Study protocol of cost-effectiveness and cost-utility of a biopsychosocial multidisciplinary intervention in the evolution of non-specific sub-acute low back pain in the working population: cluster randomised trial.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain (LBP), with high incidence and prevalence rate, is one of the most common reasons to consult the health system and is responsible for a significant amount of sick leave, leading to high health and social costs. The objective of the study is to assess the cost-effectiveness and cost-utility analysis of a multidisciplinary biopsychosocial educational group intervention (MBEGI) of non-specific sub-acute LBP in comparison with the usual care in the working population recruited in primary healthcare centres. Methods/design: The study design is a cost-effectiveness and cost-utility analysis of a MBEGI in comparison with the usual care of non-specific sub-acute LBP.Measures on effectiveness and costs of both interventions will be obtained from a cluster randomised controlled clinical trial carried out in 38 Catalan primary health care centres, enrolling 932 patients between 18 and 65 years old with a diagnosis of non-specific sub-acute LBP. Effectiveness measures are: pharmaceutical treatments, work sick leave (% and duration in days), Roland Morris disability, McGill pain intensity, Fear Avoidance Beliefs (FAB) and Golberg Questionnaires. Utility measures will be calculated from the SF-12. The analysis will be performed from a social perspective. The temporal horizon is at 3 months (change to chronic LBP) and 12 months (evaluate the outcomes at long term. Assessment of outcomes will be blinded and will follow the intention-to-treat principle. Discussion: We hope to demonstrate the cost-effectiveness and cost-utility of MBEGI, see an improvement in the patients' quality of life, achieve a reduction in the duration of episodes and the chronicity of non-specific low back pain, and be able to report a decrease in the social costs. If the intervention is cost-effectiveness and cost-utility, it could be applied to Primary Health Care Centres. Trial registration: ISRCTN: ISRCTN5871969

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box–binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)–mediated increase in Lgr5+ and Olfm4+ ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)–related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors

Study protocol of effectiveness of a biopsychosocial multidisciplinary intervention in the evolution of non-speficic sub-acute low back pain in the working population : cluster randomised trial

Background: Non-specific low back pain is a common cause for consultation with the general practitioner, generating increased health and social costs. This study will analyse the effectiveness of a multidisciplinary intervention to reduce disability, severity of pain, anxiety and depression, to improve quality of life and to reduce the incidence of chronic low back pain in the working population with non-specific low back pain, compared to usual clinical care. Methods/Design: A Cluster randomised clinical trial will be conducted in 38 Primary Health Care Centres located in Barcelona, Spain and its surrounding areas. The centres are randomly allocated to the multidisciplinary intervention or to usual clinical care. Patients between 18 and 65 years old (n = 932; 466 per arm) and with a diagnostic of a non-specific sub-acute low back pain are included. Patients in the intervention group are receiving the recommendations of clinical practice guidelines, in addition to a biopsychosocial multidisciplinary intervention consisting of group educational sessions lasting a total of 10 hours. The main outcome is change in the score in the Roland Morris disability questionnaire at three months after onset of pain. Other outcomes are severity of pain, quality of life, duration of current non-specific low back pain episode, work sick leave and duration, Fear Avoidance Beliefs and Goldberg Questionnaires. Outcomes will be assessed at baseline, 3, 6 and 12 months. Analysis will be by intention to treat. The intervention effect will be assessed through the standard error of measurement and the effect-size. Responsiveness of each scale will be evaluated by standardised response mean and receiver-operating characteristic method. Recovery according to the patient will be used as an external criterion. A multilevel regression will be performed on repeated measures. The time until the current episode of low back pain takes to subside will be analysed by Cox regression. Discussion: We hope to provide evidence of the effectiveness of the proposed biopsychosocial multidisciplinary intervention in avoiding the chronification of low back pain, and to reduce the duration of non-specific low back pain episodes. If the intervention is effective, it could be applied to Primary Health Care Centres

The Unified Multiple System Atrophy Rating Scale: Status, Critique, and Recommendations

: The Unified Multiple System Atrophy (MSA) Rating Scale was developed to provide a surrogate marker of disease severity and clinical progression in patients with MSA. It is comprised of four subscales: UMSARS-I (12 items) rates patient-reported functional disability; UMSARS-II (14 items) assesses motor impairment based on a clinical examination; UMSARS-III records blood pressure and heart rate in the supine and standing positions; and UMSARS-IV (1 item) rates chore-based disability. Strengths of the UMSARS include its wide acceptance in the field, the comprehensive coverage of motor symptoms and its clinimetric properties (including reliability and validity). However, with its increasing use, potential areas of improvement in the UMSARS have become apparent. To address these limitations, a task force, involving clinicians, researchers, patient groups, and industry representatives, has recently been endorsed by the International Parkinson’s Disease and Movement Disorders Society. The present viewpoint summarizes strengths and weaknesses of the UMSARS and suggests a roadmap to develop an improved MSA clinical outcome assessment

The Relative Gene Expression Profile of human Anterior versus Posterior Cruciate Ligament

ABSTRACT INTRODUCTION: The knee and in particular ruptures of the anterior cruciate ligament (ACL) still represents a major challenge in orthopaedics. Ex vivo organ culture models of human ACLs are a valuable tool to test degenerative and regenerative scenarios.1,2 These models require an internal control tissue for judging relative gene expression of intact ACL organ culture. In this context, the gene expression profile of donor-matched ACL versus posterior cross ligament (PCL) has never been surveyed. Here, we investigated selected RNA transcripts of teno-specific gene markers to evaluate whether the expression between ACL and PCL is relatively similar and could be used as an internal control and reference for future in vitro mechano- biological models of whole ACL in organ culture. METHODS: 9 donor-matched ACLs and PCLs were obtained from full-knee prosthesis surgery with written consent from the patients (ethically approved). Tissue was immediately transferred to RNA later, snap-frozen in liquid nitrogen and stored at -80°C prior extraction. RNA was then extracted from pulverized tissue in liquid nitrogen by piston and mortar. The grinded powder was then soaked in TRI, RNA was extracted following a combined TRI- reagent phase separation protocol and further purified using silicon column as previously described.3 Total mammalian RNA was then translated to cDNA using the iScript kit (Bio-Rad) and amplified by the iQ5 PCR cycler using SYBR green master mix (Bio-Rad). The expression of 12 human genes was measured, i.e. tenocytes important anabolic maintenance genes: biglycan (BGN), collagen type 1 and 3, (col1 & 3), scleraxis (SCX), tenascin (TNC), tenomodulin (TNMD), two genes were screened for potential dedifferentiation of fibroblasts, i.e. aggrecan (ACAN) and col2. Four genes of the catabolic side of the extracellular matrix turnover were screened, i.e. ADAMTS4 and 5, MMP3 and MMP13, respectively. Human 18S was used as an internal control. Data were tested for normality and due to deviation of it analyzed using non-parametric Wilcoxon-Signed ranked exact test. RESULTS SECTION: The overview of the donor characteristics is given in Table 1. From the totally 12 screened genes two anabolic genes, col1 and TNC, showed levels of mRNA expression deviating significantly from the baseline of ACL and PCL comparison (gene expression = 1.0, Figure 1). On the side of the catabolic genes, there were no deviations obtained from the baseline, however, the exact P-value of MMP13 was borderline (P = 0.054). DISCUSSION: For future mechano-biological experiments, caution must be taken to use the PCL as an internal control. There seem to be donor-matched differences in col1 and TNC, which indicate ligament-specific gene expression differences. In the future, gene expression profiles should be even further distinguished in different sub-zones of the ACL and PCL, which might also cause the heterogeneity presented here.4 SIGNIFICANCE: This research uses intact primary biological samples of the ACL, which has to be considered highly relevant for clinical research. Future research will focus on in vitro degenerative rupture models and testing regenerative approaches. REFERENCES: 1. Altman GH, Lu HH, Horan RL, et al. 2002. Advanced bioreactor with controlled application of multi-dimensional strain for tissue engineering. J Biomech Eng 124:742-749. 2. Hohlrieder M, Teuschl AH, Cicha K, et al. 2013. Bioreactor and scaffold design for the mechanical stimulation of anterior cruciate ligament grafts. Biomed Mater Eng 23:225-237. 3. Gantenbein B, Gadhari N, Chan SCW, et al. 2015. Mesenchymal stem cells and collagen patches for anterior cruciate ligament repair. World J Stem Cells 7:537-550. 4. Murray MM, Fleming BC. 2013. Biology of anterior cruciate ligament injury and repair: Kappa delta ann doner vaughn award paper 2013. J Orthop Res 31:1501-1506. ACKNOWLEDGEMENTS: We thank Eva Roth for assistance with the biochemical assays. This project was partially funded by the Swiss Orthopedic Society grant No. S99083814080618560 to SS Ahmad

Factors influencing the success of anterior cruciate ligament repair with dynamic intraligamentary stabilisation.

PURPOSE Primary repair of the anterior cruciate ligament (ACL) has regained interest of clinicians with recent development of novel repair techniques. Dynamic intraligamentary stabilisation was introduced in an attempt to promote healing by shielding cyclic loads acting upon the ACL during the healing phase. The aim of this study was to identify negative factors likely to influence success of this procedure. METHODS Between 2009 and 2014, 264 patients with an acute ACL rupture undergoing dynamic intraligamentary stabilisation were included in this study. Patients were evaluated for anterior/posterior laxity; range of motion and patient reported outcome measures. Adverse events and re-operations were noted. Failure was defined as AP Translation >3 mm, re-rupture or conversion to ACL reconstruction. Minimum follow-up was 24 months. Univariate and multivariate regression models were utilized to determine predictors of failure. RESULTS An overall complication rate of 15.1% was noted comprising 9.5% (n = 25) re-ruptures, 4.1% (n = 11) persistent instability, and 1.5% (n = 4) > 10° fixed flexion deformity. Two factors were identified as negative predictors of failure: (1) pursuit of competitive sport activities with a Tegner pre-injury score >7 (Odds Ratio (OR) 4.4, CI 1.2-15.9, p = 0.02) and (2) mid-substance ACL rupture location (OR 2.5, 1.1-5.7, p = 0.02). When neither of those risk factors occurred the failure rate was limited to 3.9%. CONCLUSIONS Correct patient selection and narrowing of indications are necessary to maintain high success rates of the procedure. Mid-substance ACL ruptures and a high pre-injury sports activity level are two predictors of inferior outcome. LEVEL OF EVIDENCE II