Treatment targets and outcomes in randomised controlled trials of exercise for non-specific low back pain

Persistent non-specific low back pain (NSLBP) is the leading cause of years lived with disability globally, and exercise is the most widely recommended treatment for persistent NSLBP. Previous randomised controlled trials (RCTs) tend to conclude that, on average, exercise has small to medium effects when benefits, versus comparison arms, are judged using the primary outcomes of pain and function. RCTs should select their primary outcome domain(s) and measure(s) based on the rationale of the treatment(s) they are comparing. This programme of research aimed to i) identify whether existing RCTs match their primary outcome domains to their specified exercise treatment targets, ii) explore whether better matching of primary outcome domains with exercise treatment targets might change the results and conclusions of existing RCT datasets, iii) compare whether composite outcomes composed of multiple matched outcome domains might change the estimates of the between-arm differences through secondary analysis of existing RCT datasets, and iv) gain stakeholder consensus on the treatment targets of exercise interventions in RCTs of persistent NSLBP. The systematic review included 27 exercise RCTs that, together, stated 31 treatment targets and included six primary outcome domains. Only 25% of included RCTs had primary outcomes that matched their specified treatment targets. Standardised mean differences (SMDs) of exercise versus comparison arms were larger in the matched (SMD 0.54 (95% CI 0.23 to 0.85), p=0.0006) compared to the unmatched category (SMD 0.22 (95% CI 0.01, 0.44) p=0.04), but this difference was not statistically significant (p=0.10). Secondary analyses were conducted on a total of nine previous RCT datasets. First, matching was investigated in five RCTs (n=1033) that used an unmatched primary outcome but included some of their matched outcomes as secondary outcomes, and second, by developing composite outcomes in four RCTs (n=864). Firstly, of five RCTs, three had greater SMDs and increased betweenarm statistical significance with matched outcomes compared to an unmatched primary outcome. Of four composite outcomes: three RCTs had greater SMDs and improved statistical precision using the composite outcome compared to the primary outcome in favour of exercise. Finally, a total of 39 participants contributed to two sequential nominal group consensus workshops. The final prioritised targets of exercise were: improving function, improving quality of life, reducing pain, targeting patient-specific goals, reducing fear of movement and increasing physical activity. This programme of research has highlighted the need for improved identification and specification of treatment targets of exercise interventions for persistent NSLBP. Matching the primary outcome to the treatment targets of the exercise intervention appears to be important, but composite matched outcomes may be more responsive and require further exploration in RCTs of exercise for persistent NSLBP

A systematic review and meta-analysis of pain neuroscience education for chronic low back pain: Short-and long-term outcomes of pain and disability

Background and ObjectivePain neuroscience education (PNE) has shown promising ability in previous reviews to improve pain and disability in chronic low back pain (CLBP). This review aimed to evaluate randomized controlled trials comparing the effectiveness of PNE on pain and disability in CLBP.Databases and Data TreatmentA systematic search was performed using the databases of EBSCO, Medline, Cochrane and Web of Science. Meta‐analysis was performed using the RevMan 5.1 software to pool outcomes using the random effects model, weighted mean differences (WMD), standard deviation, 95% confidence intervals and sample size. GRADEpro software was utilized to calculate overall strength of evidence.ResultsA total of 6,767 papers were found, eight were included (n = 615). Meta‐analysis for short‐term pain (n = 428) demonstrated a WMD of 0.73 (95%CI −0.14, 1.61) on a ten‐point scale of PNE against no PNE (GRADE analysis low evidence). When PNE alongside physiotherapy interventions were grouped for pain (n = 212), a WMD of 1.32 was demonstrated (95% CI 1.08, 1.56, p < 0.00001; GRADE analysis moderate evidence). Short‐term disability (RMDQ) meta‐analysis demonstrated a WMD of 0.42 (95%CI 0.28, 0.56; p < 0.00001; n = 362; GRADE analysis moderate evidence); whereas the addition of PNE to physiotherapy interventions demonstrated a WMD of 3.94 (95% CI 3.37, 4.52; p < 0.00001; GRADE analysis moderate evidence.ConclusionThis review presents moderate evidence that the addition of PNE to usual physiotherapy intervention in patients with CLBP improves disability in the short term. However, this meta‐analysis failed to show evidence of long‐term improvement on pain or disability when adding PNE to usual physiotherapy.SignificanceThis review demonstrates moderate level evidence that the use of pain neuroscience education alongside physiotherapy interventions probably improves disability and pain in the short term in chronic low back pain. These results provide greater support for the addition of pain neuroscience education in routine physiotherapy practice in chronic low back pain

Acceptability and feasibility of a multidomain harmonized data collection protocol in youth mental health

Objective To develop targeted treatment for young people experiencing mental illness, a better understanding of the biological, psychological, and social changes is required, particularly during the early stages of illness. To do this, large datasets need to be collected using standardized methods. A harmonized data collection protocol was tested in a youth mental health research setting to determine its acceptability and feasibility. Method Eighteen participants completed the harmonization protocol, including a clinical interview, self-report measures, neurocognitive measures, and mock assessments of magnetic resonance imaging (MRI) and blood. The feasibility of the protocol was assessed by recording recruitment rates, study withdrawals, missing data, and protocol deviations. Subjective responses from participant surveys and focus groups were used to examine the acceptability of the protocol. Results Twenty-eight young people were approached, 18 consented, and four did not complete the study. Most participants reported positive subjective impressions of the protocol as a whole and showed interest in participating in the study again, if given the opportunity. Participants generally perceived the MRI and neurocognitive tasks as interesting and suggested that the assessment of clinical presentation could be shortened. Conclusion Overall, the harmonized data collection protocol appeared to be feasible and generally well-accepted by participants. With a majority of participants finding the assessment of clinical presentation too long and repetitive, the authors have made suggestions to shorten the self-reports. The broader implementation of this protocol could allow researchers to create large datasets and better understand how psychopathological and neurobiological changes occur in young people with mental ill-health

Pain catastrophising and kinesiophobia mediate pain and physical function improvements with Pilates exercise in chronic low back pain::a mediation analysis of a randomised controlled trial

How much are the reductions in pain intensity and improvements in physical function from Pilates exercise mediated by changes in pain catastrophising and kinesiophobia? This was a secondary causal mediation analysis of a four-arm randomised controlled trial testing Pilates exercise dosage (once, twice or thrice per week) against a booklet control. Two hundred and fifty-five people with chronic low back pain. All analyses were conducted in R software (version 4.1.2) following a preregistered analysis plan. A directed acyclic graph was constructed to identify potential pre-treatment mediator-outcome confounders. For each mediator model, we estimated the intervention-mediator effect, the mediator-outcome effect, the total natural indirect effect (TNIE), the pure natural direct effect (PNDE), and the total effect (TE). Pain catastrophising mediated the effect of Pilates exercise compared with control on the outcomes pain intensity (TNIE MD -0.21, 95% CI -0.47 to -0.03) and physical function (TNIE MD -0.64, 95% CI -1.20 to -0.18). Kinesiophobia mediated the effect of Pilates exercise compared with control on the outcomes pain intensity (TNIE MD -0.31, 95% CI -0.68 to -0.02) and physical function (TNIE MD -1.06, 95% CI -1.70 to -0.49). The proportion mediated by each mediator was moderate (21 to 55%). Reductions in pain catastrophising and kinesiophobia partially mediated the pathway to improved pain intensity and physical function when using Pilates exercise for chronic low back pain. These psychological components may be important treatment targets for clinicians and researchers to consider when prescribing exercise for chronic low back pain. [Abstract copyright: Copyright © 2023 Australian Physiotherapy Association. Published by Elsevier B.V. All rights reserved.

Conducting a Large Public Health Data Collection Project in Uganda: Methods, Tools, and Lessons Learned

We report on the implementation experience of carrying out data collection and other activities for a public health evaluation study on whether U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) investment improved utilization of health services and health system strengthening in Uganda. The retrospective study period focused on the PEPFAR scale-up, from mid-2005 through mid-2011, a period of expansion of PEPFAR programing and health services. We visited 315 health care facilities in Uganda in 2011 and 2012 to collect routine health management information system data forms, as well as to conduct interviews with health system leaders. An earlier phase of this research project collected data from all 112 health district headquarters, reported elsewhere. This article describes the lessons learned from collecting data from health care facilities, project management, useful technologies, and mistakes. We used several new technologies to facilitate data collection, including portable document scanners, smartphones, and web-based data collection, along with older but reliable technologies such as car batteries for power, folding tables to create space, and letters of introduction from appropriate authorities to create entrée. Research in limited-resource settings requires an approach that values the skills and talents of local people, institutions and government agencies, and a tolerance for the unexpected. The development of personal relationships was key to the success of the project. We observed that capacity building activities were repaid many fold, especially in data management and technology

Transcriptome dynamics of CD4⁺ T cells during malaria maps gradual transit from effector to memory

The dynamics of CD4⁺ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4⁺ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (T_H1) and follicular helper T (T_(FH)) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T_H1 and T_(FH) trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between T_(FH) and central memory were revealed, with antimalarials modulating these responses and boosting T_H1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4⁺ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene–gene correlations (http://haquelab.mdhs.unimelb.edu.au/cd4_memory/)

Outcome measures for children with mitochondrial disease: consensus recommendations for future studies from a Delphi-based international workshop

Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the effectiveness of potential treatments. There is no consensus on which outcome measures to use in children with mitochondrial disease. The aims of this two-day Delphi-based workshop were to (i) define the protocol for an international, multi-centre natural history study in children with mitochondrial myopathy and (ii) to select appropriate outcome measures for a validation study in children with mitochondrial encephalopathy. We suggest two sets of outcome measures for a natural history study in children with mitochondrial myopathy and for a proposed validation study in children with mitochondrial encephalopathy

Transcriptome dynamics of CD4⁺ T cells during malaria maps gradual transit from effector to memory

The dynamics of CD4⁺ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4⁺ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (T_H1) and follicular helper T (T_(FH)) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T_H1 and T_(FH) trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between T_(FH) and central memory were revealed, with antimalarials modulating these responses and boosting T_H1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4⁺ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene–gene correlations (http://haquelab.mdhs.unimelb.edu.au/cd4_memory/)