Do people with knee osteoarthritis use guideline-consistent treatments after an orthopaedic surgeon recommends nonsurgical care? A cross-sectional survey with long-term follow-up.

Objective: Describe "usual care" patterns of education, exercise, weight management, pain medication and other nonsurgical treatments for knee osteoarthritis (OA) in people recommended for nonsurgical care by an orthopaedic surgeon. Methods: We used a telephone-administered questionnaire to capture treatments people with knee OA used over the three to six years after an orthopaedic surgeon recommended nonsurgical care. The primary outcome, guideline-consistent nonsurgical treatments, was an aggregate measure defined as using education, exercise, weight management, and at least one recommended medication. Secondary outcomes were first-line (education, exercise, and weight management) and guideline-inconsistent treatments (orthoses, opioids, hyaluronic acid, platelet rich plasma, and stem cell therapy). Multivariable robust Poisson regression assessed the association between participant characteristics and use of guideline-consistent, first-line and guideline-inconsistent treatments. Results: 479 people were invited and 250 participated (52%). Participants were 58% female with a mean age 66.2 years. Participants received education by a healthcare professional (64%), exercised regularly (74%), used weight management (38%), and used recommended pain medications (91%). All guideline-consistent nonsurgical treatments were used by 19% of participants, 19% of participants used first-line treatments, and 42% used guideline-inconsistent treatments. Over six years, 34% had another consult then underwent arthroplasty. Older participants were less likely to use any treatment. People without post-secondary education were less likely to use first-line treatments (RR 0.54, 95% CI: 0.30-0.96), and females were less likely to use guideline-inconsistent treatments (RR 0.62, 95% CI:0.47-0.81). Conclusions: Nonsurgical usual care for people with knee OA was not consistent with international clinical guidelines.

A lifespan approach to osteoarthritis prevention.

Prevention is an attractive solution for the staggering and increasingly unmanageable burden of osteoarthritis. Despite this, the field of osteoarthritis prevention is relatively immature. To date, most of what is known about preventing osteoarthritis and risk factors for osteoarthritis is relative to the disease (underlying biology and pathophysiology) of osteoarthritis, with few studies considering risk factors for osteoarthritis illness, the force driving the personal, financial and societal burden. In this narrative review we will discuss what is known about osteoarthritis prevention, propose actionable prevention strategies related to obesity and joint injury which have emerged as important modifiable risk factors, identify where evidence is lacking, and give insight into what might be possible in terms of prevention by focussing on a lifespan approach to the illness of osteoarthritis, as opposed to a structural disease of the elderly. By targeting a non-specialist audience including scientists, clinicians, students, industry employees and others that are interested in osteoarthritis but who do not necessarily focus on osteoarthritis, the goal is to generate discourse and motivate inquiry which propel the field of osteoarthritis prevention into the mainstream.

Osteoarthritis year in review 2020: rehabilitation and outcomes.

OBJECTIVE: Systematically review and synthesize guidelines, systematic reviews, or randomized controlled trials (RCTs) published between April 1, 2019 and April 30, 2020 which evaluated or made recommendations for rehabilitation of persons with osteoarthritis. DESIGN: Five electronic databases (Medline, EMBASE, Cochrane CENTRAL, CINHAL, Web of Science) were searched with a comprehensive search strategy. Guidelines for rehabilitation of persons with osteoarthritis, and systematic reviews and RCTs evaluating osteoarthritis rehabilitation that included at least one patient-reported outcome measure and/or clinical test of function were included. Two authors independently screened records and assessed methodological quality using the AGREE-II (guidelines), AMSTAR-2 (systematic reviews) or PEDro scale (RCTs). Data were extracted to summarize included records and a narrative synthesis of findings related to core recommended osteoarthritis rehabilitation treatments performed. RESULTS: Of 2,479 potential records, 253 records were reviewed. Two guidelines, 18 systematic reviews and 38 RCTs were included. 84% (n = 49) of included records related to knee osteoarthritis, 13% (n = 8) to hip, 10% (n = 6) to hand, 3% (n = 2) to mixed, and 1% (n = 1) to foot osteoarthritis. Exercise-therapy, methods to deliver exercise-therapy remotely, and approaches to facilitate exercise-therapy behaviour change were the most commonly evaluated interventions (n = 27). 94% of systematic reviews and 63% of RCTs rated high-quality. CONCLUSIONS: Osteoarthritis rehabilitation research continues to focus on knee osteoarthritis and exercise-based interventions. Emerging topics include rehabilitation of comorbid populations, exercise behaviour change and technology supports. A better understanding of rehabilitation of osteoarthritis in joints other than the knee, and methods to determine and promote ideal exercise-therapy prescription are needed.

CCL22 is a biomarker of cartilage injury and plays a functional role in chondrocyte apoptosis.

BACKGROUND: Osteoarthritis (OA) is one of the leading causes of disability worldwide. Previous history of knee injury is a significant risk factor for OA. It has been established that low-level chronic inflammation plays a pivotal role in the onset and pathogenesis of OA. The primary aim of this research was to determine if a history of knee joint injury is associated with systemic inflammation. A secondary aim was to determine if systemic inflammation is related to knee pain and joint structure. METHODS: Differences in serum cytokine association networks, knee joint structural changes (MRI), and self-reported pain (i.e., Knee Injury and Osteoarthritis Outcome Score Pain subscale, KOOSPAIN and Intermittent and Constant Osteoarthritis Pain score, ICOAP) between individuals who had sustained a youth (aged 15-26 years) sport-related knee injury 3-10 years previously and age- and sex-matched controls were examined. Proteins of interest were also examined in an OA rat model. RESULTS: Cytokine association networks were found to differ significantly between study groups, yet no significant associations were found between networks and KOOSPAIN or MRI-defined OA. A group of cytokines (MCP1/CCL2, CCL22 and TNFα) were differentially associated with other cytokines between study groups. In a pre-clinical rat OA model, serum CCL22 levels were associated with pain (r = 0.255, p = 0.045) and structural changes to the cartilage. CCL22 expression was also observed in human OA cartilage and furthermore, CCL22 induced apoptosis of isolated human chondrocytes. DISCUSSION: These results suggest that CCL22 may be an early factor in the onset/pathogenic process of cartilage degeneration and/or related to pain OA.

Serum cartilage oligomeric matrix protein (COMP) expression in individuals who sustained a youth sport-related intra-articular knee injury 3-10 years previously and uninjured matched controls.

OBJECTIVE: This study investigates the relationship between a youth sport-related intra-articular knee injury and cartilage oligomeric matrix protein (COMP), a biomarker of cartilage turnover. DESIGN: Participants included a sub-sample (n = 170) of the Alberta Youth Prevention of Early Osteoarthritis (PrE-OA) study group. Specifically, 85 individuals with a 3-10 year history of sport-related intra-articular knee injury and 85 age, sex and sport-matched controls. COMP levels were investigated in serum. Between group differences in COMP levels, COMP fragmentation patterns and, the relationship between serum COMP and clinical outcomes (i.e., Magnetic Resonance Imaging (MRI) Osteoarthritis Knee Score; MOAKS, Knee Osteoarthritis Outcome Score; KOOS, Fat mass index; FMI) were examined. RESULTS: Participant median age was 22.3 years (range 16-26) and 63% were female. Although there was no difference in COMP levels between previously injured and uninjured females, previously injured males demonstrated an ∼15% greater (171.5 ng/ml, 95% CI 11.0-428.0, P = 0.04) serum COMP level than uninjured males. However after controlling for FMI, this difference was absent. Within the injured participants, COMP levels were associated with MOAKSSYNOVITIS and FMI. Furthermore, COMP fragmentation patterns were distinct between injured and uninjured individuals. CONCLUSIONS: In this study group, serum COMP levels were greater in injured males, but not females, compared to matched controls. However, after controlling for FMI, no differences in COMP were observed. A unique COMP fragmentation pattern was observed in injured vs uninjured participants. These results further the hypothesis that COMP levels and/or degradation of the protein may be a marker of cartilage injury which could predispose to later OA.

Knee confidence in youth and young adults at risk of post-traumatic osteoarthritis 3-10 years following intra-articular knee injury.

OBJECTIVES: To examine differences in knee confidence between individuals with a history of youth sport-related knee injury and uninjured controls. DESIGN: Historical cohort study. METHODS: Participants include 100 individuals who sustained a youth sport-related intra-articular knee injury 3-10 years previously and 100 age-, sex- and sport-matched uninjured controls. Outcomes included: Knee confidence (Knee Osteoarthritis and Outcome Score); fat mass index (FMI; dual-energy X-ray absorptiometry); and weekly physical activity (modified Godin-Shephard Leisure Time Questionnaire). Mean within-pair differences (95% CI) were calculated for all outcomes. Unadjusted and adjusted (FMI and physical activity) conditional (matched-design) logistic regression (OR 95% CI) examined the association between injury history and knee confidence. RESULTS: Median age of participants was 22 years (range 15-26) and median age at injury was 16 years (range 9-18). Forty-nine percent (95% CI; 39.0, 59.0) of previously injured participants were bothered by knee confidence, compared to 12% (5.5, 18.5) of uninjured participants. Although there was no between group difference in physical activity, injured participants had higher FMI compared to controls (within-pair difference; (95% CI): 1.05kg/m2; (0.53, 1.57)). Logistic regression revealed that injured participants had 5.0 (unadjusted OR; 95% CI; 2.4, 10.2) and 7.5 times (adjusted OR; 95% CI: 2.7, 21.1) greater odds of being bothered by knee confidence than controls. CONCLUSIONS: Knee confidence differs between individuals with a previous youth sport-related knee injury and healthy controls. Knee confidence may be an important consideration for evaluating osteoarthritis risk after knee injury and developing secondary prevention strategies.

Running injuries in novice runners enrolled in different training interventions: a pilot randomized controlled trial.

The purpose of this trial was to evaluate injury risk in novice runners participating in different strength training interventions. This was a pilot randomized controlled trial. Novice runners (n = 129, 18-60 years old, <2 years recent running experience) were block randomized to one of three groups: a "resistance" strength training group, a "functional" strength training group, or a stretching "control" group. The primary outcome was running related injury. The number of participants with complaints and the injury rate (IR = no. injuries/1000 running hours) were quantified for each intervention group. For the first 8 weeks, participants were instructed to complete their training intervention three to five times a week. The remaining 4 months was a maintenance period. TRIAL REGISTRATION: NCT01900262. A total of 52 of the 129 (40%) novice runners experienced at least one running related injury: 21 in the functional strength training program, 16 in the resistance strength training program and 15 in the control stretching program. Injury rates did not differ between study groups [IR = 32.9 (95% CI 20.8, 49.3) in the functional group, IR = 31.6 (95% CI 18.4, 50.5) in the resistance group, and IR = 26.7 (95% CI 15.2, 43.2)] in the control group. Although this was a pilot assessment, home-based strength training did not appear to alter injury rates compared to stretching. Future studies should consider methods to minimize participant drop out to allow for the assessment of injury risk. Injury risk in novice runners based on this pilot study will inform the development of future larger studies investigating the impact of injury prevention interventions.

Outcomes associated with early post-traumatic osteoarthritis and other negative health consequences 3-10 years following knee joint injury in youth sport.

OBJECTIVE: Post-traumatic osteoarthritis (PTOA) commonly affects the knee joint. Although the risk of PTOA substantially increases post-joint injury, there is little research examining PTOA outcomes early in the period between joint injury and disease onset. Improved understanding of this interval would inform secondary prevention strategies aimed at preventing and/or delaying PTOA progression. This study examines the association between sport-related knee injury and outcomes related to development of PTOA, 3-10 years post-injury. DESIGN: This preliminary analysis of the first year of a historical cohort study includes 100 (15-26 years) individuals. Fifty with a sport-related intra-articular knee injury sustained 3-10 years previously and 50 uninjured age, sex and sport matched controls. The primary outcome was the 'Symptoms' sub-scale of the Knee Osteoarthritis and Injury Outcome Score (KOOS). Secondary outcomes included; the remaining KOOS subscales, body mass index (BMI), hip abductor/adductor and knee extensor/flexor strength, estimated aerobic capacity (VO2max) and performance scores on three dynamic balance tests. Descriptive statistics (mean within-pair difference; 95% Confidence interval (CI) and conditional odds ratio (OR, 95% CI; BMI) were used to compare study groups. RESULTS: Injured participants demonstrated poorer KOOS outcomes [symptoms -9.4 (-13.6, -5.2), pain -4.0 (-6.8, -1.2), quality-of-life -8.0 (-11.0, -5.1), daily living -3.0 (-5.0, -1.1) and sport/recreation -6.9 (-9.9, -3.8)], were 3.75 times (95% CI 1.24, 11.3) more likely to be overweight/obese and had lower triple single leg hop scores compared to controls. No significant group differences existed for remaining balance scores, estimated VO2max, hip or knee strength ratios or side-to-side difference in hip abductor/adductor or quadricep/hamstring strength. CONCLUSIONS: This study provides preliminary evidence that youth/young adults following sport-related knee injury report more symptoms and poorer function, and are at greater risk of being overweight/obese 3-10 years post-injury compared to matched uninjured controls.

Fabrication of highly elastic resilin/silk fibroin based hydrogel by rapid photo-crosslinking reaction.

A new type of hydrogel combining the highly elastic soft phase of Rec1-resilin and the mechanically strong hard phase Bombyx mori Silk fibroin has been reported using a rapid photo-crosslinking method. The improved elasticity and strength through the use of a resilin-based material and silk fibroin has been shown for the first time.

Genotype-phenotype analysis in X-linked Emery-Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype.

Direct sequencing of the emerin gene in 22 families with Emery-Dreifuss muscular dystrophy (EMD) revealed mutations in 21 (95%), confirming that emerin mutations can be identified in the majority of families with X-linked EMD. Most emerin mutations result in absence of the protein. In this study three mutations (a missense mutation Pro183Thr and two in-frame deletions removing residues 95-99 and 236-241, respectively) were unusual in being associated with expression of mutant protein. The phenotype in these families was compared in detail with the clinical features in cases with typical null mutations. For the in-frame deletions there were no significant differences. In the family with the missense mutation the phenotype was milder. Age at onset was later for first symptoms and for development of ankle contractures and muscle weakness. These findings have diagnostic implications as well as pointing to functionally important regions of the emerin protein.

Somatic neurofibromatosis type 2 gene mutations and growth characteristics in vestibular schwannoma.

BACKGROUND: The growth of hereditary and sporadic vestibular schwannomas shows wide variation, but what determines this is poorly understood. HYPOTHESIS: In neurofibromatosis type 2 (NF2), there is some correlation between the nature of the germline NF2 gene mutation and phenotype. Somatic mutations in the NF2 gene occur in sporadic tumors, but their relation to tumor behavior is unknown. METHODS: This study has investigated the molecular pathogenesis of vestibular schwannoma by looking for NF2 gene mutations. The authors have screened 17 exons of the NF2 gene in 91 sporadic vestibular schwannomas, 2 NF2, and 1 vagal schwannoma. These data have been correlated with a clinical growth index and a tumor cell proliferation index, determined using a monoclonal antibody to the proliferating cell nuclear antigen. RESULTS: Of the 94 tumors studied, 40 somatic gene mutations (38%) have been sequenced in 36 tumors. The mutations included 36 protein truncating mutations, 1 in-frame deletion, 2 splice site mutations, and 1 missense mutation. Regression analysis showed no correlation between the nature of the NF2 gene mutation and either the clinical (R2 = 0.006) or the proliferative index (R2 = 4 x 10(-8). CONCLUSION: The results of this study show no association between the nature of the intragenic NF2 gene mutation and tumor behavior. It is likely therefore that NF2 gene inactivation is not the only determinant of tumor behavior in vestibular schwannoma.

Genetic linkage of cone-rod retinal dystrophy to chromosome 19q and evidence for segregation distortion.

Inherited retinal dystrophies are the most common cause of childhood blindness in the developed world. Cone-rod retinal dystrophies are severe examples of this group of disorders. Analysis of a large cone-rod dystrophy pedigree suggested that inheritance within the family was influenced by meiotic drive (p = 0.008), a rare segregation distortion in human genetics. Two-point linkage analysis showed significant linkage with three markers mapping to chromosome 19q. Multipoint analysis gave a maximum lod score of 10.08 (theta = 0.05) distal to D19S47. Cone-rod dystrophy is therefore assigned to 19q13.1-q13.2 and a new candidate locus for other retinal dystrophies is identified.

Alterations to either c-erbB-2(neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis.

We have examined the genomic organisation of c-myc, N-myc, L-myc, neu and N-ras in tissue from 41 breast carcinomas, lymph node metastases from 10 of these carcinomas, one fibrosarcoma, 10 cases of benign fibrocystic breast and six fibroadenomas. We have not observed an alteration in either N-myc or N-ras in any of the samples studied. We have seen a 2-fold amplification of L=myc in DNA from one infiltrating ductal (ID) carcinoma, but otherwise we have seen no alterations to this gene. Amplification of c-myc was seen in 22% of ID breast carcinoma sample. Levels of amplification ranged from 2- to 10-fold. We have found a significant (p less than 0.02) correlation between an altered c-myc gene and a very poor short-term prognosis. Amplification of neu was seen in 19% of ID breast carcinomas, but the levels of amplification were higher than those seen for c-myc. Alterations to neu also correlated well with poor short-term prognosis (p less than 0.0002). Finally, we have observed a low level of amplification of c-myc in DNA from a benign fibrocystic breast lesion. This lesion exhibited some features characteristic of those thought to be associated with an increased risk of developing breast cancer.

Differential expression of cellular oncogenes in benign and malignant human breast tissue.

We have examined 62 specimens of benign fibrocystic breast tissue, fibroadenomas, carcinomas and surrounding non-malignant tissue excised from 50 patients to determine the level of expression of 4 cellular oncogenes, c-myc, c-H-ras, c-K-ras, and c-N-ras. Our results demonstrate that in breast carcinoma the frequency and relative level of expression of these oncogenes are significantly greater than those found for benign breast tissue. However, some fibrocystic specimens having prominent hyperplastic features also exhibited enhanced oncogene expression. In view of the association between the increased frequency of carcinoma of the breast in women with a previous history of benign breast disease, it will be interesting to follow up donors of benign specimens to see if there is any relationship between the expression of oncogenes in such lesions and the development of carcinomas.

Properties of rat cells transformed by DNA plasmids containing adenovirus type 12 E1 DNA or specific fragments of the E1 region: comparison of transforming frequencies.

In this paper, we describe for the first time the transformation of normal rat cells by DNA equivalent to adenovirus type 12 Early Region 1 (E1A). This DNA was 30-fold less efficient at transformation than DNA encoding the entire E1 region. Those established lines expressing a full complement of adenovirus type 12 E1 proteins were phenotypically indistinguishable from adenovirus type 12 virus-transformed cell lines. However, cell lines produced by plasmids carrying subgenomic fragments of E1 DNA and therefore not expressing E1B Mr 52,000 protein took longer to establish and produced tumors only after a protracted latent period. A Giemsa-banding study showed that adenovirus transformation can occur without disruption of the normal rat karyotype.

Isolation and characterization of four adenovirus type 12-transformed human embryo kidney cell lines.

Four transformed cell lines were established from cultures of human embryo kidney (HEK) cells microinjected or transfected with cloned adenovirus 12 (Ad12) EcoRI-C DNA (0 through 16.5 map units of the left-hand end of the viral genome). Each cell line showed a different growth pattern. Southern blotting demonstrated that all of the cell lines contained Ad12-specific DNA sequences, but in the microinjected isolates these were at a much lower copy number than in the transfected isolate. Two cell lines (Ad12 HEK 1 and 3) appeared to contain tandemly repeated Ad12 EcoRI-C DNA fragments. Immunoprecipitation and Western blotting confirmed that Ad12 early region 1 (E1) proteins were being expressed by all four of the transformed cell lines, but indicated that E1A polypeptide expression was considerably less than E1B polypeptide expression. All of the Ad12-transformed HEK cell lines were tumorigenic when inoculated intracranially into athymic nude mice.