Objective
To identify robustly differentially expressed long noncoding RNAs (lncRNAs) with osteoarthritis (OA) pathophysiology in cartilage and to explore potential target messenger RNA (mRNA) by ...establishing coexpression networks, followed by functional validation.
Methods
RNA sequencing was performed on macroscopically lesioned and preserved OA cartilage from patients who underwent joint replacement surgery due to OA (n = 98). Differential expression analysis was performed on lncRNAs that were annotated in GENCODE and Ensembl databases. To identify potential interactions, correlations were calculated between the identified differentially expressed lncRNAs and the previously reported differentially expressed protein‐coding genes in the same samples. Modulation of chondrocyte lncRNA expression was achieved using locked nucleic acid GapmeRs.
Results
By applying our in‐house pipeline, we identified 5,053 lncRNAs that were robustly expressed, of which 191 were significantly differentially expressed (according to false discovery rate) between lesioned and preserved OA cartilage. Upon integrating mRNA sequencing data, we showed that intergenic and antisense differentially expressed lncRNAs demonstrate high, positive correlations with their respective flanking sense genes. To functionally validate this observation, we selected P3H2‐AS1, which was down‐regulated in primary chondrocytes, resulting in the down‐regulation of P3H2 gene expression levels. As such, we can confirm that P3H2‐AS1 regulates its sense gene P3H2.
Conclusion
By applying an improved detection strategy, robustly differentially expressed lncRNAs in OA cartilage were detected. Integration of these lncRNAs with differential mRNA expression levels in the same samples provided insight into their regulatory networks. Our data indicates that intergenic and antisense lncRNAs play an important role in regulating the pathophysiology of OA.
Objectives
Knowledge on the epidemiology and long-term course of rotator cuff calcific tendinitis (RCCT) is scarce. We assessed demographics, radiological characteristics, and their association with ...long-term outcomes in a large patient group.
Methods
Baseline demographics, radiological characteristics and treatment were recorded in 342 patients. Interobserver agreement of radiological measures was analyzed. Long-term outcome was evaluated with questionnaires (WORC, DASH). The association of baseline characteristics with outcome was assessed.
Results
Mean age was 49.0 (SD = 10.0), and 59.5 % were female. The dominant arm was affected in 66.0 %, and 21.3 % had bilateral disease. Calcifications were on average 18.7 mm (SD = 10.1, ICC = 0.84 (p < 0.001)) and located 10.1 mm (SD = 11.8) medially to the acromion (ICC = 0.77 (p < 0.001)). Gärtner type I calcifications were found in 32.1 % (Kappa = 0.47 (p < 0.001)). After 14 years (SD = 7.1) of follow-up, median WORC was 72.5 (range, 3.0-100.0; WORC < 60 in 42 %) and median DASH 17.0 (range, 0.0-82.0). Female gender, dominant arm involvement, bilateral disease, longer duration of symptoms, and multiple calcifications were associated with inferior WORC. DASH results were similar.
Conclusions
Many subjects have persisting shoulder complaints years after diagnosis, regardless of treatment. Female gender, dominant arm involvement, bilateral disease, longer duration of symptoms, and multiple calcifications were associated with inferior outcome. Radiological measures had moderate-to-good reliability and no prognostic value.
Key Points
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Most RCCT studies report on short-term outcome and/or small patients groups.
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In this large, long-term observational study, RCCT appeared to not be self-limiting in many subjects.
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Negative prognostic factors included female gender, more calcifications, dominant arm affected, and longer duration of symptoms.
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Interobserver agreement of general radiological RCCT measures is moderate to good.
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More rigorous diagnostics and treatment might be needed in specific RCCT cases.
Background
The functional and clinical basis on which to choose whether or not to retain the posterior cruciate ligament during total knee arthroplasty surgery remained unclear after a Cochrane ...systematic review and meta‐analysis in 2005, which contained eight clinical trials. Several new trials have been conducted since then. Hence, an update of the review was performed.
Objectives
Our aim was to assess the benefits and harms of retention compared to sacrifice of the posterior cruciate ligament in total knee arthroplasty in patients with osteoarthritis of the knee.
Search methods
An extensive search was conducted in CENTRAL, MEDLINE (PubMed), EMBASE, Web of Science, CINAHL, Academic Search Premier, Current Contents Connect and Science Direct. All databases were searched, without any limitations, up to 6 December 2012. References of the articles were checked and citation tracking was performed.
Selection criteria
Randomised and quasi‐randomised controlled trials comparing retention with sacrifice of the posterior cruciate ligament in primary total knee arthroplasty in patients with osteoarthritis of the knee.
Data collection and analysis
Data were collected with a pre‐developed form. Risk of bias was assessed independently by two authors (WV, LB). The level of evidence was graded using the GRADE approach. Meta‐analysis was performed by pooling the results of the selected studies, when possible. Subgroup analyses were performed for posterior cruciate ligament retention versus sacrifice using the same total knee arthroplasty design, and for studies using a posterior cruciate ligament retaining or posterior stabilised design, and when sufficient studies were available subgroup analyses were performed for the same brand.
Main results
Seventeen randomised controlled trials (with 1810 patients and 2206 knees) were found, described in 18 articles. Ten of these were new studies compared to the previous Cochrane Review. One study from the original Cochrane review was excluded. Most new studies compared a posterior cruciate ligament retaining design with a posterior stabilised design, in which the posterior cruciate ligament is sacrificed (a posterior stabilised design has an insert with a central post which can engage on a femoral cam during flexion).
The quality of evidence (graded with the GRADE approach) and the risk of bias were highly variable, ranging from moderate to low quality evidence and with unclear or low risk of bias for most domains, respectively.
The performance outcome 'range of motion' was 2.4 ° higher in favour of posterior cruciate ligament sacrifice (118.3 ° versus 115.9 °; 95% confidence interval (CI) of the difference 0.13 to 4.67; P = 0.04), however the results were heterogeneous. On the item 'knee pain' as experienced by patients, meta‐analysis could be performed on the Knee Society knee pain score; this score was 48.3 in both groups, yielding no difference between the groups. Implant survival rate could not be meta‐analysed adequately since randomised controlled trials lack the longer term follow‐up in order to evaluate implant survival. A total of four revisions in the cruciate‐retention and four revisions in the cruciate‐sacrifice group were found. The well‐validated Western Ontario and McMaster Universities osteoarthritis index (WOMAC) total score was not statistically significantly different between the groups (16.6 points for cruciate‐retention versus 15.0 points for cruciate‐sacrifice). One study reported a patient satisfaction grade (7.7 points for cruciate‐retention versus 7.9 points for cruciate‐sacrifice on a scale from 0 to 10, 10 being completely satisfied) which did not differ statistically significantly. Complications were distributed equally between both groups. Only one study reported several re‐operations other than revision surgery; that is patella luxations, surgical manipulation because of impaired flexion.
The mean functional Knee Society Score was 2.3 points higher (81.2 versus 79.0 points; 95% CI of the difference 0.37 to 4.26; P = 0.02) in the posterior cruciate ligament sacrificing group. Results from the outcome Knee Society functional score were homogeneous. All other outcome measures (extension angle, knee pain, adverse effects, clinical questionnaire scores, Knee Society clinical scores, radiological rollback, radiolucencies, femorotibial angle and tibial slope) showed no statistically significant differences between the groups. In the subgroup analyses that allowed pooling of the results of the different studies, no homogeneous statistically significant differences were identified.
Authors' conclusions
The methodological quality and the quality of reporting of the studies were highly variable. With respect to range of motion, pain, clinical, and radiological outcomes, no clinically relevant differences were found between total knee arthroplasty with retention or sacrifice of the posterior cruciate ligament. Two statistically significant differences were found; range of motion was 2.4 ° higher in the posterior cruciate ligament sacrificing group, however results were heterogeneous; and the mean functional Knee Society Score was 2.3 points higher in the posterior cruciate ligament sacrificing group. These differences are clinically not relevant.
Background and purpose The association between excessive early migration of acetabular cups and late aseptic revision has been scantily reported. We therefore performed 2 parallel systematic reviews ...and meta-analyses to determine the association between early migration of acetabular cups and late aseptic revision.
Methods One review covered early migration data from radiostereometric analysis (RSA) studies, while the other focused on revision rates for aseptic loosening from long-term survival studies. Thresholds for acceptable and unacceptable migration were classified according the Swedish Hip Arthroplasty Register and the Australian National Joint Replacement Registry: < 5% revision at 10 years.
Results Following an elaborate literature search, 26 studies (involving 700 cups) were included in the RSA review and 49 studies (involving 38,013 cups) were included in the survival review. For every mm increase in 2-year proximal migration, there was a 10% increase in revision rate, which remained after correction for age, sex, diagnosis, hospital type, continent, and study quality. Consequently, proximal migration of up to 0.2 mm was considered acceptable and proximal migration of 1.0 mm or more was considered unacceptable. Cups with proximal migration of between 0.2 and 1.0 mm were considered to be at risk of having revision rates higher than 5% at 10 years.
Interpretation There was a clinically relevant association between early migration of acetabular cups and late revision due to loosening. The proposed migration thresholds can be implemented in a phased evidence-based introduction, since they allow early detection of high-risk cups while exposing a small number of patients.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
In trauma and orthopedic surgery, infection of implants has a major impact on the outcome for patients. Infections may develop either during the initial implantation or during the lifetime of an ...implant. Both infections, as well as aseptic loosening of the implant, are reasons for revision of the implants. Therefore, discrimination between aseptic-mechanical-loosening and septic-bacterial-loosening of implants is critical during selection of a patient-tailored treatment policy. Specific detection and visualization of infections is a challenge because it is difficult to discriminate infections from inflammation. An imaging tracer that facilitates bacterial identification in a pre- and intraoperative setting may aid the workup for patients suspicious of bacterial infections. In this study we evaluated an antimicrobial peptide conjugated to a hybrid label, which contains both a radioisotope and a fluorescent dye. After synthesis of DTPA-Cy5-UBI29–41 andwhen necessaryradiolabeling with 111In (yield 96.3 ± 2.7%), in vitro binding to various bacterial strains was evaluated using radioactivity counting and confocal fluorescence microscopy. Intramuscular bacterial infections (S. aureus or K. pneumoniae) were also visualized in vivo using a combined nuclear and fluorescence imaging system. The indium-111 was chosen as label as it has a well-defined coordination chemistry, and in pilot studies labeling DTPA-Cy5-UBI29–41 with technetium-99m, we encountered damage to the Cy5 dye after the reduction with SnCl2. As a reference, we used the validated tracer 99mTc-UBI29–41. Fast renal excretion of 111In-DTPA-Cy5-UBI29–41 was observed. Target to nontarget (T/NT) ratios were highest at 2 h post injection: radioactivity counting yielded T/NT ratios of 2.82 ± 0.32 for S. aureus and 2.37 ± 0.05 for K. pneumoniae. Comparable T/NT ratios with fluorescence imaging of 2.38 ± 0.09 for S. aureus and 3.55 ± 0.31 for K. pneumoniae were calculated. Ex vivo confocal microscopy of excised infected tissues showed specific binding of the tracer to bacteria. Using a combination of nuclear and fluorescence imaging techniques, the hybrid antimicrobial peptide conjugate DTPA-Cy5-UBI29–41 was shown to specifically accumulate in bacterial infections. This hybrid tracer may facilitate integration of noninvasive identification of infections and their extent as well as real-time fluorescence guidance during surgical resection of infected areas.
Background:
The Western Ontario Rotator Cuff Index (WORC) is an increasingly applied condition-specific outcome measure for rotator cuff (RC) conditions. However, in most WORC validation studies, ...only a limited number of psychometric properties are studied in indistinct patient groups.
Purpose:
To assess psychometric properties of the WORC according to the Scientific Advisory Committee quality criteria for health questionnaires in 3 patient groups with distinct RC conditions.
Study Design:
Cohort study (diagnosis); Level of evidence, 2.
Methods:
The WORC (range, 0-100; 21 items, 5 domains) was administered twice (T1, T2) in 92 patients (35 RC tears, 35 calcific tendinitis, 22 impingement). Additionally, the Constant score (CS) and the Disabilities of the Arm, Shoulder and Hand score (DASH) were recorded. Calcific tendinitis patients were reassessed 6 weeks after treatment with needling and lavage or a subacromial injection with corticosteroids (T3). We assessed floor and ceiling effects, internal consistency, test-retest reliability, precision, construct validity, minimally detectable change, and responsiveness in the diagnostic subgroups and the total group.
Results:
Mean age was 55.0 ± 8.7 years, and 49 of 92 (53%) patients were female. Mean baseline WORC was 46.8 ± 20.4, CS was 63.9 ± 15.4, and DASH was 40.9 ± 18.6. Significant differences were found for the CS and DASH between RC tear patients (severe symptoms) and the other patients, but not for the WORC. There were no floor and ceiling effects. Internal consistency was high: the Cronbach alpha coefficient was .95. The intraclass correlation coefficient of .89 and standard error of measurement of 6.9 indicated high reproducibility. Pearson correlations of the WORC with the CS and DASH were .56 and –.65, respectively (both P < .001). At T3, total WORC improved significantly (mean change, 18.8; 95% confidence interval, 11.3-26.2). Correlations of the WORC change scores with CS and DASH changes were .61 and –.84, respectively (both P < .001). Effect size was 0.96, with a standardized response mean of 0.91, indicating good responsiveness.
Conclusion:
Applied to a variety of RC patients, the WORC had high internal consistency, moderate to good construct validity, high test-retest reliability, and good responsiveness. These findings support the use of the WORC as a condition-specific self-reported outcome measure in RC patients, but its validity in patients with severe symptoms needs further investigation.
Purpose We performed two parallel systematic reviews and meta-analyses to determine the association between early migration of tibial components and late aseptic revision.
Methods One review ...comprised early migration data from radiostereometric analysis (RSA) studies, while the other focused on revision rates for aseptic loosening from long-term survival studies. Thresholds for acceptable and unacceptable migration were determined according to that of several national joint registries: < 5% revision at 10 years.
Results Following an elaborate literature search, 50 studies (involving 847 total knee prostheses (TKPs)) were included in the RSA review and 56 studies (20,599 TKPs) were included in the survival review. The results showed that for every mm increase in migration there was an 8% increase in revision rate, which remained after correction for age, sex, diagnosis, hospital type, continent, and study quality. Consequently, migration up to 0.5 mm was considered acceptable during the first postoperative year, while migration of 1.6 mm or more was unacceptable. TKPs with migration of between 0.5 and 1.6 mm were considered to be at risk of having revision rates higher than 5% at 10 years.
Interpretation There was a clinically relevant association between early migration of TKPs and late revision for loosening. The proposed migration thresholds can be implemented in a phased, evidence-based introduction of new types of knee prostheses, since they allow early detection of high-risk TKPs while exposing only a small number of patients.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Purpose: To examine the impact of neonatal brachial plexus palsy (NBPP) on societal participation of adolescents and adults.
Methods: This cross-sectional study was conducted among patients with ...NBPP, aged ≥16 years, who had visited our NBPP clinic. Patients completed questions on the influence of NBPP on their choices regarding education/work and their work-performance, the Impact on Participation/Autonomy questionnaire and the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P). In addition, health-related quality of life (HRQoL) was assessed.
Results: Seventy-five patients participated (median age 20, inter quartile range 17-27). Twenty were full-time students, 28 students with a job, 21 employed, two unemployed, and four work-disabled. Sixty-six patients had had a job at some stage. Patients' overall HRQoL was comparable to the general population. 27/75 patients reported that NBPP had affected their choices regarding education and 26/75 those regarding work. 33/66 reported impact on their work performance. On the Impact on Participation/Autonomy questionnaire, 80% (49/61) reported restrictions in the work-and-education domain, 74% in social-relations and 67% in autonomy-outdoors. 37/61 reported participation restrictions on the USER-P.
Conclusions: Although their overall HRQoL was not impaired, a substantial proportion of adolescent/adult patients reported that NBPP had an impact on choices regarding education and profession, as well as on work-performance. Restrictions in participation, especially in work and education were also reported. Guiding patients in making choices on education and work at an early stage and providing tailored physical as well as psychosocial care may prevent or address restrictions, which may improve participation.
Implications for Rehabilitation
Adolescent and adult patients with neonatal brachial plexus palsy perceive restrictions in societal participation, especially regarding the work-and-education domain.
All patients with neonatal brachial plexus palsy may perceive restrictions in societal participation regardless of lesion severity, treatment history and side of the lesion.
Adolescents and adults with neonatal brachial plexus palsy report that their choices regarding education and work, as well as their work-performance are influenced by their neonatal brachial plexus palsy.
Patients with neonatal brachial plexus palsy should be followed throughout their life in order to provide them with appropriate information and treatment when health- or participation-related issues arise.
Rehabilitation treatment is the best option to address all of the aforementioned issues, as surgical options in adolescents and adults are limited.
Objective
To identify osteoarthritis (OA) progression–modulating pathways in articular cartilage and their respective regulatory epigenetic and genetic determinants in end‐stage disease.
Methods
...Transcriptional activity of CpG was assessed using gene expression data and DNA methylation data for preserved and lesional articular cartilage samples. Disease‐responsive transcriptionally active CpG were identified by means of differential methylation between preserved and lesional cartilage. Transcriptionally relevant genetic determinants were addressed by means of single‐nucleotide polymorphisms (SNPs) proximal to the OA‐responsive transcriptionally active CpG. Statistical analyses were corrected for age, sex, joint, and technical covariates. A random effect was included to correct for possible correlations between paired samples.
Results
Of 9,838 transcribed genes in articular cartilage, 2,324 correlated with the methylation status of 3,748 transcriptionally active CpG; both negative (n = 1,741) and positive (n = 2,007) correlations were observed. Hypomethylation and hypermethylation (false discovery rate of <0.05, |Δβ| > 0.05) were observed for 62 and 25 transcriptionally active CpG, respectively, covering 70 unique genes. Enrichment for developmental and extracellular matrix maintenance pathways indicated possible reactivation of endochondral ossification. Finally, we observed 31 and 26 genes for which methylation and expression, respectively, were additionally affected by genetic variation.
Conclusion
We identified tissue‐specific genes involved in OA disease progression, reflected by genetic and pathologic epigenetic regulation of transcription, primarily at genes involved in development. Therefore, transcriptionally active SNPs near these genes may serve as putative susceptibility alleles. Our results constitute an important step toward understanding the reported widespread epigenetic changes occurring in OA articular cartilage and toward subsequent development of treatments targeting disease‐driving pathways.
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