Associations between regional blood-brain barrier permeability, aging, and Alzheimer's disease biomarkers in cognitively normal older adults.

BACKGROUND: Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer's disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD. METHODS: We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, Ktrans values were compared based on sex, Aß positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers. RESULTS: OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or Aß positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global Aß pathology, but there was a trend for an Ab status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR. DISCUSSION: Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aß.

An online pain management program for people with hypermobile Ehlers-Danlos Syndrome or hypermobility spectrum disorder: a three-staged development process.

PURPOSE: Hypermobile Ehlers-Danlos Syndrome (hEDS) and hypermobility spectrum disorder (HSD) are painful, chronic and multi-systemic conditions. No online pain management programs for hEDS/HSD currently exist. We aimed to develop one by exploring what people with hEDS/HSD want in such programs. MATERIALS AND METHODS: A Delphi was conducted via online surveys of stakeholders: participants with hEDS/HSD and healthcare professionals (HCP). In survey 1, participants were asked if a hEDS/HSD-specific online pain management program was important, listing up to 20 topics important to know about pain. In survey 2, participants rated the importance of those topics. Consensus was set as ≥75% rating of at least "important". Using topics that reached consensus, the online program was developed. Usability testing was performed using the Systems Usability Scale (SUS). RESULTS: 396 hEDS/HSD and 29 HCP completed survey 1; 151 hEDS/HSD and 12 HCP completed survey 2. 81% of hEDS/HSD and 69% of HCP rated a hEDS/HSD-specific program as at least "important". Thirty-five topics reached consensus to guide content for the HOPE program (Hypermobile Online Pain managemEnt). SUS score was 82.5, corresponding to "high acceptability". CONCLUSIONS: A hEDS/HSD-specific online pain management program is important to stakeholders. Utilising a Delphi approach to incorporate stakeholder input, an evidence-informed and user appropriate program was developed.

Pain is one of the most common and impactful symptom affecting those with Hypermobile Ehlers-Danlos Syndrome (hEDS) and hypermobility spectrum disorder (HSD).Online pain management programs are effective in other chronic conditions such as Fibromyalgia and Rheumatoid Arthritis, but there are no programs specific for hEDS/HSD.People with hEDS or HSD and healthcare professionals with experience in these conditions feel that an online pain management program specific to their condition is important; consensus revealed thirty-five key topics important to these stakeholders.The first hEDS/HSD-specific online pain management program, called HOPE, was developed with stakeholder input and usability tested, ready for clinical trial testing.

Delivering Load-Modifying Gait Retraining Interventions via Telehealth in People With Medial Knee Osteoarthritis: A Pilot Randomized Placebo-Controlled Clinical Trial.

We aimed to investigate the effects of delivering 3 gait retraining interventions (toe-in, toe-out, and placebo gait) on proxy measures of medial knee load (early- and late-stance peak knee adduction moment [KAM], KAM impulse, and varus thrust) in people with knee osteoarthritis, using a hybrid model of face-to-face and telehealth-delivered sessions over 5 months. This was an originally planned 3-arm randomized placebo-controlled clinical trial. However, during the 2021 COVID-19 outbreak and lockdown in Sydney, Australia, the study became a pilot randomized controlled trial with the remainder of interventions delivered via telehealth. Nine individuals with symptomatic medial knee osteoarthritis were allocated to receive either a toe-in, toe-out, or posture re-education (placebo) gait retraining intervention. Primary outcomes of early- and late-stance peak KAM, KAM impulse, and varus thrust were assessed at baseline and follow-up. Eight participants returned for their follow-up gait assessment. Participants in both active intervention groups (toe-in and toe-out) achieved foot progression angle changes at follow-up. Overall, knee biomechanics in the placebo group did not change at follow-up. It is possible to achieve biomechanical changes in individuals with medial knee osteoarthritis when delivering gait retraining interventions via a hybrid model of face-to-face and telehealth.

Toe-in and toe-out gait retraining interventions to reduce proxy measures of medial knee joint load in people with medial knee osteoarthritis: Protocol for a randomised placebo-controlled trial.

OBJECTIVE: Our primary aim is to determine the effect of a six-week toe-in, toe-out and active placebo gait retraining program on proxy measures of medial knee joint load and varus thrust in people with medial knee osteoarthritis. Our secondary aim is to determine the intervention effects on patient reported outcomes and physical function and determine if changes are maintained at three-months follow-up. METHODS: We will conduct a three-arm randomised placebo-controlled trial. Ninety participants with medial knee osteoarthritis will be randomised and stratified via varus thrust status (presence/absence) to: toe-in, toe-out or placebo gait retraining (an intervention that does not change proxy measures of medial knee joint load). The intervention involves weekly clinician-supervised sessions with biofeedback, knee osteoarthritis education, motor learning and behaviour change principles, and daily gait retraining practice. Primary outcomes are proxy measures of medial knee joint load: knee adduction moment (early- and late-stance peaks and impulse), and varus thrust (presence/absence). Secondary outcomes include pain, physical function, medication and health care utilisation, quality of life, work ability, treatment blinding, intervention credibility and other biomechanical outcomes. Assessment timepoints are at baseline, six weeks (post intensive training), and three-months following the six-week intervention. CONCLUSION: Our trial will determine whether toe-in or toe-out gait retraining is most effective at reducing proxy measures of medial knee joint load and varus thrust in people with medial knee osteoarthritis. This study will also evaluate if toe-in or toe-out gait retraining interventions are superior at improving pain, physical function and quality of life compared to placebo. CLINICAL TRIAL REGISTRATION: This clinical trial protocol is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000414819).

Prevalence of Nonsteroidal Antiinflammatory Drugs Prescribed for Osteoarthritis: A Systematic Review and Meta-Analysis of Observational Studies.

OBJECTIVE: Our systematic review aimed to investigate the proportion of participants with osteoarthritis who were prescribed nonsteroidal antiinflammatory drugs (NSAIDs) by their health care provider. METHODS: Electronic databases were searched for observational studies reporting NSAID prescribing to participants with diagnosed osteoarthritis of any region. Risk of bias was assessed using a tool designed for observational studies measuring prevalence. Random and fixed-effects meta-analysis was used. Meta-regression investigated study-level factors associated with prescribing. The overall evidence quality was assessed using Grading of Recommendations Assessment, Development, and Evaluation criteria. RESULTS: Fifty-one studies were included, published between 1989 and 2022, with 6,494,509 participants. The mean age of participants was 64.7 years (95% confidence interval [95% CI] 62.4, 67.0; n = 34 studies). Most studies were from Europe and Central Asia (n = 23 studies), and North America (n = 12 studies). Most studies were judged to be at low risk of bias (75%). Heterogeneity was eliminated when removing studies with a high risk of bias, to give a pooled estimate of NSAIDs prescribing to participants with osteoarthritis of 43.8% (95% CI 36.8, 51.1; moderate quality of evidence). Meta-regression determined that prescribing was associated with year (decreased prescribing over time; P = 0.05) and geographic region (P = 0.03; higher in Europe and Central Asia and in South Asia than in North America) but not with clinical setting. CONCLUSION: Data from over 6.4 million participants with osteoarthritis between 1989 and 2022 indicate that NSAID prescribing has decreased over time and that prescribing differs between geographic locations.

Online pain management programs for chronic, widespread musculoskeletal conditions: A systematic review with meta-analysis.

Face-to-face pain management programs demonstrate positive clinical outcomes in the chronic pain population by improving pain intensity and attitudes, depression, and functional disability scores. The effects of this modality carried out online is less known, particularly in subgroups of chronic pain. This systematic review assessed the effects of online pain management programs in chronic, widespread musculoskeletal conditions on pain measurements (intensity, interference, coping, and catastrophizing), health-related quality of life, depression, and anxiety scores immediately post-intervention. Five electronic databases (Embase, Medline, CINAHL, Scopus, and PEDro) were searched with 3546 studies identified. Eighteen randomized controlled trials fulfilled the inclusion criteria. Included studies had moderate methodological quality (using the Effective Public Health Practice Project (EPHPP) quality assessment tool) but high risk of bias (using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2)). There were significant improvements in pain intensity (11 studies, 1397 participants, SMD -0.30, 95% CI -0.50 to -0.10, p = 0.004), health-related quality of life (eight studies, 1054 participants, SMD 0.41, 95% CI 0.08 to 0.75, p = 0.02), and depression (nine studies, 1283 participants, SMD -0.32, 95% CI -0.55 to -0.08, p = 0.008). However, effect sizes were small and did not meet their respective measure's minimal clinically important change score. Guided interventions (regular interaction with an instructor) appeared to be superior to self-completed interventions. Future research should standardize outcome measures for assessing pain, use active control groups, and analyze other outcome measures such as cost and long-term effects. This study was registered with Prospero on August 15, 2021 (CRD42021267565).

Relationship Between Knee Biomechanics and Pain in People With Knee Osteoarthritis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Our primary aim was to determine the cross-sectional relationship between knee biomechanics during gait and pain in people with medial knee osteoarthritis. Our secondary aim was to evaluate differences in knee biomechanics between symptomatic and asymptomatic participants with medial knee osteoarthritis. METHODS: Four online databases were searched from inception to July 2021. Eligible studies included people with medial/nonspecific knee osteoarthritis and a reported relationship between knee biomechanics during gait and pain or biomechanics of symptomatic and asymptomatic participants. Two reviewers independently extracted data and evaluated risk of bias. Random-effects meta-analyses were performed when three or more studies reported the same biomechanical variable for pooling (knee adduction moment [KAM], KAM impulse, varus thrust, and peak knee flexion moment [KFM]). RESULTS: Forty studies were included. Methodological quality ranged from 4 to 9/10. Forty-seven unique biomechanical variables were reported. For the KAM, there was no correlation with pain for peak values pooled (early stance and overall) (r = 0.00, 95% confidence interval [95% CI]: -0.12, 0.11, k = 16), a small negative correlation for early stance peak alone (r = -0.09, 95% CI -0.18, -0.002, k = 12), and a medium positive correlation for the overall peak during stance (r = 0.30, 95% CI 0.17, 0.42, k = 4). Metaregression identified that body mass index moderated the peak KAM-pain relationship (P < 0.001). KAM impulse had a small positive correlation with pain (r = 0.23, 95% CI 0.04, 0.40, k = 5), and people with varus thrust had 3.84 greater odds of reporting pain compared with people without (95% CI 1.72, 8.53, k = 3). Meta-analyses for the peak KFM and pain correlation and secondary aim were nonsignificant. CONCLUSION: Some knee gait biomechanics were associated with pain in this cohort. Longitudinal studies are required to determine causality.

A Framework to Guide the Development of Health Care Professional Education and Training in Best Evidence Osteoarthritis Care.

Osteoarthritis (OA) is a leading cause of disability. Clinical practice guidelines recommend education on OA management, exercise, and weight control. However, many people with OA do not receive this recommended OA care. Some health care professionals (HCPs) lack the knowledge and skills to deliver recommended OA care. This article presents a framework to guide the development and evaluation of education and training for HCPs in the delivery of evidence-based OA care including: (1) Overarching principles for education and training; (2) Core capabilities for the delivery of best evidence OA care; (3) Theories of learning and preferences for delivery; (4) Evaluation of education and training.

Best-practice clinical management of flares in people with osteoarthritis: A scoping review of behavioral, lifestyle and adjunctive treatments.

INTRODUCTION: Transient episodes of increased pain, stiffness or swelling are common in people with osteoarthritis (OA). Yet, evidence-based management strategies for lessening the impact of OA flares are rarely covered in clinical guidelines and have been identified as a gap by clinicians delivering OA care. We aimed to identify evidence on behavioral, lifestyle or other adjunctive flare management strategies that could be used by clinicians or consumers. MATERIALS AND METHODS: A literature search between 1990-2020 was performed in three databases using a scoping methodology. We included qualitative or quantitative studies, and reviews that examined OA flare management, or that reported OA flare outcomes at timepoints ≤2 weeks post-intervention. Outcomes included any physical or psychological OA outcome treatable with a therapeutic intervention. RESULTS: We included 9 studies, all of which examined the relationship between therapeutic exercise/ physical activity and OA flares. All studies reported pain outcomes at the knee. Two also included the hip. Only two studies examined specific management strategies for OA flares. Both favorably reported the benefits of undertaking an exercise program modified accordingly during an episode, but the quality of the evidence was low. DISCUSSION: This scoping review highlights the paucity of evidence available on non-pharmacological treatments of OA flare management that could influence clinical practice. At present, there is no robust evidence to support or reject any specific therapies for OA flare management in clinical practice. Future work is needed, particularly around outcomes beyond pain, trajectories of symptom improvement, and for joints other than the knee.

Can we have an overall osteoarthritis severity score for the patellofemoral joint using magnetic resonance imaging? Reliability and validity.

This work aimed to assess inter-rater reliability and agreement of a magnetic resonance imaging (MRI)-based Kellgren and Lawrence (K&L) grading for patellofemoral joint osteoarthritis (OA) and to validate it against the MRI Osteoarthritis Knee Score (MOAKS). MRI scans from people aged 45 to 75 years with chronic knee pain participating in a randomised clinical trial evaluating dietary supplements were utilised. Fifty participants were randomly selected and scored using the MRI-based K&L grading using axial and sagittal MRI scans. Raters conducted inter-rater reliability, blinded to clinical information, radiology reports and other rater results. Intra- and inter-rater reliability and agreement were evaluated using the intra-class correlation coefficient (ICC) and Cohen's weighted kappa. There was a 2-week interval between the first and second readings for intra-rater reliability. Validity was assessed using the MOAKS and evaluated using Spearman's correlation coefficient. Intra-rater reliability of the K&L system was excellent: ICC 0.91 (95% CI 0.82-0.95); weighted kappa (ĸ = 0.69). Inter-rater reliability was high (ICC 0.88; 95% CI 0.79-0.93), while agreement between raters was moderate (ĸ = 0.49-0.57). Validity analysis demonstrated a strong correlation between the total MOAKS features score and the K&L grading system (ρ = 0.62-0.67) but weak correlations when compared with individual MOAKS features (ρ = 0.19-0.61). The high reliability and good agreement show consistency in grading the severity of patellofemoral OA with the MRI-based K&L score. Our validity results suggest that the scale may be useful, particularly in the clinical environment. Future research should validate this method against clinical findings.

Non-radiographic methods of measuring global sagittal balance: a systematic review.

BACKGROUND: Global sagittal balance, describing the vertical alignment of the spine, is an important factor in the non-operative and operative management of back pain. However, the typical gold standard method of assessment, radiography, requires exposure to radiation and increased cost, making it unsuitable for repeated use. Non-radiologic methods of assessment are available, but their reliability and validity in the current literature have not been systematically assessed. Therefore, the aim of this systematic review was to synthesise and evaluate the reliability and validity of non-radiographic methods of assessing global sagittal balance. METHODS: Five electronic databases were searched and methodology evaluated by two independent reviewers using the13-item, reliability and validity, Brink and Louw critical appraisal tool. RESULTS: Fourteen articles describing six methodologies were identified from 3940 records. The six non-radiographic methodologies were biophotogrammetry, plumbline, surface topography, infra-red motion analysis, spinal mouse and ultrasound. Construct validity was evaluated for surface topography (R = 0.49 and R = 0.68, p < 0.001), infra-red motion-analysis (ICC = 0.81) and plumbline testing (ICC = 0.83). Reliability ranged from moderate (ICC = 0.67) for spinal mouse to very high for surface topography (Cronbach α = 0.985). Measures of agreement ranged from 0.9 mm (plumbline) to 22.94 mm (infra-red motion-analysis). Variability in study populations, reporting parameters and statistics prevented a meta-analysis. CONCLUSIONS: The reliability and validity of the non-radiographic methods of measuring global sagittal balance was reported within 14 identified articles. Based on this limited evidence, non-radiographic methods appear to have moderate to very high reliability and limited to three methodologies, moderate to high validity. The overall quality and methodological approaches of the included articles were highly variable. Further research should focus on the validity of non-radiographic methods with a greater adherence to reporting actual and clinically relevant measures of agreement.