Unveiling the molecular mechanisms of the type IX secretion system's response regulator: Structural and functional insights.

The type IX secretion system (T9SS) is a nanomachinery utilized by bacterial pathogens to facilitate infection. The system is regulated by a signaling cascade serving as its activation switch. A pivotal member in this cascade, the response regulator protein PorX, represents a promising drug target to prevent the secretion of virulence factors. Here, we provide a comprehensive characterization of PorX both in vitro and in vivo. First, our structural studies revealed PorX harbors a unique enzymatic effector domain, which, surprisingly, shares structural similarities with the alkaline phosphatase superfamily, involved in nucleotide and lipid signaling pathways. Importantly, such pathways have not been associated with the T9SS until now. Enzymatic characterization of PorX's effector domain revealed a zinc-dependent phosphodiesterase activity, with active site dimensions suitable to accommodate a large substrate. Unlike typical response regulators that dimerize via their receiver domain upon phosphorylation, we found that zinc can also induce conformational changes and promote PorX's dimerization via an unexpected interface. These findings suggest that PorX can serve as a cellular zinc sensor, broadening our understanding of its regulatory mechanisms. Despite the strict conservation of PorX in T9SS-utilizing bacteria, we demonstrate that PorX is essential for virulence factors secretion in Porphyromonas gingivalis and affects metabolic enzymes secretion in the nonpathogenic Flavobacterium johnsoniae, but not for the secretion of gliding adhesins. Overall, this study advances our structural and functional understanding of PorX, highlighting its potential as a druggable target for intervention strategies aimed at disrupting the T9SS and mitigating virulence in pathogenic species.

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.

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.

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.

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.

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 current 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 to patients who do not access physical interventions. METHODS: Data were obtained from two previously published randomised control trials of an online psychological pain management program. Physical intervention exposure (category: None, 1-3, 4+ sessions) was assessed at baseline, post-treatment and at 3-month follow-up. Primary outcomes included depression, anxiety, pain intensity and pain-related disability. Generalised estimating equation models were used to compare treatment outcomes between those with different physical intervention frequencies and period of exposure. We assessed whether changes in primary outcomes differed (moderated) depending on the period and category of physical intervention exposure. RESULTS: N = 1,074 patients completed the baseline questionnaire across both RCTs, of whom 470 (44%) reported physical intervention use at baseline, 383 (38%) at post-treatment and 363 (42%) at 3-month follow-up. On average, there were moderate-large reductions from baseline to post-treatment with respect to all outcomes (Cohen's d = 0.36-0.82). In all outcomes, the interaction of time by physical intervention exposure was statistically non-significant. 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 and period of exposure to physical interventions did not appear moderate treatment outcomes.

DiTA: helping you search for evidence of diagnostic test accuracy in physical therapy.

BACKGROUND: Physical therapists use diagnostic tests in a variety of settings. Choosing the best diagnostic test to apply in a particular situation can be difficult. The choice of diagnostic test should be informed, at least in part, by evidence of test accuracy. Finding evidence of diagnostic test accuracy has, until recently, been challenging. Ideally, there would exist a database that comprehensively indexes evidence on diagnostic tests relevant to physical therapy practice, is free to access, and is easy to use. OBJECTIVE: This Masterclass will describe the DiTA (Diagnostic Test Accuracy) database (dita.org.au) including its development and search interface, and provide advice on how to search and retrieve records. DISCUSSION: DiTA indexes more than 2400 primary studies and systematic reviews of diagnostic test accuracy relevant to physical therapy practice. Users can search DiTA using text fields and dropdown lists to find evidence of diagnostic test accuracy. The database is freely accessible on the internet. Since its launch, DiTA has been accessed from almost every country in the world, the largest number of searches having been conducted from Brazil.

Evaluating the STarTBack stratified treatment approach for low back pain: exploring study-level factors potentially explaining differences in results of studies - a literature review.

OBJECTIVE: To explore if there are differences in the design and/or conduct of studies that have tested the STarTBack treatment approach for the management of low back pain (LBP), potentially explaining differences in study results. DESIGN: A literature review. DATA SOURCES: MEDLINE, CINAHL and EMBASE were searched from inception to 26 July 2023. ELIGIBILITY CRITERIA: We included studies that included (1) participants with LBP and/or leg pain, (2) randomised controlled trials, controlled clinical trials and interrupted time series designs, (3) used the STarTBack Tool to stratify participants into subgroups and (4) studies provided matched treatments according to participants STarTBack score. DATA EXTRACTION AND SYNTHESIS: Two review authors independently reviewed the search results and extracted data into the data extraction form. Due to the exploratory nature of this study, results are presented descriptively. RESULTS: 11 studies conducted across 5 countries were included. There were substantial differences in the proportion of participants allocated to the different risk groups; low-risk group (range: 19%-58%), medium risk group (range: 31%-52%) and high-risk group (range: 6%-38%). There were large differences between studies in the implementation of the STarTBack approach. The original STarTBack trial (Hill et al, 2011) had a more explanatory design while in many subsequent studies, the design was more pragmatic/real world. Only the two original studies provided clear evidence that the implementation of the STarTBack tool led to a higher proportion of participants receiving matched treatment. In the other studies, there was no evidence of a difference, or it was unclear. In two studies, a researcher made the decision about which matched treatment participants received based on the STartTback Tool, while in nine studies, this was done by a clinician. Most studies recommended the same matched treatment for each risk group as per the original study except for a small number of studies. Only three studies reported whether the clinician delivering matched treatment followed the recommended treatment as per the tool. There was substantial variability in the training clinicians received. CONCLUSIONS: Reporting of important study-level factors (eg, differences in study design, whether clinicians were trained and how the tool was used in each study) in how the STarTBack approach was implemented was unclear. There is some suggestion that key factors may include the individual who implemented the STarTBack tool, whether the recommendations of the tool were followed, the amount of training the clinician delivering the matched treatment received, and whether clinicians actually delivered the matched treatment.

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.

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.

Unveiling the Molecular Mechanisms of the Type-IX Secretion System's Response Regulator: Structural and Functional Insights.

The Type-IX secretion system (T9SS) is a nanomachinery utilized by bacterial pathogens to facilitate infection. The system is regulated by a signaling cascade serving as its activation switch. A pivotal member in this cascade, the response regulator protein PorX, represents a promising drug target to prevent the secretion of virulence factors. Here, we provide a comprehensive characterization of PorX both in vitro and in vivo . First, our structural studies revealed PorX harbours a unique enzymatic effector domain, which, surprisingly, shares structural similarities with the alkaline phosphatase superfamily, involved in nucleotide and lipid signaling pathways. Importantly, such pathways have not been associated with the T9SS until now. Enzymatic characterization of PorX's effector domain revealed a zinc-dependent phosphodiesterase activity, with active site dimensions suitable to accommodate a large substrate. Unlike typical response regulators that dimerize via their receiver domain upon phosphorylation, we found that zinc can also induce conformational changes and promote PorX's dimerization via an unexpected interface. These findings suggest that PorX can serve as a cellular zinc sensor, broadening our understanding of its regulatory mechanisms. Despite the strict conservation of PorX in T9SS-utilizing bacteria, we demonstrate that PorX is essential for virulence factors secretion in Porphyromonas gingivalis and affects metabolic enzymes secretion in the non-pathogenic Flavobacterium johnsoniae , but not for the secretion of gliding adhesins. Overall, this study advances our structural and functional understanding of PorX, highlighting its potential as a druggable target for intervention strategies aimed at disrupting the T9SS and mitigating virulence in pathogenic species.

Questionnaires assessing knowledge and beliefs about musculoskeletal conditions are potentially suitable for use, but further research is needed: a systematic review.

OBJECTIVES: To evaluate the measurement properties of Patient-reported outcome measures (PROMs) for knowledge and/or beliefs about musculoskeletal conditions. STUDY DESIGN AND SETTING: A systematic review was performed according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines. This review was prospectively registered on PROSPERO - ID: CRD42022303111. Electronic databases, reference lists, forward citation tracking, and contact with experts were used to identify studies. Eligible studies were reports developing or assessing a measurement property of a PROM measuring musculoskeletal condition specific-knowledge and/or beliefs. We assessed the methodological quality and measurement properties of included studies. A modified Grading of Recommendations Assessment Development and Evaluation approach was used to rate the quality of evidence for each PROM. RESULTS: The literature search was performed from inception to 11th September 2023. Sixty records were included, reporting 290 individual studies, and provided information on 25 PROMs. Five PROMs presented sufficient structural validity, three presented sufficient cross-cultural validity, ten presented sufficient reliability, three presented sufficient criterion validity, six presented sufficient hypothesis-testing, and four presented sufficient responsiveness. No PROM presented sufficient evidence for content validity, internal consistency, and measurement error. Based on the available evidence, no PROM was classified as suitable for use according to the COSMIN recommendations. Twenty-four PROMs are potentially suitable for use, and one PROM is not recommended for use. CONCLUSION: No PROM designed to assess knowledge and/or beliefs about musculoskeletal conditions meets the COSMIN criteria of suitable for use. Most PROMs identified in this systematic review were considered as potentially suitable for use and need further high-quality research to assess their measurement properties.

Swimming for low back pain: A scoping review.

BACKGROUND: Guidelines recommend exercise for treatment of chronic low back pain and prevention, but the amount and quality of evidence for different exercise modes is highly variable. Swimming is commonly recommended by health professionals, but the extent and quality of research supporting its relationship with back pain is not clear. OBJECTIVES: The aim of this scoping review was to map the extent, characteristics and findings of research investigating the relationship between swimming and low back pain. DESIGN: Scoping review. METHOD: Four electronic databases (MEDLINE, EMBASE, CINAHL, and SPORT Discus) were searched from inception to February 2023. We included primary studies and reviews that reported an association between swimming and low back pain. Hydrotherapy studies were excluded. RESULTS: 3093 articles were identified, and 44 studies included. Only one randomised controlled trial and one longitudinal cohort study were included. Most studies were cross-sectional (37/44; 84.1%), included competitive athletes (23/39; 59.0%), and did not primarily focus on the association between swimming and low back pain in the aims (41/44; 93.2%). Instead, most data available were largely incidentally collected or a secondary outcome. The reported associations between swimming and low back pain were highly variable regardless of whether the comparison was to other sports (odds ratio: 0.17 to 17.92) or no sport (odds ratio: 0.54 to 3.01). CONCLUSION: Most available literature investigating swimming and low back pain is cross-sectional in design. We did not identify any clear pattern of association between swimming and low back pain, based on the available literature.

Reducing use of seclusion on a male medium secure forensic ward.

The reduction of restrictive practices is a priority for mental health inpatient services. Often such practices are considered to increase patients' feelings of anger, loneliness, hopelessness and vulnerability. Moreover, such approaches are counterintuitive to both recovery-orientated and trauma-informed practice.Our project, based in a male 15-bed secure forensic ward, aimed to reduce the duration (outcome measure) and frequency (balancing measure) of the use of seclusion by 10% over 6 months. Following the analysis of our local data systems and feedback from both patients and staff, we identified the high levels of use of seclusion, and reluctance to terminate it. These included a lack of awareness of the effective and appropriate use of such a facility, a hesitancy to use de-escalation techniques and an over-reliance on multidisciplinary team and consultant decision making.We subsequently designed and implemented three tests of change which reviewed seclusion processes, enhanced de-escalation skills and improved decision making. Our tests of change were applied over a 6-month period. During this period, we surpassed our original target of a reduction of frequency and duration by 10% and achieved a 33% reduction overall. Patients reported feeling safer on the ward, and the team reported improvements in relationships with patients.Our project highlights the importance of relational security within the secure setting and provides a template for other wards wishing to reduce the frequency and duration of seclusions.

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.

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.

How Movement Is Assessed Matters. Changes in Forward Bending During Cognitive Functional Therapy Treatment for People With Chronic Low Back Pain.

OBJECTIVE: To investigate forward bending range of motion (ROM) and velocity in patients with low back pain who were receiving Cognitive Functional Therapy and determine (1) the amount and timing of change occurring at the trunk and pelvis (global angles), and lumbar spine (intersensor angle), and (2a) differences in changes between participants with and without sensor biofeedback, and (2b) participants with and without baseline movement limitation. DESIGN: Observational study. METHODS: Two hundred sixty-one participants attended Cognitive Functional Therapy treatment and wore sensors at the T12 and S2 spine levels while performing forward bending. Measures included ROM and velocity from both sensors, and the intersensor angle. Regression models estimated changes over time. Time-group interactions tested participants who were subgrouped by treatment and baseline movement. RESULTS: During the 90-day evaluation period, most change occurred in the first 21 days. Changes in ROM observed at T12 (3.3°, 95% CI: 1.0°, 5.5°; P = .001) and S2 (3.3°, 95% CI: 1.2°, 5.4°; P = .002) were similar. Intersensor angle remained similar (0.2°, 95% CI: -2.0°, -1.6°; P = .81). Velocity measured at T12 and S2, and the intersensor angle increased 8.5°/s (95% CI: 6.7°/s, 10.3°/s; P<.0001), 5.3°/s (95% CI: 4.0°/s, 6.5°/s; P<.0001), and 3.4°/s (95% CI: 2.4°/s, 4.5°/s; P<.0001), respectively, for 0 to 21 days. There were minimal differences in participants who received biofeedback. Larger increases occurred in participants with restricted ROM and slower velocity at baseline. CONCLUSION: During 0 to 21 days, we observed changes at the trunk and pelvis (especially in people with reduced ROM), and velocity changes across all measures (especially in people with baseline movement limitations). Biofeedback did not augment the changes. When targeting forward bending in people with low back pain, clinicians should monitor changes in velocity and global ROM. J Orthop Sports Phys Ther 2024;54(3):1-13. Epub 19 December 2023. doi:10.2519/jospt.2023.12023.

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.

Adverse childhood experience is associated with an increased risk of reporting chronic pain in adulthood: a stystematic review and meta-analysis.

Background: Adverse childhood experiences (ACEs) have been shown to negatively affect health in adulthood. Estimates of associations between ACEs and chronic painful conditions are lacking.Objectives: This systematic review and meta-analysis aimed to evaluate associations between exposure to ACEs and chronic pain and pain-related disability in adults.Methods: We searched 10 electronic databases from inception to February 2023. We included observational studies assessing associations between direct ACEs (childhood sexual, physical, emotional abuse, or neglect) alone or in combination with indirect ACEs (witnessing domestic violence, household mental illness), and adult chronic pain (≥3 months duration) and pain-related disability (daily activities limited by chronic pain). Pairs of reviewers independently extracted data and assessed study risks of bias. Random-effect models were used to calculate pooled adjusted odds ratios [aOR]. Tau square [T2], 95% prediction intervals [95%PI] and I2 expressed the amount of heterogeneity, and meta-regressions and subgroup meta-analyses investigated sources of heterogeneity (PROSPERO: CRD42020150230).Results: We identified 85 studies including 826,452 adults of which 57 studies were included in meta-analyses. Study quality was generally good or fair (n = 70). The odds of reporting chronic pain in adulthood were significantly higher among individuals exposed to a direct ACE (aOR, 1.45, 95%CI, 1.38-1.53). Individuals reporting childhood physical abuse were significantly more likely to report both chronic pain (aOR, 1.50, 95CI, 1.39-1.64) and pain-related disability (1.46, 95CI, 1.03-2.08) during adulthood. Exposure to any ACEs alone or combined with indirect ACEs significantly increase the odds of adult chronic painful conditions (aOR, 1.53, 95%CI, 1.42-1.65) and pain-related disability (aOR, 1.29; 95%CI, 1.01-1.66). The risk of chronic pain in adulthood significantly increased from one ACE (aOR, 1.29, 95%CI, 1.22-1.37) to four or more ACEs (1.95, 95%CI, 1.73-2.19).Conclusions: Single and cumulative ACEs are significantly associated with reporting of chronic pain and pain-related disability as an adult.

Previous meta-analyses highlighted the negative impact of adverse childhood experiences on physical, psychological, and behavioural health across the lifespan.We found exposure to any direct adverse childhood experience, i.e. childhood sexual, physical, emotional abuse, or neglect alone or combined, increased the risk of reporting chronic pain and pain-related disability in adulthood.The risk of reporting chronic painful disorders increased with increasing numbers of adverse childhood experiences.