Developing a novel dual-injection FDG-PET imaging methodology to study the functional neuroanatomy of gait.

Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, we used a hybrid PET/MR system and measured glucose metabolism related to both walking and standing with a dual-injection paradigm in a single study session. For this study, 15 healthy older adults (10 females, age range: 60.5-70.7 years) with normal cognition were recruited from the community. Each participant received an intravenous injection of [18F]-2-fluoro-2-deoxyglucose (FDG) before engaging in two distinct tasks, a static postural control task (standing) and a walking task. After each task, participants were imaged. To discern independent neural functions related to walking compared to standing, we applied a bespoke dose correction to remove the residual 18F signal of the first scan (PETSTAND) from the second scan (PETWALK) and proportional scaling to the global mean, cerebellum, or white matter (WM). Whole-brain differences in walking-elicited neural activity measured with FDG-PET were assessed using a one-sample t-test. In this study, we show that a dual-injection paradigm in healthy older adults is feasible with biologically valid findings. Our results with a dose correction and scaling to the global mean showed that walking, compared to standing, increased glucose consumption in the cuneus (Z = 7.03), the temporal gyrus (Z = 6.91) and the orbital frontal cortex (Z = 6.71). Subcortically, we observed increased glucose metabolism in the supraspinal locomotor network including the thalamus (Z = 6.55), cerebellar vermis and the brainstem (pedunculopontine/mesencephalic locomotor region). Exploratory analyses using proportional scaling to the cerebellum and WM returned similar findings. Here, we have established the feasibility and tolerability of a novel method capable of capturing neural activations related to actual walking and extended previous knowledge including the recruitment of brain regions involved in sensory processing. Our paradigm could be used to explore pathological alterations in various gait disorders.

In vitro bioaccessibility round robin testing for arsenic and lead in standard reference materials and soil samples.

In this study, we assessed the suitability of using a standard reference material (SRM) other than National Institute of Standards and Technology (NIST) 2710a or NIST 2711a in USEPA Method 1340 to determine arsenic (As) and lead (Pb) in vitro bioaccessibility (IVBA) and the capabilities of Canadian-based laboratories to perform the method. Five laboratories participated in an initial round robin study and analyzed NIST 2710a, NIST 2711a, BGS119, and Enviromat SS-2. Intra- and inter-laboratory variability were generally acceptable with percentage relative standard deviations (RSD) of less than 20%. The mean total As and Pb concentrations obtained for BGS119 (332 and 936 mg/kg, respectively) and the mean IVBA values (As = 14.3% and Pb = 78.1%) suggested it may be a suitable and acceptable SRM, whereas the concentration of As in Enviromat SS-2 as received (3.2 mg/kg) was deemed too low. Ten soil samples from sites with varying land use were analyzed in a follow-up round robin study using the modified IVBA method that included BGS119 as SRM. The concentrations of As and Pb in the IVBA extracts reported by the participating laboratories were comparable. The mean As IVBA values for the field-collected samples ranged from 0.1% to 56.4%; for Pb, they ranged from 7.0% to 121%. The lowest IVBA values were measured in mine site samples; the highest values were associated with smelter-affected soils. The low IVBA values correlated with high iron content. Intra- and interlaboratory reproducibility were acceptable (RSD < 30%). Based on the findings of the study, laboratories can use the modified method to provide reproducible and comparable As and Pb IVBA data. The use of BGS119 as an alternative SRM to assess contaminated sites in the province of British Columbia for regulatory purposes is recommended, as it is representative of As and Pb concentrations in contaminated soils in British Columbia. Integr Environ Assess Manag 2024;00:1-10. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

The long-term impacts of opioid use before and after joint arthroplasty: matched cohort analysis of New Zealand linked register data.

BACKGROUND: Opioids are commonly used both before and after total joint arthroplasty (TJA). OBJECTIVE: The objective of this study was to estimate the long-term effects of pre- and perioperative opioid use in patients undergoing TJA. METHODS: We used linked population datasets to identify all (n =18,666) patients who had a publicly funded TJA in New Zealand between 2011 and 2013. We used propensity score matching to match individuals who used opioids either before surgery, during hospital stay, or immediately post-discharge with individuals who did not based on a comprehensive set of covariates. Regression analysis was used to estimate the effect of opioid use on health and socio-economic outcomes over 5 years. RESULTS: Opioid use in the 3 months prior to surgery was associated with significant increases in healthcare utilization and costs (number of hospitalizations 6%, days spent in hospital 14.4%, opioid scripts dispensed 181%, and total healthcare costs 11%). Also increased were the rate of receiving social benefits (2 percentage points) and the rates of opioid overdose (0.5 percentage points) and mortality (3 percentage points). Opioid use during hospital stay or post-discharge was associated with increased long-term opioid use, but there was little evidence of other adverse effects. CONCLUSIONS: Opioid use before TJA is associated with significant negative health and economic consequences and should be limited. This has implications for opioid prescribing in primary care. There is little evidence that peri- or post-operative opioid use is associated with significant long-term detriments.

Opioids are commonly used both before and after total joint replacement surgery to manage pain in patients with osteoarthritis. This study investigates the long-term consequences of opioid use around total joint replacement surgery in New Zealand during 2011­2013 using administrative data. We compare the outcomes of surgery patients who used opioids (treatment group) to those who did not (control group) but who had very similar pre-surgery characteristics as the treatment cohort. We find that opioid use in the months prior to surgery was associated with significant increases in healthcare utilization and costs, higher likelihood of receiving social benefits, and higher risk of opioid overdose and mortality 5 years post-surgery. Opioid use during hospital stay or post-discharge was associated with increased long-term opioid use, but there was little evidence of other adverse effects. These results highlight the importance of ongoing efforts to reduce opioid use before surgery.

Healthy grocery delivery in the usual care for adults recovering from an acute coronary event: protocol for a three-arm randomised controlled trial.

INTRODUCTION: Coronary heart disease is a major contributor to the global burden of disease. Appropriate nutrition is a cornerstone of the prevention and treatment of coronary heart disease; however, barriers including cost and access to recommended foods limits long-term adherence for many. We are conducting, in adults with coronary heart disease, a randomised controlled trial comparing usual care with two dietary interventions in which usual care is augmented by 12 weeks free delivered groceries. METHODS AND ANALYSIS: Three hundred adults recovering from an acute coronary event will be recruited from outpatient cardiovascular services in three regions of Aotearoa New Zealand. Participants will be randomly allocated to three arms: usual care (control group), usual care and the free delivery of foods high in dietary fibre or usual care and the free delivery of foods high in unsaturated fats. Interventions duration is 12 weeks, with a further 12 months follow-up. The primary outcome measures are change in low-density lipoprotein (LDL) cholesterol concentration following the intervention, and a cost-effectiveness analysis of healthcare access and social costs in the year after the intervention. A broad range of secondary outcome measures include other blood lipids, anthropometry, glycaemia, inflammatory markers, gut microbiome, dietary biomarkers, food acceptability, dietary change and the facilitators and barriers to dietary change. The trial will determine whether the free provision of groceries known to reduce cardiovascular risk within usual care will be clinically beneficial and justify the cost of doing so. Results may also provide an indication of the relative benefit of foods rich in dietary fibre or unsaturated fats in coronary heart disease management. ETHICS AND DISSEMINATION: This trial, The Healthy Heart Study, has Health and Disability Ethics Committee approval (20/NTB/121), underwent Maori consultation, and has locality authority to be conducted in Canterbury, Otago and Southland. TRIAL REGISTRATION NUMBER: ACTRN12620000689976, U1111-1250-1499.

Peptide-mediated delivery of CRISPR enzymes for the efficient editing of primary human lymphocytes.

CRISPR-mediated genome editing of primary human lymphocytes is typically carried out via electroporation, which can be cytotoxic, cumbersome and costly. Here we show that the yields of edited primary human lymphocytes can be increased substantially by delivering a CRISPR ribonucleoprotein mixed with an amphiphilic peptide identified through screening. We evaluated the performance of this simple delivery method by knocking out genes in T cells, B cells and natural killer cells via the delivery of Cas9 or Cas12a ribonucleoproteins or an adenine base editor. We also show that peptide-mediated ribonucleoprotein delivery paired with an adeno-associated-virus-mediated homology-directed repair template can introduce a chimaeric antigen receptor gene at the T-cell receptor α constant locus, and that the engineered cells display antitumour potency in mice. The method is minimally perturbative, does not require dedicated hardware, and is compatible with multiplexed editing via sequential delivery, which minimizes the risk of genotoxicity. The peptide-mediated intracellular delivery of ribonucleoproteins may facilitate the manufacturing of engineered T cells.

Reducing the burden of knee osteoarthritis through community pharmacy: Protocol for a randomised controlled trial of the Knee Care for Arthritis through Pharmacy Service.

INTRODUCTION: Knee osteoarthritis (OA) negatively impacts the health outcomes and equity, social and employment participation, and socio-economic wellbeing of those affected. Little community-based support is offered to people with knee OA in Aotearoa New Zealand. Identifying Maori and non-Maori with knee OA in community pharmacy and providing co-ordinated, evidence- and community-based care may be a scalable, sustainable, equitable, effective and cost-effective approach to improve health and wellbeing. AIM: Assess whether the Knee Care for Arthritis through Pharmacy Service (KneeCAPS) intervention improves knee-related physical function and pain (co-primary outcomes). Secondary aims assess impacts on health-related quality of life, employment participation, medication use, secondary health care utilisation, and relative effectiveness for Maori. METHODS AND ANALYSIS: A pragmatic randomised controlled trial will compare the KneeCAPS intervention to the Pharmaceutical Society of New Zealand Arthritis Fact Sheet and usual care (active control) at 12 months for Maori and non-Maori who have knee OA. Participants will be recruited in community pharmacies. Knee-related physical function will be measured using the function subscale of the Short Form of the Western Ontario and McMaster Universities Osteoarthritis Index. Knee-related pain will be measured using an 11-point numeric pain rating scale. Primary outcome analyses will be conducted on an intention-to-treat basis using linear mixed models. Parallel within-trial health economic analysis and process evaluation will also be conducted. ETHICS AND TRIAL DISSEMINATION: Ethical approval was obtained from the Central Health and Ethics Committee (2022-EXP-11725). The trial is registered with ANZCTR (ACTRN12622000469718). Findings will be submitted for publication and shared with participants.

Are the outcomes of relative motion extension orthoses non-inferior and cost-effective compared with dynamic extension orthoses for management of zones V-VI finger extensor tendon repairs: A randomized controlled trial.

INTRODUCTION: There is no comparative evidence for relative motion extension (RME) orthosis with dynamic wrist-hand-finger-orthosis (WHFO) management of zones V-VI extensor tendon repairs. PURPOSE OF THE STUDY: To determine if RME with wrist-hand-orthosis (RME plus) is noninferior to dynamic WHFO for these zones in clinical outcomes. STUDY DESIGN: Randomized controlled non-inferiority trial. METHODS: Skilled hand therapists managed 37 participants (95% male; mean age 39 years, SD 18) with repaired zones V-VI extensor tendons randomized to RME plus (n = 19) or dynamic WHFO (n = 18). The primary outcome of percentage of total active motion (%TAM) and secondary outcomes of satisfaction, function, and quality of life were measured at week-6 and -12 postoperatively; percentage grip strength (%Grip), complication rates, and cost data at week-12. Following the intention-to-treat principle non-inferiority was assessed using linear regression analysis (5% significance) and adjusted for injury complexity factors with an analysis of costs performed. RESULTS: RME plus was noninferior for %TAM at week-6 (adjusted estimates 2.5; 95% CI -9.0 to 14.0), %TAM at week-12 (0.3; -6.8 to 7.5), therapy satisfaction at week-6 and -12, and orthosis satisfaction, QuickDASH, and %Grip at week-12. Per protocol analysis yielded 2 tendon ruptures in the RME plus orthoses and 1 in the dynamic WHFO. There were no differences in health system and societal cost, or quality-adjusted life years. DISCUSSION: RME plus orthosis wearers had greater injury complexity than those in dynamic WHFOs, with overall rupture rate for both groups comparatively more than reported by others; however, percentage %TAM was comparable. The number of participants needed was underestimated, so risk of chance findings should be considered. CONCLUSIONS: RME plus management of finger zones V-VI extensor tendon repairs is non-inferior to dynamic WHFO in %TAM, therapy and orthotic satisfaction, QuickDASH, and %Grip. Major costs associated with this injury are related to lost work time.

Is recursive "mindreading" really an exception to limitations on recursive thinking?

The ability to mindread recursively-for example, by thinking what person 1 thinks person 2 thinks person 3 thinks-is a prime example of recursive thinking in which one process, representation, or idea becomes embedded within a similar one. It has also been suggested that mindreading is an exceptional example, with five recursive steps commonly observed for mindreading, in comparison with just one or two in other domains. However, conceptual analysis of existing recursive mindreading tasks suggests that conclusions about exceptional mindreading are insecure. Revised tasks were devised to provide a more rigorous test of recursive mindreading capacity. Study 1 (N = 76) found significantly worse performance at level-5 recursive mindreading on the revised tasks (17% correct) compared with the original tasks (80% correct), and no effect of moderate financial bonuses for good performance. Study 2 (N = 74) replicated poor performance at level-5 recursive mindreading on the revised tasks (15% correct) in the absence of bonuses, but found better performance (45% correct) when participants were offered large bonuses for accuracy, encouraged to take as much time as needed, and assisted with a strategy for recursive reasoning. These findings suggest that, like recursive thinking in other domains, recursive mindreading is effortful and limited. We discuss how the proposed role for high levels of recursive mindreading in communication, culture, and literature might be reconciled with these limitations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Safety and tolerability of adjunct non-invasive vagus nerve stimulation in people with parkinson's: a study protocol.

BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological condition worldwide. Recent theories suggest that symptoms of PD may arise due to spread of Lewy-body pathology where the process begins in the gut and propagate transynaptically via the vagus nerve to the central nervous system. In PD, gait impairments are common motor manifestations that are progressive and can appear early in the disease course. As therapies to mitigate gait impairments are limited, novel interventions targeting these and their consequences, i.e., reducing the risk of falls, are urgently needed. Non-invasive vagus nerve stimulation (nVNS) is a neuromodulation technique targeting the vagus nerve. We recently showed in a small pilot trial that a single dose of nVNS improved (decreased) discrete gait variability characteristics in those receiving active stimulation relative to those receiving sham stimulation. Further multi-dose, multi-session studies are needed to assess the safety and tolerability of the stimulation and if improvement in gait is sustained over time. DESIGN: This will be an investigator-initiated, single-site, proof-of-concept, double-blind sham-controlled randomised pilot trial in 40 people with PD. Participants will be randomly assigned on a 1:1 ratio to receive either active or sham transcutaneous cervical VNS. All participants will undergo comprehensive cognitive, autonomic and gait assessments during three sessions over 24 weeks, in addition to remote monitoring of ambulatory activity and falls, and exploratory analyses of cholinergic peripheral plasma markers. The primary outcome measure is the safety and tolerability of multi-dose nVNS in PD. Secondary outcomes include improvements in gait, cognition and autonomic function that will be summarised using descriptive statistics. DISCUSSION: This study will report on the proportion of eligible and enrolled patients, rates of eligibility and reasons for ineligibility. Adverse events will be recorded informing on the safety and device tolerability in PD. This study will additionally provide us with information for sample size calculations for future studies and evidence whether improvement in gait control is enhanced when nVNS is delivered repeatedly and sustained over time. TRIAL REGISTRATION: This trial is prospectively registered at www.isrctn.com/ISRCTN19394828 . Registered August 23, 2021.

Education plus exercise for persistent gluteal tendinopathy improves quality of life and is cost-effective compared with corticosteroid injection and wait and see: economic evaluation of a randomised trial.

QUESTION: For patients with gluteal tendinopathy, what is the cost utility from health system and societal perspectives of three management approaches: education plus exercise, ultrasound-guided corticosteroid injection or wait and see? DESIGN: Economic evaluation alongside a three-group, parallel, randomised clinical efficacy trial. PARTICIPANTS: People aged between 35 and 70 years with image-confirmed gluteal tendinopathy were recruited via advertisements. INTERVENTIONS: Education plus exercise, consisting of 14 visits to a physiotherapist, with detailed instruction on tendinopathy management, twice weekly supervised exercise sessions, daily home exercises, a handout and a CD; corticosteroid injection, consisting of one ultrasound-guided injection and a handout on general tendon care; and 'wait and see', consisting of one visit to a physiotherapist with assurance and advice on staying active whilst respecting pain. OUTCOME MEASURES: Economic outcome measures were quality-adjusted life years (QALYs) calculated from EuroQol EQ-5D-3L using Australian population preference weights, and total economic costs obtained from participant-reported data collected over the 1-year follow-up period. Missing data (<12% per group) were imputed. Linear regression was used to estimate incremental QALYs and costs between interventions; uncertainty was assessed by calculating 90% confidence intervals, cost-effectiveness acceptability curves and confidence ellipses. RESULTS: A total of 204 individuals (82% women) were enrolled. Incremental cost-effectiveness ratio favoured education plus exercise over corticosteroid injection (AU$12,719 and $5,592 on societal and health system perspectives, respectively) and over wait and see ($29,258 and $3,444 on societal and health system perspectives, respectively). Complete case analysis and varying the direct intervention costs did not change the (imputed analysis) results, with the exception that corticosteroid injection was less cost-effective. CONCLUSION: Education plus exercise for gluteal tendinopathy improves health-related quality of life and is cost-effective compared with corticosteroid injection and wait and see for treating gluteal tendinopathy. REGISTRATION: ACTRN12612001126808.

A Guideline-Implementation Intervention to Improve the Management of Low Back Pain in Primary Care: A Difference-in-Difference-in-Differences Analysis.

BACKGROUND: Real-world adherence to clinical practice guidelines is often poor, resulting in sub-standard patient care and unnecessary healthcare costs. This study evaluates the effect of a guideline-implementation intervention for the management of low back pain (LBP) in general practice-the Fear Reduction Exercised Early (FREE) approach-on LBP-related injury insurance claims, healthcare utilisation, and costs of treatment. DESIGN: Data were extracted from comprehensive nationwide New Zealand injury insurance claims records. Data were analysed using a 'triple-difference' (difference-in-difference-in-differences) method to isolate the causal effect of FREE training on LBP claims activity, comparing the difference in general practitioner (GP) LBP claims and associated activity before and after training with their non-musculoskeletal injury claims for the same periods (assumed to be unaffected by training), relative to the same comparisons for GPs not trained in the FREE approach. RESULTS: Training GPs in the FREE approach resulted in significant reductions in the number of LBP injury claims lodged (- 19%, 95% CI -34 to -5), the use of physiotherapy (-30%, 95% CI - 42 to - 18) and imaging (- 27%, 95% CI - 46 to - 8%), and the healthcare costs (- 21%, 95% CI - 41 to - 1) of LBP injury. Changes in claims for earnings' compensation (- 10%, 95% CI - 34 to 13) were not significant. CONCLUSIONS: A brief guideline-implementation intervention following best-practice LBP management and guideline-implementation strategies achieved significant reductions, persisting over at least 6 to18 months, in healthcare utilisation consistent with improved delivery of guideline-concordant care.

Epidemiology of cruciate ligament injuries in New Zealand: exploring differences by ethnicity and socioeconomic status.

OBJECTIVES: To investigate the temporal trends and ethnic and socioeconomic disparities in cruciate ligament (CL) injury incidence and associated costs in New Zealand over a 14-year period. METHODS: All CL injury claims lodged between 2007 and 2020 were extracted from the Accident Compensation Corporation (a nationwide no-fault injury compensation scheme) claims dataset. Age-adjusted and sex-adjusted incidence rates, total injury costs and costs per claim were calculated for each year for total population and subgroups. RESULTS: The total number of CL injury claims increased from 6972 in 2007 to 8304 in 2019, then decreased to 7068 in 2020 (likely due to widespread COVID-19 restrictions; analysis is therefore restricted to 2007-2019 hereafter). The (age-adjusted and sex-adjusted) incidence rate remained largely unchanged and was 173 cases per 100 000 people in 2019. There was a 127% increase in total injury claims costs and a 90% increase in costs per claim. Pacific people had the highest incidence rate and costs per 100 000 people, while Asians had the lowest; European, Maori and 'other' ethnicities had similar incidence rates and total costs. Incidence rates and total costs increased with income and decreased with neighbourhood deprivation. Costs per claim differed little by ethnicity, but increased with income level. CONCLUSION: The number and costs of CL injury claims in New Zealand are increasing. There are ethnic and socioeconomic disparities in CL incidence rates and costs, which are important to address when designing CL injury prevention programmes and programmes aimed at improving equity of access to medical care.

Reliability, Validity, Responsiveness, and Minimum Important Change of the Stair Climb Test in Adults With Hip and Knee Osteoarthritis.

OBJECTIVE: The Osteoarthritis Research Society International (OARSI) recommends assessment of physical function using a performance-based test of stair negotiation but was unable to recommend any specific test. We assessed the reliability, validity, responsiveness, measurement error, and minimum important change (MIC) of the 6-step timed Stair Climb Test (SCT). METHODS: We used pooled data from 397 participants with hip or knee osteoarthritis (54% women) from 4 clinical trials (86% retained at 12-week follow-up). Construct validity was assessed by testing 6 a priori hypotheses against other OARSI-recommended physical function measures. A self-reported Global Rating of Change scale was used to classify participants as worsened, improved, and stable. Participants who worsened in physical function were excluded from all analyses. Responsiveness and MIC were assessed using multiple anchor-based and distribution-based approaches. Test-retest reliability, standard error of measurement (SEM), and smallest detectable change (SDC) were assessed on stable participants. RESULTS: Five of 6 hypotheses (83%) for construct validity were met. Test-retest reliability was excellent (intraclass correlation coefficient2,1 0.83; 95% confidence interval 0.71-0.90). The SEM and SDC values were 0.44 and 1.21 seconds, respectively. We did not find adequate support for responsiveness. The MIC values ranged from 0.78 to 1.95 seconds using different approaches (median 1.37 seconds). CONCLUSION: The 6-step timed SCT adequately assesses the construct of physical function in individuals with hip or knee osteoarthritis with excellent 12-week test-retest reliability. However, support for its responsiveness was inadequate to recommend its use as an outcome measure in people with osteoarthritis for research and clinical practice.

Economic evaluation: a reader's guide to studies of cost-effectiveness.

BACKGROUND: Understanding what an economic evaluation is, how to interpret it, and what it means for making choices in a health delivery context is necessary to contribute to decisions about healthcare resource allocation. The aim of this paper to demystify the working parts of a health economic evaluation, and explain to clinicians and clinical researchers how to read and interpret cost-effectiveness research. MAIN BODY: This primer distils key content and constructs of economic evaluation studies, and explains health economic evaluation in plain language. We use the PICOT (participant, intervention, comparison, outcome, timeframe) clinical trial framework familiar to clinicians, clinical decision-makers, and clinical researchers, who may be unfamiliar with economics, as an aide to reading and interpreting cost-effectiveness research. We provide examples, primarily of physiotherapy interventions for osteoarthritis. CONCLUSIONS: Economic evaluation studies are essential to improve decisions about allocating resources, whether those resources be your time, the capacity of your service, or the available funding across the entire healthcare system. The PICOT framework can be used to understand and interpret cost-effectiveness research.

Tailored exercise and manual therapy versus standardised exercise for patients with shoulder subacromial pain: a feasibility randomised controlled trial (the Otago MASTER trial).

OBJECTIVES: The aim of this study was to assess whether it was feasible to conduct a full trial comparing a tailored versus a standardised exercise programme for patients with shoulder subacromial pain. DESIGN: Two-arm, patient-blinded and assessor-blinded, randomised controlled feasibility trial. METHODS: Twenty-eight participants with shoulder subacromial pain were randomly allocated into one of two intervention groups-tailored or standardised exercise. Participants in the tailored exercise programme received exercises and manual therapy tailored to their scapular and shoulder movement impairments. Participants in the standardised exercise programme received progressive strengthening exercise. The primary outcome measures were (1) the participant recruitment rate; (2) the proportion of participants enrolled from the total number screened; (3) drop-out rates; and (4) adherence to the rehabilitation programme. Other outcome measures were: (5) pain levels; (6) Patient-Specific Functional Scale; (7) the Shoulder Pain and Disability Index; and (8) pain self-efficacy. We compared changes in pain and disability scores between groups using a repeated mixed-model analysis of variance. Since this is a feasibility study, we did not adjust alpha for multiple comparisons, and considered 75% CI as the probability threshold at 3-month follow-up. Health-related quality of life was assessed using the Short-Form 12 and quality-adjusted life years (QALYs) were estimated. RESULTS: The recruitment rate was 3 participants per month, the proportion of participants enrolled was 23%, the drop-out rate was 14% and the overall adherence to the rehabilitation programme was 85%. No between-group differences were found for most outcome measures. Adverse events (n=2, only in the tailored group) were minor in nature and included skin injury or pain following taping. CONCLUSIONS: Our feasibility trial showed that additional strategies are required for improving recruitment, enrolment and minimising drop-out of participants into the trial and making it feasible to conduct a full trial. TRIAL REGISTRATION NUMBER: ANZCTR: 12617001405303.

Measurement Properties of the Patient-Specific Functional Scale and Its Current Uses: An Updated Systematic Review of 57 Studies Using COSMIN Guidelines.

OBJECTIVE: To systematically review measurement properties, including acceptability, feasibility, and interpretability, and current uses of the Patient-Specific Functional Scale (PSFS). DESIGN: Systematic review of a patient-reported outcome measure using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guidelines. LITERATURE SEARCH: We searched 11 databases from January 2010 to July 2020 for articles on measurement properties or use of PSFS. STUDY SELECTION CRITERIA: Published primary articles without language restrictions. DATA SYNTHESIS: Two independent reviewers screened all records, extracted data, and performed risk of bias assessments using COSMIN guidelines. We qualitatively synthesized findings for each measurement property in musculoskeletal and nonmusculoskeletal conditions, and 2 reviewers independently performed Grading of Recommendations Assessment, Development and Evaluation assessments. This study was preregistered with the Open Science Framework (https://doi.org/10.17605/OSF.IO/42UZT). RESULTS: Of the 985 articles screened, we included 57 articles on measurement properties and 255 articles on the use of PSFS. The PSFS had sufficient test-retest reliability in musculoskeletal (22 studies, 845 participants, low-to-moderate certainty) and nonmusculoskeletal conditions (6 studies, 197 participants, very low certainty), insufficient construct validity as a measure of physical function (21 studies, 2 945 participants, low-to-moderate certainty), and sufficient responsiveness (32 studies, 13 770 participants, moderate-to-high certainty). The standard error of measurement ranged from 0.35 to 1.5. The PSFS was used in 87 unique health conditions, some without prior evidence of validity. CONCLUSION: The PSFS is an easy-to-use, reliable, and responsive scale in numerous musculoskeletal conditions, but the construct validity of PSFS remains uncertain. Further study of the measurement properties of the PSFS in nonmusculoskeletal conditions is necessary before clinical use. J Orthop Sports Phys Ther 2022;52(5):262-275. Epub: 05 Feb 2022. doi:10.2519/jospt.2022.10727.

Prioritizing Healthcare Interventions: A Comparison of Multicriteria Decision Analysis and Cost-Effectiveness Analysis.

OBJECTIVES: To investigate the extent to which stated preferences for treatment criteria elicited using multicriteria decision analysis (MCDA) methods are consistent with the trade-offs (implicitly) applied in cost-effectiveness analysis (CEA), and the impact of any differences on the prioritization of treatments. METHODS: We used existing MCDA and CEA models developed to evaluate interventions for knee osteoarthritis in the New Zealand population. We established equivalent input parameters for each model, for the criteria "treatment effectiveness," "cost," "risk of serious harms," and "risk of mild-to-moderate harms" across a comprehensive range of (hypothetical) interventions to produce a complete ranking of interventions from each model. We evaluated the consistency of these rankings between the 2 models and investigated any systematic differences between the (implied) weight placed on each criterion in determining rankings. RESULTS: There was an overall moderate-to-strong correlation in intervention rankings between the MCDA and CEA models (Spearman correlation coefficient = 0.51). Nevertheless, there were systematic differences in the evaluation of trade-offs between intervention attributes and the resulting weights placed on each criterion. The CEA model placed lower weights on risks of harm and much greater weight on cost (at all accepted levels of willingness-to-pay per quality-adjusted life-year than did respondents to the MCDA survey. CONCLUSIONS: MCDA and CEA approaches to inform intervention prioritization may give systematically different results, even when considering the same criteria and input data. These differences should be considered when designing and interpreting such studies to inform treatment prioritization decisions.

The Coiled-Coil Forming Peptide (KVSALKE)5 Is a Cell Penetrating Peptide that Enhances the Intracellular Delivery of Proteins.

Protein-based therapeutics have the potential to treat a variety of diseases, however, safe and effective methods for delivering them into cells need to be developed before their clinical potential can be realized. Peptide fusions have great potential for improving intracellular delivery of proteins. However, very few peptides have been identified that can increase the intracellular delivery of proteins, and new peptides that can enhance intracellular protein delivery are greatly needed. In this report, the authors demonstrate that the coiled-coil forming peptide (KVSALKE)5 (termed K5) can function as a cell penetrating peptide (CPP), and can also complex other proteins that contain its partner peptide E5. It is shown here that GFP and Cas9 fused to the K5 peptide has dramatically enhanced cell uptake in a variety of cell lines, and is able to edit neurons and astrocytes in the striatum and hippocampus of mice after a direct intracranial injection. Collectively, these studies demonstrate that the coiled-coil forming peptide (KVSALKE)5 is a new class of multifunctional CPPs that has great potential for improving the delivery of proteins into cells and in vivo.

Are manual therapy or booster sessions worthwhile in addition to exercise therapy for knee osteoarthritis: Economic evaluation and 2-year follow-up of a randomized controlled trial.

BACKGROUND: Exercise therapy is known to be an effective intervention for patients with osteoarthritis, however the evidence is limited as to whether adding manual therapy or booster sessions are cost-effective strategies to extend the duration of benefits. OBJECTIVE: To investigate the cost-effectiveness, at 2-year follow-up, of adding manual therapy and/or booster sessions to exercise therapy. DESIGN: 2-by-2 factorial randomized controlled trial. METHODS: Participants with knee osteoarthritis were randomly allocated (1:1:1:1) to: exercise therapy delivered in consecutive sessions within 9 weeks (control group), exercise therapy distributed over 1 year using booster sessions, exercise therapy plus manual therapy delivered within 9 weeks, and exercise therapy plus manual therapy with booster sessions. The primary outcome was incremental cost-effectiveness from health system and societal perspectives interpreted as incremental net monetary benefit (INMB). RESULTS: Of 75 participants, 66 (88 %) were retained at 1-year and 40 (53 %) at 2-year follow-up. All three interventions were cost-effective from both the health system and societal perspectives (INMBs, at 0.5 × GDP/capita willingness to pay (WTP) threshold: $3278 (95%CI -3244 to 9800) and $3904 (95%CI -2823 to 10,632) respectively for booster sessions; $2941 (95%CI -3686 to 9568) and $2618 (95%CI -4005 to 9241) for manual therapy; $270 (95%CI -6139 to 6679) and $404 (95%CI -6097 to 6905) for manual therapy with booster sessions). CONCLUSION: Manual therapy or booster sessions in addition to exercise therapy are cost-effective at 2-year follow-up. The evidence did not support combining both booster sessions and manual therapy in addition to exercise therapy.