Assembly of the Tn7 targeting complex by a regulated stepwise process.

The Tn7 family of transposons is notable for its highly regulated integration mechanisms, including programmable RNA-guided transposition. The targeting pathways rely on dedicated target selection proteins from the TniQ family and the AAA+ adaptor TnsC to recruit and activate the transposase at specific target sites. Here, we report the cryoelectron microscopy (cryo-EM) structures of TnsC bound to the TniQ domain of TnsD from prototypical Tn7 and unveil key regulatory steps stemming from unique behaviors of ATP- versus ADP-bound TnsC. We show that TnsD recruits ADP-bound dimers of TnsC and acts as an exchange factor to release one protomer with exchange to ATP. This loading process explains how TnsC assembles a heptameric ring unidirectionally from the target site. This unique loading process results in functionally distinct TnsC protomers within the ring, providing a checkpoint for target immunity and explaining how insertions at programmed sites precisely occur in a specific orientation across Tn7 elements.

Inhibition of BACE1 affected both its Aß producing and degrading activities and increased Aß42 and Aß40 levels at high-level BACE1 expression.

The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the predominant ß-secretase, cleaving the amyloid precursor protein (APP) via the amyloidogenic pathway. In addition, BACE1 as an amyloid degrading enzyme (ADE), cleaves Aß to produce the C-terminally truncated non-toxic Aß fragment Aß34 which is an indicator of amyloid clearance. Here, we analyzed the effects of BACE1 inhibitors on its opposing enzymatic functions, i.e., amyloidogenic (Aß producing) and amyloidolytic (Aß degrading) activities, using cell culture models with varying BACE1/APP ratios. Under high-level BACE1 expression, low-dose inhibition unexpectedly yielded a two-fold increase in Aß42 and Aß40 levels. The concomitant decrease in Aß34 and secreted APPß levels suggested that the elevated Aß42 and Aß40 levels were due to the attenuated Aß degrading activity of BACE1. Notably, the amyloidolytic activity of BACE1 was impeded at lower BACE1 inhibitor concentrations compared to its amyloidogenic activity, thereby suggesting that the Aß degrading activity of BACE1 was more sensitive to inhibition than its Aß producing activity. Under endogenous BACE1 and APP levels, "low-dose" BACE1 inhibition affected both the Aß producing and degrading activities of BACE1, i.e., significantly increased Aß42/Aß40 ratio and decreased Aß34 levels, respectively. Further, we incubated recombinant BACE1 with synthetic Aß peptides and found that BACE1 has a higher affinity for Aß substrates over APP. In summary, our results suggest that stimulating BACE1's ADE activity and halting Aß production without decreasing Aß clearance could still be a promising therapeutic approach with new, yet to be developed, BACE1 modulators.

Identification and characterization of calreticulin as a novel plasminogen receptor.

Calreticulin (CRT) was originally identified as a key calcium-binding protein of the endoplasmic reticulum. Subsequently, CRT was shown to possess multiple intracellular functions, including roles in calcium homeostasis and protein folding. Recently, several extracellular functions have been identified for CRT, including roles in cancer cell invasion and phagocytosis of apoptotic and cancer cells by macrophages. In the current report, we uncover a novel function for extracellular CRT and report that CRT functions as a plasminogen-binding receptor that regulates the conversion of plasminogen to plasmin. We show that human recombinant or bovine tissue-derived CRT dramatically stimulated the conversion of plasminogen to plasmin by tissue plasminogen activator or urokinase-type plasminogen activator. Surface plasmon resonance analysis revealed that CRT-bound plasminogen (KD = 1.8 µM) with moderate affinity. Plasminogen binding and activation by CRT were inhibited by ε-aminocaproic acid, suggesting that an internal lysine residue of CRT interacts with plasminogen. We subsequently show that clinically relevant CRT variants (lacking four or eight lysines in carboxyl-terminal region) exhibited decreased plasminogen activation. Furthermore, CRT-deficient fibroblasts generated 90% less plasmin and CRT-depleted MDA MB 231 cells also demonstrated a significant reduction in plasmin generation. Moreover, treatment of fibroblasts with mitoxantrone dramatically stimulated plasmin generation by WT but not CRT-deficient fibroblasts. Our results suggest that CRT is an important cellular plasminogen regulatory protein. Given that CRT can empower cells with plasmin proteolytic activity, this discovery may provide new mechanistic insight into the established role of CRT in cancer.

Effectiveness and cost-effectiveness of an individualised, progressive walking and education intervention for the prevention of low back pain recurrence in Australia (WalkBack): a randomised controlled trial.

BACKGROUND: Recurrence of low back pain is common and a substantial contributor to the disease and economic burden of low back pain. Exercise is recommended to prevent recurrence, but the effectiveness and cost-effectiveness of an accessible and low-cost intervention, such as walking, is yet to be established. We aimed to investigate the clinical effectiveness and cost-effectiveness of an individualised, progressive walking and education intervention to prevent the recurrence of low back pain. METHODS: WalkBack was a two-armed, randomised controlled trial, which recruited adults (aged 18 years or older) from across Australia who had recently recovered from an episode of non-specific low back pain that was not attributed to a specific diagnosis, and which lasted for at least 24 h. Participants were randomly assigned to an individualised, progressive walking and education intervention facilitated by six sessions with a physiotherapist across 6 months or to a no treatment control group (1:1). The randomisation schedule comprised randomly permuted blocks of 4, 6, and 8 and was stratified by history of more than two previous episodes of low back pain and referral method. Physiotherapists and participants were not masked to allocation. Participants were followed for a minimum of 12 months and a maximum of 36 months, depending on the date of enrolment. The primary outcome was days to the first recurrence of an activity-limiting episode of low back pain, collected in the intention-to-treat population via monthly self-report. Cost-effectiveness was evaluated from the societal perspective and expressed as incremental cost per quality-adjusted life-year (QALY) gained. The trial was prospectively registered (ACTRN12619001134112). FINDINGS: Between Sept 23, 2019, and June 10, 2022, 3206 potential participants were screened for eligibility, 2505 (78%) were excluded, and 701 were randomly assigned (351 to the intervention group and 350 to the no treatment control group). Most participants were female (565 [81%] of 701) and the mean age of participants was 54 years (SD 12). The intervention was effective in preventing an episode of activity-limiting low back pain (hazard ratio 0·72 [95% CI 0·60-0·85], p=0·0002). The median days to a recurrence was 208 days (95% CI 149-295) in the intervention group and 112 days (89-140) in the control group. The incremental cost per QALY gained was AU$7802, giving a 94% probability that the intervention was cost-effective at a willingness-to-pay threshold of $28 000. Although the total number of participants experiencing at least one adverse event over 12 months was similar between the intervention and control groups (183 [52%] of 351 and 190 [54%] of 350, respectively, p=0·60), there was a greater number of adverse events related to the lower extremities in the intervention group than in the control group (100 in the intervention group and 54 in the control group). INTERPRETATION: An individualised, progressive walking and education intervention significantly reduced low back pain recurrence. This accessible, scalable, and safe intervention could affect how low back pain is managed. FUNDING: National Health and Medical Research Council, Australia.

Cognitive functional therapy with or without movement sensor biofeedback versus usual care for chronic, disabling low back pain (RESTORE): a randomised, controlled, three-arm, parallel group, phase 3, clinical trial.

BACKGROUND: Low back pain is the leading cause of years lived with disability globally, but most interventions have only short-lasting, small to moderate effects. Cognitive functional therapy (CFT) is an individualised approach that targets unhelpful pain-related cognitions, emotions, and behaviours that contribute to pain and disability. Movement sensor biofeedback might enhance treatment effects. We aimed to compare the effectiveness and economic efficiency of CFT, delivered with or without movement sensor biofeedback, with usual care for patients with chronic, disabling low back pain. METHODS: RESTORE was a randomised, controlled, three-arm, parallel group, phase 3 trial, done in 20 primary care physiotherapy clinics in Australia. We recruited adults (aged ≥18 years) with low back pain lasting more than 3 months with at least moderate pain-related physical activity limitation. Exclusion criteria were serious spinal pathology (eg, fracture, infection, or cancer), any medical condition that prevented being physically active, being pregnant or having given birth within the previous 3 months, inadequate English literacy for the study's questionnaires and instructions, a skin allergy to hypoallergenic tape adhesives, surgery scheduled within 3 months, or an unwillingness to travel to trial sites. Participants were randomly assigned (1:1:1) via a centralised adaptive schedule to usual care, CFT only, or CFT plus biofeedback. The primary clinical outcome was activity limitation at 13 weeks, self-reported by participants using the 24-point Roland Morris Disability Questionnaire. The primary economic outcome was quality-adjusted life-years (QALYs). Participants in both interventions received up to seven treatment sessions over 12 weeks plus a booster session at 26 weeks. Physiotherapists and patients were not masked. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12618001396213. FINDINGS: Between Oct 23, 2018 and Aug 3, 2020, we assessed 1011 patients for eligibility. After excluding 519 (51·3%) ineligible patients, we randomly assigned 492 (48·7%) participants; 164 (33%) to CFT only, 163 (33%) to CFT plus biofeedback, and 165 (34%) to usual care. Both interventions were more effective than usual care (CFT only mean difference -4·6 [95% CI -5·9 to -3·4] and CFT plus biofeedback mean difference -4·6 [-5·8 to -3·3]) for activity limitation at 13 weeks (primary endpoint). Effect sizes were similar at 52 weeks. Both interventions were also more effective than usual care for QALYs, and much less costly in terms of societal costs (direct and indirect costs and productivity losses; -AU$5276 [-10 529 to -24) and -8211 (-12 923 to -3500). INTERPRETATION: CFT can produce large and sustained improvements for people with chronic disabling low back pain at considerably lower societal cost than that of usual care. FUNDING: Australian National Health and Medical Research Council and Curtin University.

An Updated Systematic Review and Meta-Analysis of Unimodal Prehabilitation with Exercise Intervention to Enhance Postoperative Outcomes in Cancer Surgery.

BACKGROUND: The objective of this systematic review and meta-analysis was to update the body of evidence on the efficacy of prehabilitation with exercise interventions, in reducing postoperative complications and length of hospital stay after cancer surgery. METHODS: A comprehensive literature search was conducted on MEDLINE, Embase, The Cochrane Library, CINAHL, AMED, and PsycINFO to identify randomized controlled trials investigating the impact of prehabilitation with exercise interventions for patients undergoing cancer surgery. Primary and secondary outcomes assessed were postoperative complications and length of hospital stay, respectively. Risk of bias was evaluated using the Cochrane risk of bias tool, and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology was used to determine the strength of evidence. Relative risk and mean difference were calculated using random-effects meta-analysis. RESULTS: In this updated review, 32 trials (n = 2304 participants) were identified, with 5 trials focused on patients undergoing surgery for genitourinary cancer (n = 422 participants), 9 for lower gastrointestinal cancer (n = 639 participants), 6 for upper gastrointestinal cancer (n = 526), and 11 for lung cancer (n = 717 participants). The majority of included trials exhibited some risk of bias. Evidence of low-to-moderate quality indicated that prehabilitation with preoperative exercise significantly reduced postoperative complication rates by approximately 50% and decreased the length of hospital stay by 2.5 days in patients undergoing lung resection. Preoperative exercise did not demonstrate effectiveness in reducing postoperative complications or length of hospital stay for other cancer populations. CONCLUSIONS: Evidence supports the efficacy of prehabilitation with exercise in reducing postoperative complications and length of hospital stay in patients undergoing lung cancer surgery. Further research is warranted to establish the efficacy of unimodal prehabilitation with exercise in genitourinary, lower gastrointestinal, and upper gastrointestinal cancer populations having cancer surgery.

The association between physical intervention use and treatment outcomes in patients participating in an online and psychologically informed pain management program.

BACKGROUND: The availability of multidisciplinary care for the management of chronic pain is uncommon outside specialist clinics. The present study aims to determine the physical intervention use of patients participating in an online psychological pain management program and whether exposure to physical interventions in these patients alters treatment outcomes compared with patients who do not access physical interventions. METHODS: Data were obtained from 2 previously published randomized controlled trials of an online psychological pain management program. Physical intervention exposure (categories: none, 1-3 sessions, 4+ sessions) was assessed at baseline, after treatment, and at 3-month follow-up. Primary outcomes included depression, anxiety, pain intensity, and pain-related disability. Generalized estimating equation models were used to compare treatment outcomes among those with different physical intervention frequencies and periods of exposure. We assessed whether changes in primary outcomes differed (moderated) by the period and category of physical intervention exposure. RESULTS: Of the patients (n = 1074) who completed the baseline questionnaire across both randomized controlled trials, 470 (44%) reported physical intervention use at baseline, 383 (38%) reported physical intervention use after treatment, and 363 (42%) reported physical intervention use at 3-month follow-up. On average, there were moderate-large reductions from baseline to after treatment with respect to all outcomes (Cohen's d = 0.36-0.82). For all outcomes, the interaction of time by physical intervention exposure was statistically nonsignificant. CONCLUSION: A substantial proportion of patients who participated in a psychologically informed pain management program were establishing, continuing, or stopping additional physical interventions. The frequency of and period of exposure to physical interventions did not appear to moderate treatment outcomes. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12613000252718 and ACTRN12615001003561). The website for registration information is https://www.anzctr.org.au.

A review of patient recruitment in randomised controlled trials of preoperative exercise.

BACKGROUND: Randomised controlled trials (RCTs) are considered the gold standard design to determine the effectiveness of an intervention, as the only method of decreasing section bias and minimising random error. However, participant recruitment to randomised controlled trials is a major challenge, with many trials failing to recruit the targeted sample size accordingly to the planned protocol. Thus, the aim of this review is to detail the recruitment challenges of preoperative exercise clinical trials. METHODS: A comprehensive search was performed on MEDLINE, Embase, The Cochrane Library, CINAHL, AMED and PsycINFO from inception to July 2021. Randomised controlled trials investigating the effectiveness of preoperative exercise on postoperative complication and/or length of hospital stay in adult cancer patients were included. Main outcomes included recruitment rate, retention rate, number of days needed to screen and recruit one patient and trial recruitment duration. Descriptive statistics were used to summarise outcomes of interest. RESULTS: A total of 27 trials were identified, including 3656 patients screened (N = 21) and 1414 randomised (median recruitment rate (interquartile range) = 53.6% (25.2%-67.6%), N = 21). The sample size of the included trials ranged from 19 to 270 (median = 48.0; interquartile range = 40.0-85.0) and the duration of trial recruitment ranged from 3 to 50 months (median = 19.0 months; interquartile range = 10.5-34.0). Overall, a median of 3.6 days was needed to screen one patient, whereas 13.7 days were needed to randomise one participant. Over the trials duration, the median dropout rate was 7.9%. Variations in recruitment outcomes were observed across trials of different cancer types but were not statistically significant. CONCLUSION: The recruitment of participants to preoperative exercise randomised controlled trials is challenging, but patient retention appears to be less of a problem. Future trials investigating the effectiveness of a preoperative exercise programme following cancer surgery should consider the time taken to recruit patients. Strategies associated with improved recruitment should be investigated in future studies.

Exercises for the prevention of non-specific low back pain.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effects of exercise alone or exercise plus education compared with inactive control or education alone to prevent non-specific LBP.

A Decision Aid for Patients Considering Surgery for Sciatica: Codesign and User-Testing With Patients and Clinicians.

BACKGROUND: Surgery can help patients with leg pain caused by sciatica recover faster, but by 12 months outcomes are similar to nonsurgical management. For many the decision to have surgery may require reflection, and patient decision aids are an evidence-based clinical tool that can help guide patients through this decision. OBJECTIVE: The aim of this study was to develop and refine a decision aid for patients with sciatica who are deciding whether to have surgery or 'wait and see' (i.e., try nonsurgical management first). DESIGN: Semistructured interviews with think-aloud user-testing protocol. PARTICIPANTS: Twenty clinicians and 20 patients with lived experience of low back pain or sciatica. OUTCOME MEASURES: Items from Technology Acceptance Model, Preparation for Decision Making Scale and Decision Quality Instrument for Herniated Disc 2.0 (knowledge instrument). METHODS: The prototype integrated relevant research with working group perspectives, decision aid standards and health literacy guidelines. The research team refined the prototype through seven rounds of user-testing, which involved discussing user-testing feedback and implementing changes before progressing to the next round. RESULTS: As a result of working group feedback, the decision aid was divided into sections: before, during and after a visit to the surgeon. Across all rounds of user-testing, clinicians rated the resource 5.9/7 (SD = 1.0) for perceived usefulness, and 6.0/7 for perceived ease of use (SD = 0.8). Patients reported the decision aid was easy to understand, on average correctly answering 3.4/5 knowledge questions (SD = 1.2) about surgery for sciatica. The grade reading score for the website was 9.0. Patients scored highly on preparation for decision-making (4.4/5, SD = 0.7), suggesting strong potential to empower patients. Interview feedback showed that patients and clinicians felt the decision aid would encourage question-asking and help patients reflect on personal values. CONCLUSIONS: Clinicians found the decision aid acceptable, patients found it was easy to understand and both groups felt it would empower patients to actively engage in their care and come to an informed decision that aligned with personal values. Input from the working group and user-testing was crucial for ensuring that the decision aid met patient and clinician needs. PATIENT OR PUBLIC CONTRIBUTION: Patients and clinicians contributed to prototype development via the working group.

Implementation of back to living well, a community-based program for the tertiary prevention of low back pain: a study protocol.

BACKGROUND: The current literature supports the effectiveness of exercise, education, and self-management interventions for the long-term management of persistent low back pain. However, there is significant uncertainty about the implementation of interventions related to barriers, facilitators, and patient's preferences. This study will evaluate the Back to Living Well program implementation from a participant and organizational perspective. More specifically we address the following objectives: 1) identify program barriers and facilitators from participants' perspectives, 2) identify factors related to program, personal and contextual factors that contribute to negative and positive outcomes, and outcome trajectories, 3) identify factors influencing participants' selection of an in-person or e-health program, and 4) evaluate program specific barriers and facilitators from the organization and care delivery perspectives. METHODS: This study will utilize a mixed-method convergent design including a longitudinal cohort strand and a longitudinal qualitative interview strand. The RE-AIM framework will be used to assess program implementation. Participants (n = 90, 1:1: in person or virtual) who choose to register in the program as well as staff (n = 10 to 15) involved in the delivery of the program will be invited to participate. Participants will participate in a 12-week physical activity, education, and self-management program. Implementation outcomes will be measured at 3-, 6-, 12-months, and six months after the end of the follow-ups. Interview scripts and directed content analysis will be constructed based on the Theoretical Domains Framework and the Neuromatrix Model of Pain, Theoretical Domains Framework. Staff interviews will be constructed and analyzed using the Consolidated Framework for Implementation Research. Participants will also complete pain, disability, quality of life and psychological questionnaires, wear an activity tracker at all time points, and complete weekly pain and activity limitation questions using a mobile application. DISCUSSION: The study results will provide evidence to inform potential future implementation of the program. An effective, appropriately targeted, and well implemented exercise program for the long-term management (i.e., tertiary prevention) of LBP could minimize the burden of the condition on patients, the health care system and society. TRIAL REGISTRATION: ClinicalTrials.gov NCT05929846. This (Registration Date: July 3 2023) study has been approved by the Hamilton Integrated Research Ethics Board Project ID#15,354.

Back pain Knowledge and beliefs Survey (BacKS): development and assessment of measurement properties.

OBJECTIVE: To develop and evaluate a new patient-reported outcome measure (PROM) to assess people's knowledge and beliefs about low back pain. METHODS: This study followed the COnsensus-based Standards for the selection of health Measurement INstruments guidelines. An 18-item preliminary version of the Back pain Knowledge and beliefs Survey (BacKS) was generated based on evidence-based key messages and current clinical guidelines for low back pain. Four items were added following input from three consumers and seven experts. Focus groups (n=9) confirmed content validity. The 22-item version was completed by 258 Australian-based adults (>18 years) with self-reported low back pain. A follow-up survey was sent 1 week later. The following measurement properties were evaluated to produce, and then assess the final version of BacKS: structural validity (exploratory factor analysis); internal consistency (Cronbach's alpha); test-retest reliability (intraclass correlation coefficient); measurement error (Smallest Detectable Change); construct validity (hypothesis tested: moderate positive Pearson correlation between BacKS and Back Beliefs Questionnaire); plus, interpretability and feasibility. RESULTS: The final BacKS comprised 20 items with a 2-factor structure (biomedical factor: 9 items, score ranging from 9 to 45, and self-care factor: 11 items, score ranging from 11 to 55). Internal consistency and reliability were adequate (>0.70) for each factor. Smallest detectable change was 4.4 (biomedical factor) and 7.0 (self-care factor). Our construct validity hypothesis was confirmed (Pearson correlation=0.53). No floor or ceiling effects were detected. CONCLUSION: The BacKS is a valid, reliable and feasible PROM to measure knowledge and beliefs about low back pain in clinical practice and research settings.

Development of low back pain curriculum content standards for entry-level clinical training.

BACKGROUND: The management of low back pain (LBP) is highly variable and patients often receive management that is not recommended and/or miss out on recommended care. Clinician knowledge and behaviours are strongly influenced by entry-level clinical training and are commonly cited as barriers to implementing evidence-based management. Currently there are no internationally recognised curriculum standards for the teaching of LBP content to ensure graduating clinicians have the appropriate knowledge and competencies to assess and manage LBP. We formed an international interdisciplinary working group to develop curriculum content standards for the teaching of LBP in entry-level clinical training programs. METHODS: The working group included representatives from 11 countries: 18 academics and clinicians from healthcare professions who deal with the management of LBP (medicine, physiotherapy, chiropractic, osteopathy, pharmacology, and psychology), seven professional organisation representatives (medicine, physiotherapy, chiropractic, spine societies), and one healthcare consumer. A literature review was performed, including database and hand searches of guidelines and accreditation, curricula, and other policy documents, to identify gaps in current LBP teaching and recommended entry-level knowledge and competencies. The steering group (authors) drafted the initial LBP Curriculum Content Standards (LBP-CCS), which were discussed and modified through two review rounds with the working group. RESULTS: Sixty-two documents informed the draft standards. The final LBP-CCS consisted of four broad topics covering the epidemiology, biopsychosocial contributors, assessment, and management of LBP. For each topic, key knowledge and competencies to be achieved by the end of entry-level clinical training were described. CONCLUSION: We have developed the LBP-CCS in consultation with an interdisciplinary, international working group. These standards can be used to inform or benchmark the content of curricula related to LBP in new or existing entry-level clinical training programs.

The amyloid-ß1-42-oligomer interacting peptide D-AIP possesses favorable biostability, pharmacokinetics, and brain region distribution.

We have previously developed a unique 8-amino acid Aß42 oligomer-Interacting Peptide (AIP) as a novel anti-amyloid strategy for the treatment of Alzheimer's disease. Our lead candidate has successfully progressed from test tubes (i.e., in vitro characterization of protease-resistant D-AIP) to transgenic flies (i.e., in vivo rescue of human Aß42-mediated toxicity via D-AIP-supplemented food). In the present study, we examined D-AIP in terms of its stability in multiple biological matrices (i.e., ex-vivo mouse plasma, whole blood, and liver S9 fractions) using MALDI mass spectrometry, pharmacokinetics using a rapid and sensitive LC-MS method, and blood brain barrier (BBB) penetrance in WT C57LB/6 mice. D-AIP was found to be relatively stable over 3 h at 37 °C in all matrices tested. Finally, label-free MALDI imaging showed that orally administered D-AIP can readily penetrate the intact BBB in both male and female WT mice. Based upon the favorable stability, pharmacokinetics, and BBB penetration outcomes for orally administered D-AIP in WT mice, we then examined the effect of D-AIP on amyloid "seeding" in vitro (i.e., freshly monomerized versus preaggregated Aß42). Complementary biophysical assays (ThT, TEM, and MALDI-TOF MS) showed that D-AIP can directly interact with synthetic Aß42 aggregates to disrupt primary and/or secondary seeding events. Taken together, the unique mechanistic and desired therapeutic potential of our lead D-AIP candidate warrants further investigation, that is, testing of D-AIP efficacy on the altered amyloid/tau pathology in transgenic mouse models of Alzheimer's disease.

Red flags to screen for vertebral fracture in people presenting with low back pain.

BACKGROUND: Low back pain is a common presentation across different healthcare settings. Clinicians need to confidently be able to screen and identify people presenting with low back pain with a high suspicion of serious or specific pathology (e.g. vertebral fracture). Patients identified with an increased likelihood of having a serious pathology will likely require additional investigations and specific treatment. Guidelines recommend a thorough history and clinical assessment to screen for serious pathology as a cause of low back pain. However, the diagnostic accuracy of recommended red flags (e.g. older age, trauma, corticosteroid use) remains unclear, particularly those used to screen for vertebral fracture. OBJECTIVES: To assess the diagnostic accuracy of red flags used to screen for vertebral fracture in people presenting with low back pain. Where possible, we reported results of red flags separately for different types of vertebral fracture (i.e. acute osteoporotic vertebral compression fracture, vertebral traumatic fracture, vertebral stress fracture, unspecified vertebral fracture). SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 26 July 2022. SELECTION CRITERIA: We considered primary diagnostic studies if they compared results of history taking or physical examination (or both) findings (index test) with a reference standard test (e.g. X-ray, magnetic resonance imaging (MRI), computed tomography (CT), single-photon emission computerised tomography (SPECT)) for the identification of vertebral fracture in people presenting with low back pain. We included index tests that were presented individually or as part of a combination of tests. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data for diagnostic two-by-two tables from the publications or reconstructed them using information from relevant parameters to calculate sensitivity, specificity, and positive (+LR) and negative (-LR) likelihood ratios with 95% confidence intervals (CIs). We extracted aspects of study design, characteristics of the population, index test, reference standard, and type of vertebral fracture. Meta-analysis was not possible due to heterogeneity of studies and index tests, therefore the analysis was descriptive. We calculated sensitivity, specificity, and LRs for each test and used these as an indication of clinical usefulness. Two review authors independently conducted risk of bias and applicability assessment using the QUADAS-2 tool. MAIN RESULTS: This review is an update of a previous Cochrane Review of red flags to screen for vertebral fracture in people with low back pain. We included 14 studies in this review, six based in primary care, five in secondary care, and three in tertiary care. Four studies reported on 'osteoporotic vertebral fractures', two studies reported on 'vertebral compression fracture', one study reported on 'osteoporotic and traumatic vertebral fracture', two studies reported on 'vertebral stress fracture', and five studies reported on 'unspecified vertebral fracture'. Risk of bias was only rated as low in one study for the domains reference standard and flow and timing. The domain patient selection had three studies and the domain index test had six studies rated at low risk of bias. Meta-analysis was not possible due to heterogeneity of the data. Results from single studies suggest only a small number of the red flags investigated may be informative. In the primary healthcare setting, results from single studies suggest 'trauma' demonstrated informative +LRs (range: 1.93 to 12.85) for 'unspecified vertebral fracture' and 'osteoporotic vertebral fracture' (+LR: 6.42, 95% CI 2.94 to 14.02). Results from single studies suggest 'older age' demonstrated informative +LRs for studies in primary care for 'unspecified vertebral fracture' (older age greater than 70 years: 11.19, 95% CI 5.33 to 23.51). Results from single studies suggest 'corticosteroid use' may be an informative red flag in primary care for 'unspecified vertebral fracture' (+LR range: 3.97, 95% CI 0.20 to 79.15 to 48.50, 95% CI 11.48 to 204.98) and 'osteoporotic vertebral fracture' (+LR: 2.46, 95% CI 1.13 to 5.34); however, diagnostic values varied and CIs were imprecise. Results from a single study suggest red flags as part of a combination of index tests such as 'older age and female gender' in primary care demonstrated informative +LRs for 'unspecified vertebral fracture' (16.17, 95% CI 4.47 to 58.43). In the secondary healthcare setting, results from a single study suggest 'trauma' demonstrated informative +LRs for 'unspecified vertebral fracture' (+LR: 2.18, 95% CI 1.86 to 2.54) and 'older age' demonstrated informative +LRs for 'osteoporotic vertebral fracture' (older age greater than 75 years: 2.51, 95% CI 1.48 to 4.27). Results from a single study suggest red flags as part of a combination of index tests such as 'older age and trauma' in secondary care demonstrated informative +LRs for 'unspecified vertebral fracture' (+LR: 4.35, 95% CI 2.92 to 6.48). Results from a single study suggest when '4 of 5 tests' were positive in secondary care, they demonstrated informative +LRs for 'osteoporotic vertebral fracture' (+LR: 9.62, 95% CI 5.88 to 15.73). In the tertiary care setting, results from a single study suggest 'presence of contusion/abrasion' was informative for 'vertebral compression fracture' (+LR: 31.09, 95% CI 18.25 to 52.96). AUTHORS' CONCLUSIONS: The available evidence suggests that only a few red flags are potentially useful in guiding clinical decisions to further investigate people suspected to have a vertebral fracture. Most red flags were not useful as screening tools to identify vertebral fracture in people with low back pain. In primary care, 'older age' was informative for 'unspecified vertebral fracture', and 'trauma' and 'corticosteroid use' were both informative for 'unspecified vertebral fracture' and 'osteoporotic vertebral fracture'. In secondary care, 'older age' was informative for 'osteoporotic vertebral fracture' and 'trauma' was informative for 'unspecified vertebral fracture'. In tertiary care, 'presence of contusion/abrasion' was informative for 'vertebral compression fracture'. Combinations of red flags were also informative and may be more useful than individual tests alone. Unfortunately, the challenge to provide clear guidance on which red flags should be used routinely in clinical practice remains. Further research with primary studies is needed to improve and consolidate our current recommendations for screening for vertebral fractures to guide clinical care.

Concurrent validity of DorsaVi wireless motion sensor system Version 6 and the Vicon motion analysis system during lifting.

BACKGROUND: Wearable sensor technology may allow accurate monitoring of spine movement outside a clinical setting. The concurrent validity of wearable sensors during multiplane tasks, such as lifting, is unknown. This study assessed DorsaVi Version 6 sensors for their concurrent validity with the Vicon motion analysis system for measuring lumbar flexion during lifting. METHODS: Twelve participants (nine with, and three without back pain) wore sensors on T12 and S2 spinal levels with Vicon surface markers attached to those sensors. Participants performed 5 symmetrical (lifting from front) and 20 asymmetrical lifts (alternate lifting from left and right). The global-T12-angle, global-S2-angle and the angle between these two sensors (relative-lumbar-angle) were output in the sagittal plane. Agreement between systems was determined through-range and at peak flexion, using multilevel mixed-effects regression models to calculate root mean square errors and standard deviation. Mean differences and limits of agreement for peak flexion were calculated using the Bland Altman method. RESULTS: For through-range measures of symmetrical lifts, root mean squared errors (standard deviation) were 0.86° (0.78) at global-T12-angle, 0.90° (0.84) at global-S2-angle and 1.34° (1.25) at relative-lumbar-angle. For through-range measures of asymmetrical lifts, root mean squared errors (standard deviation) were 1.84° (1.58) at global-T12-angle, 1.90° (1.65) at global-S2-angle and 1.70° (1.54) at relative-lumbar-angle. The mean difference (95% limit of agreement) for peak flexion of symmetrical lifts, was - 0.90° (-6.80 to 5.00) for global-T12-angle, 0.60° (-2.16 to 3.36) for global-S2-angle and - 1.20° (-8.06 to 5.67) for relative-lumbar-angle. The mean difference (95% limit of agreement) for peak flexion of asymmetrical lifts was - 1.59° (-8.66 to 5.48) for global-T12-angle, -0.60° (-7.00 to 5.79) for global-S2-angle and - 0.84° (-8.55 to 6.88) for relative-lumbar-angle. CONCLUSION: The root means squared errors were slightly better for symmetrical lifts than they were for asymmetrical lifts. Mean differences and 95% limits of agreement showed variability across lift types. However, the root mean squared errors for all lifts were better than previous research and below clinically acceptable thresholds. This research supports the use of lumbar flexion measurements from these inertial measurement units in populations with low back pain, where multi-plane lifting movements are assessed.

Reliability of reporting differences in degenerative MRI findings of the lumbar spine from the supine to the upright position.

OBJECTIVE: To determine the inter-rater reliability of identifying differences and types of differences in lumbar degenerative findings comparing supine and upright MRI. MATERIALS AND METHODS: Fifty-nine participants, low back pain patients (LBP) with or without leg pain and no-LBP individuals were consecutively enrolled to receive supine and upright MRI of the lumbar spine. Three raters independently evaluated the MRIs for degenerative spinal pathologies and compared for differences. Presence/absence of degenerative findings were recorded for all supine and upright images, and then differences from the supine to the upright positions were classified into no-change, appeared, disappeared, worsened, or improved at each individual disc level. Reliability and agreement were calculated using Gwet's agreement coefficients (AC1 or AC2) and absolute agreement. RESULTS: Inter-rater reliability of evaluating differences in eight degenerative lumbar findings comparing the supine and upright MRI position, ranged from 0.929 to 0.996 according to Gwet's agreement coefficients (AC2). The total number of positive MRI findings in the supine position ranged from 270 to 453, with an average of 366 per rater. Observed differences from supine to upright MRI ranged from 18 to 80, with an average of 56 per rater. CONCLUSION: Inter-rater reliability was found overall acceptable for classification of differences in eight types of degenerative pathology observed with supine and upright MRI of the lumbar spine. Results were primarily driven by high numbers and high reliability of rating negative findings, whereas agreement regarding positive findings and positive positional differences was lower.

Informing National Health Service patients about participation in clinical research: A comparison of opt-in and opt-out approaches across the United Kingdom.

OBJECTIVE: Recruitment to clinical research in the National Health Service remains challenging. One barrier is accessing patients to discuss research participation. Two general approaches are used in the United Kingdom to facilitate this: an 'opt-in' approach (when clinicians communicate research opportunities to patients) and an 'opt-out' approach (all patients have the right to be informed of relevant research opportunities). No evidence-based data are available, however, to inform the decision about which approach is preferable. This study aimed to collect information from 'opt-in' and 'opt-out' Trusts and identify which of the two approaches is optimal for ensuring National Health Service patients are given opportunities to discuss research participation. METHOD: This sequential mixed methods study comprised three phases: (1) an Appreciative Inquiry across UK Trusts, (2) online surveys and (3) focus groups with National Health Service staff and patients at a representative mental health Trust. RESULTS: The study was conducted between June and October 2019. Out of seven National Health Service Mental Health Trusts contacted (three 'opt-out' and four 'opt-in'), only four took part in phase 1 of the study and three of them were 'opt-out' Trusts. Benefits of an 'opt-out' approach included greater inclusivity of patients and the removal of research gatekeepers, while the involvement of research-active clinicians and established patient-clinician relationships were cited as important to 'opt-in' success. Phases 2 and 3 were conducted at a different Trust (Oxford Health NHS Foundation Trust) which was using an 'opt-in' approach. Of 333 staff and member survey responders, 267 (80.2%) favoured moving to an 'opt-out' approach (phase 2). Nineteen staff and 16 patients and carers participated in focus groups (phase 3). Concern was raised by staff regarding the lack of time for clinical research, with clinical work taking precedence over research; patients were concerned about a lack of research activity; all considered research to be beneficial and were supportive of a move to 'opt-out'. CONCLUSION: Findings suggest that 'opt-out' is more beneficial than 'opt-in', with the potential to vastly increase patient access to research opportunities and to enable greater equality of information provision for currently marginalised groups. This should ensure that healthcare research is more representative of the entire population, including those with a mental health diagnosis.

Healthcare expenditure and its predictors in a cohort of Australians living with sciatica.

PURPOSE: To estimate the healthcare resource utilisation of an Australian cohort of people with sciatica and explore individual-level factors associated with expenditure. METHODS: Healthcare utilisation (services and medication) data from a randomised, double-blind, placebo-controlled trial of pregabalin in patients with sciatica (n = 185) were analysed to estimate healthcare expenditure of participants over 12 months. Associations between key baseline socio-economic, pain and quality of life characteristics and healthcare expenditure were examined using generalised linear imputation models. RESULTS: On average, participants accessed AUD$1,134 of healthcare over the year, predominantly made up of $114 of medication and $914 of health services, which included $418 of physiotherapy services. Participants randomised to receive pregabalin incurred higher expenditure ($1,263 compared to $1,001 for placebo), which was largely driven by pregabalin ($158) and greater health services ($107). Healthcare expenditure was significantly higher for participants prescribed pregabalin, earning greater than $1,700 per week ($88,400 per year) and reporting poorer quality of life (physical and mental). CONCLUSION: Our results suggest inefficiency in the use of healthcare resources due to increased healthcare resource utilisation in people with sciatica treated with pregabalin, compared to placebo. Costs of treating sciatica varied based on individual quality of life and socio-economic characteristics.

Patient education booklet to support evidence-based low back pain care in primary care - a cluster randomized controlled trial.

BACKGROUND: Inappropriate imaging and low-value care for low back pain (LBP) are common. A new patient-education booklet was created to overcome identified barriers to the delivery of recommended care, including the use of inappropriate imaging. Our aim was to assess the effectiveness of this booklet as part of primary care for LBP patients in comparison to usual care. METHODS: A cluster-randomized trial was performed. The intervention involved providing practitioners with the new patient-education booklet and a 30-min training session on its use. The booklet was provided during the clinical consult to all consenting LBP patients in the intervention group. Primary outcomes were the proportion of patients presenting with LBP who underwent imaging examinations during the first three months of follow-up and PROMIS PF-20 (Patient-Reported Outcomes Measurement Information System, 20-item physical functioning short form) change between baseline and three-month follow-up. Secondary outcomes, including sick leave and imaging examinations at 12 months, were investigated. Logistic regression using GEE-estimation was used for dichotomous outcomes, Poisson regression using GEE-estimation for count outcomes, and linear mixed models for continuous outcomes. RESULTS: Using the patient education booklet appeared to substantially reduce the proportion of LBP patients who underwent an imaging examination at three months, but the result was not statistically significant (OR 0.57, 95% confidence interval (Cl) 0.27 to 1.22). At 12 months, the effect was slightly larger and statistically significant (OR 0.50, 95%Cl 0.30 to 0.83, p = 0.008). No difference was observed in the PROMIS PF-20 T-score change between baseline and 3 months or 12 months (p = 0.365 and p = 0.923, respectively). The number of sick leave days in the intervention group was less than that in the control group at 3 months (RR 0.47, 95%Cl 0.26 to 0.83, p = 0.010) and at 12 months (RR 0.36, 95%Cl 0.18 to 0.72, p = 0.004). CONCLUSIONS: The booklet appeared to be effective in reducing the proportion of LBP patients who underwent imaging examinations over 12 months. The intervention had no discernible effect on the PROMIS PF20 T-score change. The number of sick leave days was substantially lower in the intervention group. TRIAL REGISTRATION: ISRCTN, ISRCTN14389368 , Registered 4 April 2019-Retrospectively registered.