (BE-VRG) is comparable with the McKenzie extension therapy in its effect on pain and pain-related characteristics, disability and quality of life. a block size of four was chosen for this study. Computer-generated block permutations for four blocks of two group /((2!)(2!)) yielded 24 permutation . The process of drawing block permuted sequence and randomisation was repeated as participants were recruited. Single blind approach where only the researchers know whether a patient was receiving conventional treatment or the new one, in order to reduce bias.This study utilised a randomised controlled trial design. Patients were randomised into the experimental group received the BE-VRG. Whereas, the control group received the Clinic-Based Mckenzie Therapy (CBMT). In order to ensure equal-sized treatment groups, random permuted blocks was used,Ethical approval for the study was obtained from the Health Research Ethics Committee of the Institute of Public Health, Obafemi Awolowo University, Ile-Ife, Nigeria (IPHOAU/12/885). Informed consent was obtained from all participants following full disclosure of the objective of the study. The calculator uses the n = (Zα/2+Zβ)2 *2*σ2/d2, where Zα/2 is the critical value of the Normal distribution at α/2 , Zβ is the critical value of the Normal distribution at β , σ2 is the population variance and d is the difference to be detected. Therefore, using a confidence level of 95%, power of 80%, population variance of 100 and a difference of 5, therefore n = 16 per group. Accounting for 20% possible attrition, approximately 20 participants per group will be required (N = 40). A total of 72 patients were assessed for eligibility in this study. 57 of them were found eligible and then randomized into both groups. However, only 46 of the eligible participants completed the study. Treatment discontinuation in both groups were mainly due to lack of interest, especially due to noticeable improvement in patients’ conditions.Participants with chronic non-specific LBP were recruited from selected physiotherapy facilities, namely: Obafemi Awolowo University (OAU) Teaching Hospital, Ile Ife, Nigeria (OAUTHC); Department of Medical Rehabilitation, OAU and Ladoke Akintola University of Technology Teaching Hospital, Osogbo, Nigeria. The sample size for the study was based on a statistical calculation comparing two means – sample size. In order to ensure homogeneity of samples, patients who demonstrated Directional Preference (DP) for extension only were recruited. DP is described as the posture or movement that reduces or centralises radiating pain that originates from the spine. DP is important for the derangement group of patients with mechanical LBP.22 Patients with DP for flexion, positive history of red flags indicative of serious spinal pathology; any obvious spinal deformity or neurological disease; pregnancy; previous spinal surgery; and previous experience of MDT extension protocol, as well as, those with underlying systemic or visceral disease and specific condition such as dementia, cognitive dysfunction, visual impairment and previous history of epilepsy were excluded.Eligible participants for this study were patients with LBP of not less than 3 months. The standard McKenzie Institute Lumbar Spine Assessment Algorithm was used to determine eligibility criteria to participate in the study.Each intervention comprised of warm up and the cool down phases. These phases involved a low intensity active stretching of the upper extremities, as well as the low back for about 5 min. The stretching exercises were carried out in a top-to-bottom sequence involving overhead triceps and arm-cross-chest stretch, forearm flexion and extension contraction and torso twist stretch performed in routine in a balanced standing position. Thereafter, the interventions were carried out by the participants in both groups.The BE-VRG is an interactive video game which involves a less invasive three dimensional graphic environment on computer/television screen. The BE-VRG was developed and built into a Microsoft’s Kinect platform as virtual reality tasks. The choice and design of the tasks in the BE-VRG was based on the intention to achieve therapeutic activities that is comparable with the McKenzie ‘extension in standing’ protocol, as well as, the relevance of the tasks in rehabilitation of the patient. Participants in the BE-VRG group carried out the activities in an upright standing position with the feet slightly apart, while holding the waist with both hands. Then, they were asked to head virtual balls seen on the screen as though coming towards them, while their feet were stationary but the trunk and head moves to accomplish heading of the ball. The trajectory of the balls was set in such a way that it elicited the required therapeutic movements. The main therapeutic movement that was intended is trunk extension while standing. However, side-glide of the spine to the left and also to the right were accompanied movements during the tasks. This BE-VRG was designed to provide a progression of increasingly difficult challenges that can help keep the players (participants) engaged and motivated over extended period of time. During game play, visual and textual feedback on the patient’s performance and results were displayed on the screen. Then, the participant was asked to stretched the trunk backwards at the waist level as far as he/she could, using the hands as a fulcrum while keeping the knees straight. The protocol involves a course of specific lumbosacral repeated movements in extension that cause the symptoms to centralize, decrease or abolish. While the McKenzie extension protocol have different starting positions, however, in order to ensure comparability in orientation with the BE-VRG, the CBMT in this study was delimited to the standing position. The movement was repeated up to 10 times. Both interventions were carried out thrice weekly for 8weeks. Both groups received a set of back care education instructions comprising a 9-item instructional guide on standing, sitting, lifting and other activities of daily living for home.Participants in the CBMT group received the McKenzie ‘extension in standing’ protocol. The protocol required that a participant stand upright with the feet slightly apart while placing his/her hands in the small of the back with the fingers pointing backwards. The tool covers 10 items including pain intensity, personal care, lifting, walking, sitting, standing, sleeping, sex life, social life and travelling. Each item scores from 0 (better) to 5 (worse). The ODI score was recorded for each participant and it was transferred in to a 0 to 100 scale. In order to estimate the health related quality of life of each participant to be used in economic evaluations of the interventions, the ODI score was mapped to SF-6D as described by Carreon and colleagues.All baseline data and measurements were recorded for each participant before and after randomisation. In addition, information such as age, gender, educational level, occupation, marital status, onset of back pain, recurrence, duration of complaint and previous intervention were recorded for each participant. Treatment health outcomes were assessed at the end of fourth and eighth week of the study. Oswestry Disability Index (ODI) was used to examine level of disability of the participants due from LBP.The SF-6D instrument was used to provide estimation of utility using data from ODI, and this has enabled the researchers to perform a cost-utility analysis (CUA) . CUA could be used to determine the cost in terms of utilities, and it combines the quantity and quality life. After obtaining the SF-6D values of each participant, the quality adjusted life year (QALY) of each participants was calculated. QALY was calculated by multiplying the SF-6D values and the duration of time (years). For the purpose of this study, the average of QALYs at 4 weeks and 8 weeks period of each participant was considered.Healthcare resource use and costs were assessed from the health system perspective. The direct healthcare resources for implementing the BE-VRG and CBMT were: back treatment, consultation, development of Microsoft connect device and flat screen monitor, development of BE-VRG, refreshment and consumables. Costs were measured in Nigerian Naira and US$ using the 2021 currency conversion rate (US$1 = ₦367). Patient participants were the sources of all the healthcare resource uses included for this study. These resources were documented from McKenzie therapy protocols. Personal costs associated with CBMT was not included in this analysis. As the patients were those attending outpatient physiotherapy departments, cost of medications were not included in this study. Moreover, in the context of this study, most of the participants were able to access healthcare through out-of-pocket means, in addition to undisclosed self-medication practices that is often encouraged by over the counter access to more than the regulated medications. Productivity lost by the patient was not quantified. Costs are reported to the nearest Nigerian Naira and US$.p = .05 was adopted for those comparisons. Incremental cost-effectiveness ratio (ICER) was used to assess the cost-effectiveness of TBMT compared to CBMT using the formula below.Descriptive statistics of the mean or standard deviation and inferential data analysis were performed using the Statistical Package for the Social Sciences for Windows (version 23). Mann–Whitney U test and Friedman tests were used to compare the mean effects between the treatment regimen across the fourth- and eighth-week period and the changes of the effects of the interventions from baseline at the fourth week and eighth week for the categorical variables, respectively. A significance level of  The numerator in the cost-effectiveness ratio is the monetary cost of the TBMT intervention minus the monetary cost of CBMT. The annual costs of the projects were calculated by converting the 8 weeks costs, the time period used for implementation. The denominator is the QALY gained by BE-VRG minus the QALY gained by CBMT. Bootstrapping was used for pair wise comparison for the mean costs and effects between the BE-VRG and CBMT groups. Confidence intervals for the mean differences in effects were obtained by bootstrapping (1000 replications). The bootstrapped costs and effects pairs were also graphically represented on a cost effectiveness plane.The incremental cost-effectiveness ratio is the differential costs and outcomes between new intervention (BE-VRG) and the control (CBMT).n = 22; CBMT, n = 24) with the mean (±SD) age of 47.62 ± (11.5) years for BE-VRG and 48.8± (10.2) years for CBMT intervention completed in this study. A total of five and six participants in the CBMT and BE-VRG, respectively, have discontinued with the interventions  at baseline, week 4 and week 8. Over the 8 weeks period, there was an indication that functional disability of participants has improved in the two arms.N1,000 (US$2.78) per visit, and transportation and refreshments for each clinic visit estimate was ₦500 (US$1.39) per visit. The total costs estimate for the development VRG and purchase of Microsoft connect device and flat screen monitor were US$1018 and US$971.00, respectively. Moreover, the common costs to both groups were costs of physiotherapy consultation (before randomisation into group), and were estimated ₦1000.00 (US$2.78). Patients allocated to the BE-VRG group had slightly lower costs than CBMT.We estimated the mean direct cost of the BE-VRG and CBMT over the 8 weeks period of time . A totalp = .003). The ICER values indicate that the healthcare costs and QALY favoured the BE-VRG. In other words, BE-VRG had lower costs and better patient outcomes compared to CBMT and the calculation of the ICER is inappropriate as it can be misleading.To our knowledge, this is the first economic evaluation of BE-VRG interventions for chronic LBP. Compared to the CBMT, the BE-VRG lead to the reduced healthcare costs and increase in QALYs for patients with chronic LBP. We estimated the incremental cost effectiveness ratio to be dominant. However, it is important to note that adherence of patients to the treatment for better outcomes and or much shorter contact times are the factors that might have contributed to the cost-effectiveness of BE-VRG compared with CBMT.p < .05) in the scores of ODI between BE-VRG and CBMT at baseline, weeks 4 and weeks 8. A meta-analysis of randomised controlled trials have also indicated that the McKenzie method and video games are more effective than passive therapy showed a statistically significant difference in pain and disability.30 Further, a moderate evidence for the reduction of pain and functional impairment was found in patients with acute pain when video-based virtual reality system was used as an adjunct therapy. However, these studies have emphasised that there was limited evidence within the included studies for adherence and effectiveness specifically in the long-term trials.This study showed that there was a significant difference  to the extension movement would give added effects and in turn influence outcomes in the BE-VRG group. This is because the gliding movements are also important therapeutically. McKenzie describes side-gliding as the simultaneous combination of lumbar rotation and side-bending. This movement is thought to produce relief of pain among patients with LBP. Lastly, the McKenzie extension in standing’ is one of the most common therapies utilised by physical therapists in active rehabilitation of patients with LBP in the clinical settings, as well as in self-care prescriptions for home programmes. Also, most therapeutic games are typically carried out in the ‘standing’ fundamental position. Thus, comparing the outcome of the BE-VRG utilized in this study should be delimited to findings of studies that employed the McKenzie ‘extension is standing’ only. Overall, there is a considerable potential for more research to be considered in the future in the longer term and from societal and patient perspective as healthcare is largely out of pocket in LMIC, and LBP is hugely associated with productivity loss.In the current study, the cost-effectiveness analysis is largely supportive of the BE-VRG intervention given the current evidence and compared to CBMT alternative. This is because of the BE-VRG intervention was both more effective at producing health benefits than the CBMT and were associated with net cost savings. However, there are a number of limitations to this study. Firstly, the adoption of health system perspective in this study have excluded patients’ time and personal costs and loss of production due to treatment and poor health. The authors believe that the cost-effectiveness of the intervention could have been different if societal perspective was used. Secondly, the imbalance between groups at baseline in function as measured with ODI could be by chance due to the characteristics of the patients.The findings of this study suggest that VRG was cost saving in the management of chronic non-specific LBP compared to CBMT from healthcare perspective. This evidence could guide policy makers, payers and clinicians to consider BE-VRG for people with chronic non-specific LBP as it seems to improve health related quality of life at lower costs. The findings can also provide support for the global health initiative of improving access to physiotherapy interventions for patients with LBP in low and middle-income countries.


Fatigue and lymphatic pain are the most common and debilitating long-termadverse effects of breast cancer treatment. Fatigue and pain independentlyhave negative effects on quality of life, physical functions, and cancerrecurrence-free survival. The interactions between fatigue and pain mayaggravate their negative effects.Examine the effects of co-occurring fatigue and lymphatic pain on activitiesof daily living (ADLs), emotional distress, and overall health of breastcancer patients.A cross-sectional and observational design was used to enroll 354 breastcancer patients. Valid and reliable instruments were used to assess fatigue,lymphatic pain, ADLs, emotional distress, and overall health. Descriptivestatistics and multivariable regression models were used for dataanalysis.P < .001) andemotional distress  compared to patients with only fatigue andonly lymphatic pain. Patients with co-occurring fatigue and lymphatic painhad 179% increase in impaired ADL scores  and 211% increase in emotional distress scores compared to those withoutco-occurring fatigue and lymphatic pain. Patients with co-occurring fatigueand lymphatic pain had a 34% decrease  and patients with only fatigue had a 33% decreasein overall health scores , indicating poor overall health.After controlling for demographic and clinical factors, patients withco-occurring fatigue and lymphatic pain had higher odds of having impairedADLs (OR = 24.43, CI = [5.44-109.67], Fatigue and lymphatic pain affected 66.4% of breast cancer patients. Findingsfrom this study suggest that co-occurring fatigue and lymphatic pain havenegative effects on breast cancer patients’ ADLs, emotional distress, andoverall health. The synergistic interactions between fatigue and lymphaticpain incrementally aggravated their negative effects on ADLs and emotionaldistress. Findings of the study highlight the need to evaluate theunderlying mechanisms for co-occurring fatigue and lymphatic pain anddevelop interventions that target both fatigue and lymphatic pain to improvebreast cancer patients’ the quality of life. Fatigue andlymphatic pain are the most common and debilitating long-term adverse effects thatnegatively impact patients’ quality of life (QOL) as well as cancer recurrence-freesurvival.26 Compared to other types ofcancer, patients treated for breast cancer have more lost disability-adjusted life years. Persistent fatigue and lymphatic pain may be 2 of the adverse effects thatcontribute to lost disability-adjusted life years in these patients.6With advances in diagnosis and treatments for breast cancer, the 5-year survival ratefor these patients has increased up to 90%.78 While fatigue usually subsidesafter the completion of treatment, more than 40% of patients experience persistentfatigue even years after the completion of cancer treatment. Lymphatic pain is defined as a variety of pain sensations  in the ipsilateral upper limb or body due to an accumulation of lymphfluid from a compromised lymphatic system after cancer treatment.46 Lymphatic pain occurs mostcommon in patients with a diagnosis of lymphedema, however, more than 50% of patients without a diagnosis of lymphedema alsoreport lymphatic pain.11 Lymphedema is defined as an increased limb size or girth in theipsilateral upper limb.11 For patients without a diagnosis of lymphedema, the experienceof lymphatic pain indicates an early stage of lymphedema because lymphatic painoften precedes changes in limb size or girth and a lymphedema diagnosis.11 Patients who report pain onthe affected ipsilateral upper limb or body are nearly twice as likely to develop lymphedema. Risk factors for fatigue and lymphatic pain are similar, includingdemographic characteristics  and clinical characteristics .In addition, fatigue and lymphatic pain are inflammatory conditions9 and both are the most commonand debilitating long-term adverse effects after cancer treatment.26 It is important to investigateif these 2 adverse symptoms occur concurrently.Cancer-related fatigue is defined as a sense of physical, emotional, and/or cognitivetiredness or exhaustion that is not proportional to recent activity and interfereswith usual functioning due to cancer or cancer treatment.14 and pain had negative effects on physical activity, QOL, and survival. However, nostudies have examined the effects of co-occurring fatigue and lymphatic pain onactivities of daily living (ADLs), emotional distress, and overall health of breastcancer patients. The interaction between fatigue and pain may aggravate poor healthconditions, negative emotions, decreased physical function, and even multi-organ toxicity. Therefore, the purpose of this study was to investigate the effects ofco-occurring fatigue and lymphatic pain on ADLs, emotional distress, and overallhealth of breast cancer patients. We hypothesized that co-occurring fatigue andlymphatic pain would have incremental negative effects on patients’ ADLs, emotionaldistress, and overall health.While breast cancer patients report the co-occurrence of fatigue and pain, moststudies have investigated each symptom separately. Across these studies,fatigueThis analysis is part of a larger study (IRB s16-01665) approved by theInstitutional Review Board of New York University (NYU) Langone Health, in NewYork City of the United States. The protection of human subjects was ensured byfollowing the guidelines set forth by the Institutional Review Board. Writteninformed consent was obtained from each patient.A cross-sectional and observational design was used.This study was conducted in a nursing research laboratory located in the breastcancer clinic of NYU Perlmutter Cancer Center, a National Cancer Institutedesignated Cancer Center in New York City, United States.The sample consisted of female patients (n = 354) who were older than 21 years ofage; had completed acute treatment  forbreast cancer greater than 3 months before enrollment; and had no signs ofmetastatic disease or recurrence. Women were excluded if they had: (a) renal orheart failure, cardiac pacemaker or defibrillator, artificial limbs, or werepregnant because accurate measurement of body mass index (BMI) may not bepossible with an impedance device, and/or (b) known metastatic disease,recurrence of cancer, or lymphedema due to cancer recurrence, or being diagnosedwith and treated for lymphedema, or other bulk disease in the thoracic orcervical regions. Of the 356 patients enrolled, 2 were excluded from this dataanalysis due to incomplete data.Demographic data included: age, education, marital status, employment status,and ethnicity. Medical records were reviewed to obtain information on:breast cancer diagnosis, stage of the disease, cancer location, type ofsurgery (mastectomy versus lumpectomy), lymph node procedures , type of adjuvanttherapy (radiation and chemotherapy), and years since breast cancerdiagnosis.18 The SF-36-VS has goodvalidity and reliability in patients with cancer.20 The subscale assessesfatigue in terms of how much of the time during the past 4 weeks patientshave felt full of life, full of energy, felt worn out, or felt tired.Responses are scored on a 0 to 100 scale, with higher scores indicating lessfatigue. Scores of ≤ 50 have been established as a marker for clinicallymeaningful fatigue.The 4-item Vitality Subscale of the 36-Item Short Form Health Survey(SF-36-VS) was used to assess fatigue. We operationalized lymphatic pain as the self-report of co-occurringpain sensations  and swelling in the affectedipsilateral upper limb. Lymphatic pain was assessed using The BreastCancer and Lymphedema Symptom Experience Index (BCLE-SEI) PartI.22 This valid and reliable self-report instrument hasa Cronbach’s alpha of 0.92 for symptom occurrence. A response frame of thepast three months was used to ensure that the symptoms were persistent. Eachitem was rated on a 5-point Likert scale . Higher scores indicatemore severe lymphatic pain.Lymphatic pain was defined as the co-occurrence of pain and swelling in theaffected ipsilateral upper limb following breast cancer treatment.BCLE-SEI Part II was used in thisstudy.2123 The ADLs subscale assesses self-reported difficulty inperforming thirteen ADLs, . Each item was rated on a 5-pointLikert scale . Patients were asked to indicate if a particularactivity did not apply to them . Scores were summed to a possibletotal of 52 with higher scores indicating higher impairment in ADLs. The13-item ADLs subscale has a Cronbach’s alpha of 0.94.The ADLs subscale from BCLE-SEI Part IIwas used in this study.22 This 12-item subscaleassesses emotional distress . Emotional distressencompasses being frustrated, sad, guilt/self-blame, worried, irritable,fear, angry, lonely, helpless, hopeless, anxious, and depressed. Each itemwas rated on a 5-point Likert scale . Scores were summed to a possible total of48 with higher scores indicating higher levels of emotional distress.Cronbach’s alpha for the emotional distress subscale was 0.91.The emotional distress subscale from the 24 This subscale includes 1 item that asks patients torate their overall general health from 1 (poor) to 5 (excellent) and 4additional questions that ask patients to rate whether they get sick easierthan other people, are as healthy as other people, are expecting health toworsen, and have excellent health on a scale of 1 (definitely true) to 5. Raw scores were converted to a standardized score thatranged from 0 to 100 based on the instructions in the SF-36 manual. Thehigher overall health scores indicate better overall health.The General Health Subscale of the SF-36 was used to assess overallhealth.2).Height was measured without shoes to the nearest 0.1 cm using a digitalstadiometer . A stand-onbioimpedance analysis (BIA) device  was used to measure weight without shoes to the nearest0.05 kilograms (kg). This device automatically calculated BMI within 2 hours prior to their appointment.Data were analyzed using Stata 16 SE .For this study, 4 symptom groups were created: Group 1: no symptoms ; Group 2:only lymphatic pain ; Group 3: only fatigue; and Group 4:co-occurring fatigue and lymphatic pain .Medians and interquartile ranges (IQR) were calculated for continuous variablesand frequencies for categorical variables. Group differences in demographic andclinical characteristics were evaluated using Kruskal–Wallis and Chi-Squaretests, with Holm-adjusted Chi-square and Dunn’s post hoc analyses for pairwisecomparisons. The first part of the models used a multivariable logistic regression topredict the likelihood of a non-zero  versus a zero  on theoutcome variables of ADLs and emotional distress. The second part of the modelsused ordinary least squares (OLS) regression to predict the magnitude of theeffects of the symptoms within patients who reported a non-zero value . For the outcome of overall health,OLS regression was used because no zero inflation was found.To examine the effects of co-occurring fatigue and lymphatic pain on ADLs andemotional distress, 2-part multivariable regression models were used because ofthe zero inflation of the outcome variables .16 The demographic covariates were: age, BMI, ethnicity,marital status, level of education, and employment status. The clinicalcovariates included type of cancer surgery (mastectomy versus lumpectomy), typeof lymph node procedure , number of lymph nodes removed, receipt of radiation and/orchemotherapy, and years since breast cancer diagnosis. All the tests wereconducted at 0.05 alpha level and 95% confidence interval (CI).Potential confounders included in the regression analyses were demographic andclinical characteristics that are associated with fatigue and chronic cancerpain.As shown in Z = 7.12, P < .001) and the no symptoms groups. No significant difference in SF-36-VSscores were found between the only fatigue group and the co-occurring fatigueand lymphatic pain group , indicating thatpatients in both groups experienced comparable severity of fatigue. The nosymptoms and only lymphatic pain groups had SF-36-VS scores >50, indicatingno fatigue.Of the 354 patients, 16.1% had co-occurring fatigue and lymphatic pain, 44.6% hadonly lymphatic pain, 5.6% had only fatigue, and 33.6% had neither fatigue norlymphatic pain. The only fatigue group had lowest SF-36-VS scores , compared to the co-occurringfatigue and lymphatic pain group , the onlylymphatic pain , onlyfatigue  groups.The median lymphatic pain score of the total patient sample was 4 . Patients in the co-occurring fatigue and lymphatic pain group had significantly higher lymphatic painscores compared to patients in the only lymphatic pain  and nosymptoms  groups. Patients with co-occurring fatigue andlymphatic pain  and patients with onlylymphatic pain  had higher BMI than thosein the no symptoms group . Patientswith co-occurring fatigue and lymphatic pain were closer to their breast cancerdiagnosis  thanpatients with no symptoms .Patients with co-occurring fatigue and lymphatic pain were younger  than those in only fatigue  and onlyfatigue  groups. 2(18) = 71.03, P < .001)showed that patients in the co-occurring fatigue and lymphatic pain group hadhigher odds  ofhaving impaired ADLs than patients in only lymphatic pain group . Patients in the only fatiguegroup had no significant risk of having impaired ADLs. In terms of magnitude ofthe effect of the symptoms on ADLs, patients with co-occurring fatigue andlymphatic pain had an overall 179% increase in the ADLs scores  compared to patients with nosymptoms . Both beingnon-white  and having a higher BMI  were associated with more impaired ADLs. The adjusted modelexplained 22% of the variance in ADL scores .As shown in Z = 4.10, P < .001) and only lymphaticpain  groups. 2(18) = 142.85, P < .001)demonstrated that patients with co-occurring fatigue and lymphatic pain had thehighest odds of having emotional distress , followed by those with only lymphatic pain. Younger age, having axillarylymph node dissection , and having more lymph nodes removed  were associated with higheremotional distress. In terms of magnitude of the effect of the symptoms onemotional distress, patients with co-occurring fatigue and lymphatic pain had anoverall 211% increase in emotional distress scores compared to patients with no symptoms .The adjusted model explained 23% of the variance in emotional distress scores.As shown in As shown in F [18.335] = 8.06, P < .001;R2 = .30).CI = [−10.06 to −1.51]) were significant predictors of lower overall healthscores. Other significant predictors of overall health included BMI (B = −0.73),having a mastectomy (B = −10.11), and having a lumpectomy (B = −11.55). Theadjusted model explained 30% of the variance in overall health scores, co-occurring fatigue and lymphatic pain (16.1%),or only fatigue (5.6%). Consistent with prior studies that observed thatapproximately 20% of women reported fatigue and 61% reported lymphaticpain,27 Our study is the first to demonstrate the incremental negativeeffects of co-occurring fatigue and lymphatic pain on ADLs among patients without adiagnosis of lymphedema. This finding extends recent work on the negative effects ofincreased limb volumes on ADLs as well as prior studies showing that chronic pain and lymphedema arepredictors of impaired physical function.28 It should be noted that theexperience of only lymphatic pain and co-occurring fatigue and lymphatic pain weresignificant predictors for impaired ADLs while the experience of only fatigue wasnot. These findings support our hypothesis that co-occurring fatigue and lymphaticpain have incremental negative effects on impaired ADLs. As a significant riskfactor for impairments in ADLs, higher BMI can be modified through lifestylechanges. Because obesity, lymphatic pain, and fatigue are inflammatoryconditions,2628 futureresearch should explore the interactions among these conditions and their underlyingmechanisms. This knowledge will provide directions for interventions for fatigue andlymphatic pain.Previous research found that traditional measures of ADLs  were less relevant to breast cancer patients in terms ofphysical function. Previous studies found that younger age, more extended disease, more extendedsurgery, receipt of chemotherapy, poor body image, presence of lymphedema, pain andimpaired mobility were risk factors for emotional distress in breast cancerpatients.2934 In addition, worst painseverity profiles were associated with significant stress and multiple co-occurring symptoms. Our study focused on the emotional distress associated with co-occurringsymptoms defined as the negative emotions or feelings evoked by an individual’sexperience of symptoms.22 Findings from our study demonstrated the incremental negativeeffects of co-occurring fatigue and lymphatic pain on emotional distress. It shouldbe noted that the experience of only lymphatic pain and co-occurring fatigue andlymphatic pain were significant predictors of emotional distress while theexperience of only fatigue was not. These findings support our hypothesis thatco-occurring fatigue and lymphatic pain have incremental negative effects onemotional distress in breast cancer patients.Approximately 20% to 40% of breast cancer patients reported negative emotions.1315 It should be noted that amongthe 4 symptom groups, the patients with co-occurring fatigue and lymphatic pain hadworst lymphatic pain. Interestingly, patients in the only fatigue groups had minimalpain. The incremental effects of co-occurring fatigue and lymphatic pain may be theresult of synergistic interactions between the 2 symptoms. As both fatigue and lymphatic pain are associated with increases ininflammatory responses,27 future research should investigate physiological interactionsbetween these 2 symptoms. Different from our hypothesis, our study found comparablenegative effects of only fatigue and co-occurring fatigue and lymphatic pain onoverall health. Both groups had comparably poorer overall health.By providing initial evidence that co-occurring fatigue and lymphatic pain haveincremental negative effects on breast cancer patients’ ADLs and emotional distress,our study extends previous research that each symptom has negative effect onphysical activity, QOL, and survival.21 The primary outcome of this study was to investigate theadditive effect of fatigue and lymphatic pain on ADLs and emotional distress inbreast cancer survivors and not to identify the tumor and treatment-relatedpredictors of these symptoms. For this reason, we did not extractclinicopathological and detailed cancer treatment data from participant recordsto include in the analyses. Nonetheless, further consideration of tumor-specificfeatures and treatment modalities could further identify those at risk fordeveloping lymphatic pain, fatigue or both in future studies.The cross-sectional study design prevents an evaluation of changes over time infatigue and lymphatic pain and symptom group memberships. Nevertheless, thisstudy is the first to provide initial evidence of negative effects ofco-occurring fatigue and lymphatic pain on ADLs, emotional distress, and overallhealth. A strength of the study is the use of a valid and reliable instrumentsto evaluate symptoms, allowing for precision classification of fatigue andlymphatic pain. The breast cancer specific measures of ADLs is another strengthof this study.15 Our findings extended existing knowledge and suggest thatfatigue and lymphatic pain exerted negative effects on patients’ ADLs, emotionaldistress, and overall health. Our findings provide the initial evidence that thesynergistic interactions between fatigue and lymphatic pain incrementally aggravatethe negative effects on ADLs and emotional distress. In clinical practice andresearch, fatigue and lymphatic pain as well as their impact are usually assessed asseparate phenomena. Findings of the study highlight the need to investigate themechanisms that underlie the co-occurring fatigue and lymphatic pain to developinterventions that target both symptoms. Findings of our study also illuminate theneed to conduct assessment on both fatigue and lymphatic pain as well as theirimpact as part of routine clinical practice and make appropriate referrals  to improve breastcancer patients’ QOL and decrease years lost due to disability.Findings from this study support previous work that fatigue and lymphatic painaffected many breast cancer patients and impact patients’ QOL, physical functions,and survival.