Educating health professionals to implement evidence-based falls screening in hospitals.

OBJECTIVE: International evidence-based guidelines advise traditional Falls Risk Assessment Tools (FRATs) should not be routinely used to predict the risk of a patient falling in hospital. However, disinvestment from existing services can be challenging. This study applied evidence-based approaches to education design to implement best practice guidelines. DESIGN: Mixed methods using questionnaires to evaluate health professionals' knowledge of evidence-based falls risk assessment and mitigation, followed by semi-structured interviews with individual health professionals. SETTING: Five Australian hospitals. PARTICIPANTS: There were two cohorts per hospital; Cohort 1 (C1) comprised 10 clinical leaders from nursing and allied health professions. Cohort 2 (C2) included clinicians involved in routine hospital falls screening and prevention. METHODS: 46 clinical leaders received a 3-h high quality education workshop on the latest evidence in hospital falls risk assessment and how to implement a new falls screening and management tool. They were also taught the practical skills to deliver a 1-h education session to C2 (n = 129). RESULTS: The education workshop significantly changed C1's views about evidence-based guidelines for falls screening and prevention. C1 were significantly more likely than C2 to feel confident in assessing falls risk and judging and implementing the best mitigation strategies. After the workshop, C1 were prepared and motivated to educate others on falls prevention and were satisfied with the skills gained. Six months after the workshop, C1 reported feeling more prepared for preventing falls. CONCLUSION: Health professionals benefitted from an interactive education workshop on how to use a new evidence-based hospital falls screening tool to help mitigate risk. An abridged version of the workshop did not result in long lasting effects. Education is an important element aiding disinvestment from non-evidence-based services, and implementation of clinical guidelines.

Educating health professionals to optimise falls screening in hospitals: protocol for a mixed methods study.

BACKGROUND: Falls in hospitals remain a major challenge to patient safety. All hospitalised adults are at risk of falling during their inpatient stay, though this risk is not always realised by patients and clinicians. This study will evaluate the outcomes of a hospital clinician education program that teaches clinicians how to screen for falls risk and assign mitigation strategies using clinical reasoning, rather than relying on a standardised falls risk assessment tool (FRAT). The education program aims to increase clinician knowledge, motivation and confidence in screening falls risk and selecting individual falls prevention interventions. Perceptions of the education intervention will also be examined. METHODS: Participants will be a sample of convenience of nurses and allied health professionals from five Australian hospitals. For each hospital there will be two cohorts. Cohort 1 will be clinical leaders who shall receive a three-hour education program on the latest evidence in hospital falls risk assessment and how to implement a new falls screening and management tool. They will also be taught practical skills to enable them to deliver an effective one-hour in-service training session to Cohort 2. Cohort 2 will be recruited from the workforce as a whole and include nurses and other health professionals involved in routine hospital falls screening and prevention. The investigation will be framed on Keller's Model of Motivational Design and Kirkpatrick's evaluation framework. It will involve a mixed methods pre and post-test questionnaire design inclusive of semi-structured telephone interviews, to triangulate the data from multiple approaches. DISCUSSION: This study will quantify the outcomes of a high-quality clinician education program to increase knowledge of evidence-based practice for falls prevention. It is predicted that positive behavioural changes will occur in health professionals, leading to organisational change and improved patient outcomes. Furthermore, the findings from the study will inform the future refinement of educational delivery to health professionals across hospital sites. TRIAL REGISTRATION: The study has also been approved by the Australian New Zealand Clinical Trials Registry: Preventing Hospital Falls: Optimal Screening UTN U1111-1225-8450. Universal Trial Number (UTN): U1111-1228-0041 (obtained 5/2/19). Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12619000200189 (obtained 12/2/19).

JNK activation and translocation to mitochondria mediates mitochondrial dysfunction and cell death induced by VDAC opening and sorafenib in hepatocarcinoma cells.

The multikinase inhibitor sorafenib, and opening of voltage dependent anion channels (VDAC) by the erastin-like compound X1 promotes oxidative stress and mitochondrial dysfunction in hepatocarcinoma cells. Here, we hypothesized that X1 and sorafenib induce mitochondrial dysfunction by increasing reactive oxygen species (ROS) formation and activating c-Jun N-terminal kinases (JNKs), leading to translocation of activated JNK to mitochondria. Both X1 and sorafenib increased production of ROS and activated JNK. X1 and sorafenib caused a drop in mitochondrial membrane potential (ΔΨ), a readout of mitochondrial metabolism, after 60 min. Mitochondrial depolarization after X1 and sorafenib occurred in parallel with JNK activation, increased superoxide (O2•-) production, decreased basal and oligomycin sensitive respiration, and decreased maximal respiratory capacity. Increased production of O2•- after X1 or sorafenib was abrogated by JNK inhibition and antioxidants. S3QEL 2, a specific inhibitor of site IIIQo, at Complex III, prevented depolarization induced by X1. JNK inhibition by JNK inhibitors VIII and SP600125 also prevented mitochondrial depolarization. After X1, activated JNK translocated to mitochondria as assessed by proximity ligation assays. Tat-Sab KIM1, a peptide selectively preventing the binding of JNK to the outer mitochondrial membrane protein Sab, blocked the depolarization induced by X1 and sorafenib. X1 promoted cell death mostly by necroptosis that was partially prevented by JNK inhibition. These results indicate that JNK activation and translocation to mitochondria is a common mechanism of mitochondrial dysfunction induced by both VDAC opening and sorafenib.

Interventions for cancer-related fatigue: a scoping review.

Cancer-related fatigue (CRF) is common and can be distressing for some survivors. There is increasing interest in measuring levels of CRF, highlighting its impact on quality of life. This review describes the nature and scope of evidence relating to interventions for CRF. Scoping review methodology was used to identify studies, extract data, collate and summarise results. Data were collated according to cancer tumour streams, stage of illness and the types of trial interventions. A total of 447 trials and 37 systematic reviews met the inclusion criteria. Nine papers reported longitudinal results. Populations studied were predominantly of mixed cancer diagnoses and breast cancer. The most frequent interventions were exercise, pharmacological, psycho-education and mind-body interventions. Fatigue was identified as a primary outcome measure (OM) in 58% of studies, with 58 different fatigue measures reported. Emerging evidence exists for the effectiveness of fatigue interventions for some cancer types. More research on interventions with participants with the same cancer type and illness phase is needed. Measurement of severity and impact of CRF using fewer, robust OMs will permit comparisons across studies.

Monocarboxylate Transporters: Therapeutic Targets and Prognostic Factors in Disease.

Solute carrier (SLC) transporters represent 52 families of membrane transport proteins that function in endogenous compound homeostasis and xenobiotic disposition, and have been exploited in drug delivery and therapeutic targeting strategies. In particular, the SLC16 family that encodes for the 14 isoforms of the monocarboxylate transporter (MCT) family plays a significant role in the absorption, tissue distribution, and clearance of both endogenous and exogenous compounds. MCTs are required for the transport of essential cell nutrients and for cellular metabolic and pH regulation. Recent publications have indicated their novel roles in disease, and thus their potential as biomarkers and new therapeutic targets in disease are under investigation. More research into MCT isoform function, specificity, expression, and regulation will allow researchers to exploit the potential utility of MCTs in the clinic as therapeutic targets and prognostic factors of disease.

Complementary physical therapies for movement disorders in Parkinson's disease: a systematic review.

BACKGROUND: The growth and popularity of complementary physical therapies for Parkinson's disease (PD) attempt to fill the gap left by conventional exercises, which does not always directly target wellbeing, enjoyment and social participation. AIM: To evaluate the effects of complementary physical therapies on motor performance, quality of life and falls in people living with PD. DESIGN: Systematic review with meta-analysis. POPULATION: Outpatients--adults diagnosed with idiopathic PD, male or female, modified Hoehn and Yahr scale I-IV, any duration of PD, any duration of physical treatment or exercise. METHODS: Randomized controlled trials, non-randomized controlled trials and case series studies were identified by systematic searching of health and rehabilitation electronic databases. A standardized form was used to extract key data from studies by two independent researchers. RESULTS: 1210 participants from 20 randomized controlled trials, two non-randomized controlled trials and 13 case series studies were included. Most studies had moderately strong methodological quality. Dancing, water exercises and robotic gait training were an effective adjunct to medical management for some people living with PD. Virtual reality training, mental practice, aerobic training, boxing and Nordic walking training had a small amount of evidence supporting their use in PD. CONCLUSION: On balance, alternative physical therapies are worthy of consideration when selecting treatment options for people with this common chronic disease. CLINICAL REHABILITATION IMPACT: Complementary physical therapies such as dancing, hydrotherapy and robotic gait training appear to afford therapeutic benefits, increasing mobility and quality of life, in some people living with PD.

Validity and reliability of eye healthcare professionals in the assessment of glaucoma - a systematic review.

OBJECTIVE(S): To explore the validity and reliability of eye healthcare professionals with different levels of training in diagnosing and/or identifying glaucomatous progression. CLINICAL RELEVANCE: Substantial pressure is being placed on our current eye healthcare workforce by chronic diseases such as glaucoma. Shared care schemes and role expansion of professionals other than ophthalmologists are being proposed to alleviate this pressure. A sound evidence base is imperative to determine whether other allied health professionals are skilled and clinically competent, when it comes to taking on these new roles in glaucoma management. METHODS: A systematic review of research articles identified in MEDLINE, CINAHL, Embase, Scopus and Cochrane Library was performed. Studies which investigated rater reliability of various health professionals in diagnosing and/or identifying glaucoma progression against a reference standard were included. RESULTS: Of the 4088 publications identified by the initial database search, 32 met the inclusion criteria. The majority of studies demonstrated positive results, with most finding moderate to substantial agreement for inter- and intra-rater reliability across all testing modalities. The eye health professionals with ophthalmology training consistently attained the greatest agreement. When allied health professionals with different levels of training were compared, those who had completed residency training were significantly better than those who had not. CONCLUSION: The studies included in this review show promising results, including those raters without ophthalmology training. A lack of power calculations, unequal sample sizes in some studies and the diversity of the testing procedures used make it difficult to make sound inferences.

Rural living and health-related quality of life in Australians with Parkinson's disease.

INTRODUCTION: The motor and non-motor symptoms associated with idiopathic Parkinson's disease (PD) may compromise the health-related quality of life (HRQOL) of some individuals living with this debilitating condition. Although growing evidence suggests that PD may be more prevalent in rural communities, there is little information about the life quality of these individuals. This study examines whether HRQOL ratings vary in relation to rural and metropolitan life settings. METHODS: An analytic cross-sectional study was conducted to compare the HRQOL of two separate samples of people with PD living in metropolitan Melbourne and rural Victoria. The metropolitan sample consisted of 210 individuals who had participated in the baseline assessment for an existing clinical trial. The rural sample comprised 24 participants who attended community-based rehabilitation programs and support groups in rural Victoria. Health-related quality of life was quantified using the Parkinson's Disease Questionnaire-39 (PDQ-39). RESULTS: The HRQOL of participants in rural Australia differed from individuals living in a large metropolitan city (p=0.025). Participants in rural Australia reported worse overall HRQOL, after controlling for differences in disease duration. Their overall HRQOL was lower than for city dwellers. Rural living was also found to be a significant negative predictor of HRQOL (ß=0.14; 95% CI -1.27 to -0.08; p=0.027). CONCLUSION: The findings of this study suggest that some people with PD living in rural Victoria perceive their HRQOL to be relatively poor. In order to minimise the debilitating consequences of this disease, further studies examining the factors that may contribute to the HRQOL of individuals living in rural and remote areas are required.

A comparison of hip joint centre localisation techniques with 3-DUS for clinical gait analysis in children with cerebral palsy.

Functional calibration techniques have been proposed as an alternative to regression equations for estimating the position of the hip within the pelvic co-ordinate system for clinical gait analysis. So far validation of such techniques has focussed on healthy adults. This study evaluated a range of techniques based on regression equations or functional calibration procedures techniques in 46 children representative of those attending a major clinical gait analysis service against previously validated 3-D ultrasound techniques for determining the hip joint centre. Best agreement with ultrasound for the position of the hip within the pelvic coordinate system was found for the Harrington equations (mean 14 mm, sd 8 mm). Sphere fitting (mean≈22 mm, sd 11 mm) performed better than transformational techniques applied locally (mean≈33 mm, sd 12 mm) or globally (mean=30 mm, sd 14 mm). The participants with cerebral palsy showed reduced range of movement compared with healthy adults. Differences between these results and studies modelling the effects of simulated noise on functional techniques can probably be attributed to differences between that noise and the soft tissue displacements that are actually occurring.

Planned stopping in people with Parkinson.

The aim of this study was to quantify gait termination in people with Parkinson (PwP) as the basis for understanding the underlying pathophysiology of stopping difficulties. Fourteen PwP and 14 age- and gender-matched comparisons completed five trials each of four walking tasks: preferred walk, preferred walk with secondary motor task, coming to a planned stop, and planned stop with a secondary motor task. Spatio-temporal data of walks were compared to steady state walking in stopping trials. Results showed that PwP walked with shorter step length, slower speed, yet similar cadence to comparisons. Both groups decreased step length and step speed when performing a secondary task. Neither group showed changes of gait characteristics in steady state walking prior to stopping. For stopping trials, the number of steps, time, and distance taken to stop were compared for PwP and controls. In planned stops PwP used more steps and took a longer time to stop, but both groups stopped within a similar distance. A secondary motor task did not alter stopping distance or number of steps to stop, but stopping time increased in the comparisons. The results indicate that central control mechanisms regulating planned stopping appear to be intact in people with mild to moderate Parkinson.

The role of cervical dysfunction in migraine: a systematic review.

This systematic review evaluates the strength of the evidence for the role of cervical musculoskeletal dysfunction in migraine. In this review, cervical musculoskeletal dysfunction will refer to the abnormal sensory afferentation from cervical region structures contained within the receptive field of the trigeminocervical nucleus. Electronic database searches using MEDLINE, PubMed and CINAHL were performed, and 17 studies investigating cervical musculoskeletal dysfunction in people with migraine were selected for review. The methodological quality of the included studies was assessed by two independent reviewers using a customized checklist. The review found that intersubject differences were inadequately reported and controlled, which resulted in grouping of participants with varying pathologies and symptoms. A diverse range of assessment procedures was used by the reviewed studies, which made comparison of their findings difficult. The assessment procedures were mainly used to quantify the degree of cervical musculoskeletal dysfunction, rather than to identify a cause and effect relationship between cervical structure and migrainous pain. Although animal study evidence proposes a role for cervical musculoskeletal dysfunction in migraine, this systematic review of the literature found that there is currently no convincing evidence to confirm this phenomenon in humans.

Kinematic patterns associated with accuracy of the drop punt kick in Australian Football.

Research into the kinematics of movement associated with the accuracy of the drop punt kick in Australian Football has been limited. The aim of this study was to examine pelvic and lower limb kinematics during the performance of a drop punt kick, in order to identify factors associated with accurate kicking performance. Ten professional Australian Football League (AFL) players performed 20 drop punt kicks towards a target situated 15m away, using their preferred leg. A three-dimensional motion analysis system was used to record the kicking motion from heel contact of the support limb through to ball contact. The subjects were divided into an accurate group (> or =50% accuracy; n=5) and an inaccurate group (<50% accuracy; n=5) based on target hit rate. Kinematic profiles for both kicking and support limbs were compared between the two groups. Results showed that the accurate group had significantly greater hip flexion in both limbs and greater knee flexion in the support limb throughout the kicking movement. The accurate group also had significantly greater anterior pelvic tilt at heel contact (accurate 20.8 degrees ; inaccurate 12.7 degrees ). These data show that kinematic differences in lower limb joint angles may be related to kicking accuracy.

Clinician agreement on gait pattern ratings in children with spastic hemiplegia.

The level of agreement between clinicians' ratings of gait patterns in children with spastic hemiplegia was investigated using the Winters, Gage, and Hicks (WGH) classification scale. Sixteen clinicians (nine physiotherapists, seven orthopaedic surgeons) from six gait laboratories in five different countries rated gait patterns in 34 children with spastic hemiplegia (22 males, 12 females; mean age 10y [SD 3y], range 6-18y). Archived three-dimensional gait reports (kinematic and video data) and videos (video clips only) were rated for each child. Agreement between clinicians was substantial for reports (weighted kappa [wkappa] 0.77, range 0.62-0.89). Agreement was lower for videos (wkappa 0.63, range 0.39-0.97) and for clinicians' agreement between reports and corresponding videos (wkappa 0.62, range 0.47-0.76). Exact agreement was unacceptable for some gait patterns using reports (mean 65%, range 32-74%) and videos (mean 53%, range 35-94%). Not all gait patterns could be rated using the original WGH categories. It was concluded that: (1) agreement is acceptable using the WGH tool; (2) kinematic data from 3D instrumented gait analysis and video should be used together when using the WGH scale; and (3) further refinement of this classification is required.

Foot rotation--a potential target to modify the knee adduction moment.

Isolating the particular joints/limb segments associated with knee adductor moment variability may provide clinically important data that could help to identify strategies to reduce medial tibiofemoral joint load. The aim of this study was to examine whether or not foot and thigh rotation during human locomotion are significant determinants of knee adductor moment variability. Three-dimensional gait analyses were performed on 32 healthy adult women (mean age 54+/-12 years, mean BMI 25+/-4 kg m(-2)) with radiologically normal knees. The relationships between foot rotation, thigh rotation and the external knee adduction moment were examined during early and late-stance phases of the gait cycle. The degree of foot rotation correlated significantly with the magnitude of the peak knee adduction moment during late stance (r=0.40, p=0.024). No significant associations were apparent between thigh rotation and the peak knee adduction moment. The association between foot rotation and the knee adduction moment in this study suggests that women who walk with external rotation at the foot reduce their knee adduction moment during late stance. This result implies that changes in foot kinematics can modify the medial tibiofemoral load during gait, which may be important in the prevention and management of knee osteoarthritis.

Sagittal plane movement at the tibiofemoral joint influences patellofemoral joint structure in healthy adult women.

OBJECTIVES: The influence exerted on cartilage and bone volumes by locomotor patterns is poorly understood, particularly at the patellofemoral joint. The aim of this study was to investigate the relationship between sagittal plane movement at the tibiofemoral joint and patella cartilage and bone volumes during the locomotion of healthy adult females. METHODS: Three-dimensional Vicon gait analyses and magnetic resonance imaging were performed on 20 healthy adult women. The relationships between the degree of tibiofemoral flexion and extension at varying stages of the gait cycle and the concomitant medial, lateral and total patella cartilage and total bone volumes were examined. RESULTS: For every degree the knee flexed during mid-stance, there was a 62.8 microL (95% confidence interval 3.7-122.0) increase in the medial patella facet cartilage volume after adjustment for age and the body mass index (BMI) (P = 0.04). A similar relationship that approached significance was observed for the lateral patella facet cartilage volume after adjustment for age and the BMI (P = 0.08). No association was observed between the sagittal plane tibiofemoral movements and the patella bone volume. CONCLUSIONS: The association between patella cartilage volume and tibiofemoral knee movement suggests that for every degree increase in knee flexion during mid-stance, there is an associated increase in patella cartilage volume. This may be the result of the geometry of the femoral condyle influencing patella tracking and or the retropatellar load exerted on the patella during walking. These results may have important implications for people who hyperextend their knee during gait and the pathogenesis of patellofemoral osteoarthritis.

The high-level mobility assessment tool (HiMAT) for traumatic brain injury. Part 1: Item generation.

PRIMARY OBJECTIVE: To generate a comprehensive list of items for a scale suitable for assessing high-level mobility in people with traumatic brain injury (TBI). RESEARCH DESIGN: High-level mobility items were generated following a critical evaluation of existing adult and paediatric mobility scales and by surveying expert clinicians for opinions about items appropriate for inclusion on a high-level mobility scale. MAIN OUTCOMES AND RESULTS: The critical evaluation identified 18 different items from 31 mobility scales. These included nine walking items in addition to higher level activities such as stair use, running, jumping and hopping. Expert clinicians generated 157 items that were collated and condensed to 88 items for ranking on a questionnaire. Fifteen items on the questionnaire were rated as very important by 80% of the expert clinicians. These included walking forwards, walking on slopes and different surfaces, changing direction, walking long distances and stair use. Running items included forwards, backwards, on slopes and over different surfaces, changing direction, stopping and starting as well as running long distances. Balancing in single limb stance was also included. CONCLUSION: The final list comprised walking, running, hopping, skipping, jumping and balance items. This initial version of the HiMAT has face and content validity although requires further testing to investigate whether it is uni-dimensional and valid for people with TBI.

High reproducibility of patellar tendon vascularity assessed by colour Doppler ultrasonography: a reliable measurement tool for quantifying tendon pathology.

BACKGROUND: This study examined whether patellar tendon vascularity could be quantified accurately in the clinical setting using colour Doppler ultrasonography. METHODS: A sonographer and two radiologists visually estimated tendon vascularity in millimetres in 74 tendons during ultrasound (US) examination and from hard copy films. These estimates were then compared to the length of vessels measured from the digital image in millimetres and the correlation between them was determined. A subset of 16 tendons was used to compare the estimates of vascularity by two examiners at US examination. RESULTS: The estimation of vascular length at US examination correlated highly with the measured vascular length (r = 0.92; 95% confidence interval (CI) 0.87 to 0.94), as did the length estimated from the films (r = 0.94; 95% CI 0.9 to 0.96). The correlation between examiners was 0.84 (95% CI 0.51 to 0.94) for the estimates made during US examination and 0.85 (95% CI 0.59 to 0.95) for the vessel lengths measured from the digital images. CONCLUSIONS: These excellent correlations indicate that tendon vascularity can be reliably estimated using colour Doppler ultrasonography and tendon vascularity could therefore be used by clinicians to rate clinical change. This method of quantifying tendon vascularity could also be used in research to investigate the effects of tendon treatments on vascularity.

The high-level mobility assessment tool (HiMAT) for traumatic brain injury. Part 2: content validity and discriminability.

PRIMARY OBJECTIVES: (i) To assess the measurement properties of the high-level mobility assessment tool (HiMAT) for people with traumatic brain injury (TBI), (ii) to measure the extent to which the HiMAT is a uni-dimensional, discriminative hierarchical outcome scale. RESEARCH DESIGN: The content validity was assessed using a three-stage process of investigating internal consistency, factor analysis and Rasch analysis. The uni-dimensionality of the HiMAT items was also tested. Discriminability was investigated by correlating raw and logit scores obtained from Rasch analysis. The study was conducted at a major rehabilitation facility using a convenience sample of 103 adults with TBI. MAIN OUTCOMES AND RESULTS: The internal consistency for the high-level items was very high (Cronbach's alpha = 0.99). Principal axis factoring identified several balance items as belonging to a second factor not related to high-level mobility, hence these items were excluded. Rasch analysis identified several misfitting items, such as walking around a figure of eight and stopping from a run, which were also excluded. Logit scores were used to exclude clustered and, therefore, redundant items. Raw scores correlated very highly (r = 0.98) with logit scores, indicating that raw scores provided good discriminability and were suitable for use by clinicians. CONCLUSION: The HiMAT, which assesses higher-level mobility requirements of people with TBI for return to pre-accident social, leisure and sporting activities, is a uni-dimensional and discriminative scale for quantifying therapy outcomes.

Multilevel orthopaedic surgery in group IV spastic hemiplegia.

Most children with spastic hemiplegia have high levels of function and independence but fixed deformities and gait abnormalities are common. The classification proposed by Winters et al is widely used to interpret hemiplegic gait patterns and plan intervention. However, this classification is based on sagittal kinematics and fails to consider important abnormalities in the transverse plane. Using three-dimensional gait analysis, we studied the incidence of transverse-plane deformity and gait abnormality in 17 children with group IV hemiplegia according to Winters et al before and after multilevel orthopaedic surgery. We found that internal rotation of the hip and pelvic retraction were consistent abnormalities of gait in group-IV hemiplegia. A programme of multilevel surgery resulted in predictable improvement in gait and posture, including pelvic retraction. In group IV hemiplegia pelvic retraction appeared in part to be a compensating mechanism to control foot progression in the presence of medial femoral torsion. Correction of this torsion can improve gait symmetry and function.

Reviewing knee osteoarthritis--a biomechanical perspective.

Osteoarthritis (OA) is the most common form of arthritis and is a major cause of disability in people aged over 65. Despite the major socioeconomic burden imposed by OA, the aetiology of this condition remains unclear. Although controversial, several metabolic factors have been implicated in the disease pathogenesis. Nevertheless, no unequivocal systemic risk factors for the onset or progression of OA have been identified. Recently, there has been a growing interest in the biomechanical factors associated with the pathogenesis of OA. This review aims to discuss several of the more pertinent biomechanical and neuromuscular factors, such as the knee adduction moment and muscle strength, that are becoming increasingly accepted as factors that contribute toward the pathogenesis of knee OA.