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1.
Artigo em Inglês | MEDLINE | ID: mdl-33576770

RESUMO

OBJECTIVE: To describe the associations of blood pressure and arterial stiffness with knee cartilage volume in patients with knee osteoarthritis (OA). METHOD: A secondary analysis was performed on the data from participants of a randomized controlled trial, which identified the effects of vitamin D supplementation on knee structures and symptoms among patients with symptomatic knee OA. Brachial and central blood pressure, arterial stiffness indicators and knee cartilage volume were measured at baseline and 2-year follow-up. Associations were assessed using generalized estimating equations. RESULTS: Among 231 participants (average age 63.2 years), 48.9% were females. Higher supine systolic and diastolic pressures were significantly associated with lower tibial cartilage volume (Systolic: Lateral ß -6.23, medial ß -5.14, total ß -11.35 mm3/mmHg. Diastolic: Lateral ß -10.25, medial ß -11.29, total ß -21.50 mm3/mmHg). Higher supine systolic pressure was associated with lower femoral cartilage volume (Lateral ß -17.35, total ß -28.31 mm3/mmHg). Central systolic pressure and arterial stiffness indicators (including pulse wave velocity, central pulse pressure, and peripheral pulse pressure) were largely not associated with knee cartilage volume; however, higher augmentation index was associated with lower tibial and femoral cartilage volume (Tibial: Medial ß -8.24, total ß -19.13 mm3/percent. Femoral: Lateral ß -23.70, medial ß -26.42, total ß -50.12 mm3/percent). CONCLUSIONS: Blood pressure and arterial stiffness are associated with knee cartilage volume at several sites among knee OA patients. This supports that blood pressure and arterial stiffness may involve in the progression of knee OA.

2.
J Transl Med ; 18(1): 466, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298067

RESUMO

BACKGROUND: An important task in developing accurate public health intervention evaluation methods based on historical interrupted time series (ITS) records is to determine the exact lag time between pre- and post-intervention. We propose a novel continuous transitional data-driven hybrid methodology using a non-linear approach based on a combination of stochastic and artificial intelligence methods that facilitate the evaluation of ITS data without knowledge of lag time. Understanding the influence of implemented intervention on outcome(s) is imperative for decision makers in order to manage health systems accurately and in a timely manner. METHODS: To validate a developed hybrid model, we used, as an example, a published dataset based on a real health problem on the effects of the Italian smoking ban in public spaces on hospital admissions for acute coronary events. We employed a continuous methodology based on data preprocessing to identify linear and nonlinear components in which autoregressive moving average and generalized structure group method of data handling were combined to model stochastic and nonlinear components of ITS. We analyzed the rate of admission for acute coronary events from January 2002 to November 2006 using this new data-driven hybrid methodology that allowed for long-term outcome prediction. RESULTS: Our results showed the Pearson correlation coefficient of the proposed combined transitional data-driven model exhibited an average of 17.74% enhancement from the single stochastic model and 2.05% from the nonlinear model. In addition, data demonstrated that the developed model improved the mean absolute percentage error and correlation coefficient values for which 2.77% and 0.89 were found compared to 4.02% and 0.76, respectively. Importantly, this model does not use any predefined lag time between pre- and post-intervention. CONCLUSIONS: Most of the previous studies employed the linear regression and considered a lag time to interpret the impact of intervention on public health outcome. The proposed hybrid methodology improved ITS prediction from conventional methods and could be used as a reliable alternative in public health intervention evaluation.

3.
Aging (Albany NY) ; 12(24): 24778-24797, 2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33361529

RESUMO

Osteoarthritis (OA) is the most common musculoskeletal disorder among the elderly. It is characterized by progressive cartilage degradation, synovial inflammation, subchondral bone remodeling and pain. Lipocalin prostaglandin D synthase (L-PGDS) is responsible for the biosynthesis of PGD2, which has been implicated in the regulation of inflammation and cartilage biology. This study aimed to evaluate the effect of L-PGDS deficiency on the development of naturally occurring age-related OA in mice. OA-like structural changes were assessed by histology, immunohistochemistry, and micro-computed tomography. Pain related behaviours were assessed using the von Frey and the open-field assays. L-PGDS deletion promoted cartilage degradation during aging, which was associated with enhanced expression of extracellular matrix degrading enzymes, matrix metalloprotease 13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), and their breakdown products, C1,2C, VDIPEN and NITEG. Moreover, L-PGDS deletion enhanced subchondral bone changes, but had no effect on its angiogenesis. Additionally, L-PGDS deletion increased mechanical sensitivity and reduced spontaneous locomotor activity. Finally, we showed that the expression of L-PGDS was elevated in aged mice. Together, these findings indicate an important role for L-PGDS in naturally occurring age-related OA. They also suggest that L-PGDS may constitute a new efficient therapeutic target in OA.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33253381

RESUMO

OBJECTIVE: To describe the association between change in subchondral bone marrow lesions (BMLs) and change in tibiofemoral cartilage volume and knee symptoms in patients with symptomatic knee OA. METHODS: In total, 251 participants (mean 61.7 years, 51% female) were included. Tibiofemoral cartilage volume was measured at baseline and 24 months, and BML size at baseline, 6 and 24 months. Knee pain and function scores were evaluated at baseline, 6 and 24 months. Change in total and compartment-specific BML size was categorized according to the Least Significance Criterion. Linear mixed-effects models were used to evaluate the associations of change in BMLs over 6 and 24 months with change in cartilage volume over 24 months and knee symptoms over 6 and 24 months. RESULTS: Total BML size enlarged in 26% of participants, regressed in 31% and remained stable in 43% over 24 months. Compared with stable BMLs in the same compartment, enlarging BMLs over 24 months were associated with greater cartilage loss (difference: -53.0mm3, 95% CI: -100.0, -6.0), and regressing BMLs were not significantly associated with reduced cartilage loss (difference: 32.4mm3, 95% CI: -8.6, 73.3) over 24 months. Neither enlargement nor regression of total BML size over 6 and 24 months was associated with change in knee pain and function over the same time intervals. CONCLUSIONS: In subjects with symptomatic knee osteoarthritis and BMLs, enlarging BMLs may lead to greater cartilage loss but regressing lesions are not associated with reduced cartilage loss while neither is associated with change in knee symptoms.

5.
Front Cell Dev Biol ; 8: 567813, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072752

RESUMO

Mesenchymal stem cell (MSC) therapy represents a promising approach for the treatment of osteoarthritis (OA). MSCs can be readily isolated from multiple sources and expanded ex vivo for possible clinical application. They possess a unique immunological profile and regulatory machinery that underline their therapeutic effects. They also have the capacity to sense the changes within the tissue environment to display the adequate response. Indeed, there is a close interaction between MSCs and the host cells. Accordingly, MSCs demonstrate encouraging results for a variety of diseases including OA. However, their effectiveness needs to be improved. In this review, we selected to discuss the importance of the immunological features of MSCs, including the type of transplantation and the immune and blood compatibility. It is important to consider MSC immune evasive rather than immune privileged. We also highlighted some of the actions/mechanisms that are displayed during tissue healing including the response of MSCs to injury signals, their interaction with the immune system, and the impact of their lifespan. Finally, we briefly summarized the results of clinical studies reporting on the application of MSCs for the treatment of OA. The research field of MSCs is inspiring and innovative but requires more knowledge about the immunobiological properties of these cells. A better understanding of these features will be key for developing a safe and efficient medicinal product for clinical use in OA.

6.
Ther Adv Musculoskelet Dis ; 12: 1759720X20933468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849918

RESUMO

Objectives: The aim was to identify the most important features of structural knee osteoarthritis (OA) progressors and classification using machine learning methods. Methods: Participants, features and outcomes were from the Osteoarthritis Initiative. Features were from baseline (1107), including articular knee tissues (135) assessed by quantitative magnetic resonance imaging (MRI). OA progressors were ascertained by four outcomes: cartilage volume loss in medial plateau at 48 and 96 months (Prop_CV_48M, 96M), Kellgren-Lawrence (KL) grade ⩾ 2 and medial joint space narrowing (JSN) ⩾ 1 at 48 months. Six feature selection models were used to identify the common features in each outcome. Six classification methods were applied to measure the accuracy of the selected features in classifying the subjects into progressors and non-progressors. Classification of the best features was done using an automatic machine learning interface and the area under the curve (AUC). To prioritize the top five features, sparse partial least square (sPLS) method was used. Results: For the classification of the best common features in each outcome, Multi-Layer Perceptron (MLP) achieved the highest AUC in Prop_CV_96M, KL and JSN (0.80, 0.88, 0.95), and Gradient Boosting Machine for Prop_CV_48M (0.70). sPLS showed the baseline top five features to predict knee OA progressors are the joint space width, mean cartilage thickness of the medial tibial plateau and sub-regions and JSN. Conclusion: In this comprehensive study using a large number of features (n = 1107) and MRI outcomes in addition to radiological outcomes, we identified the best features and classification methods for knee OA structural progressors. Data revealed baseline X-ray and MRI-based features could predict early OA knee progressors and that MLP is the best classification method.

7.
Sci Rep ; 10(1): 13789, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796866

RESUMO

Although intra-articular corticosteroid injections (IACI) are commonly used for the treatment of knee osteoarthritis (OA), there is controversy regarding possible deleterious effects on joint structure. In this line, this study investigates the effects of IACI on the evolution of knee OA structural changes and pain. Participants for this nested case-control study were from the Osteoarthritis Initiative. Knees of participants who had received an IACI and had magnetic resonance images (MRI) were named cases (n = 93), and each matched with one control (n = 93). Features assessed at the yearly visits and their changes within the follow-up period were from MRI (cartilage volume, meniscal thickness, bone marrow lesions, bone curvature, and synovial effusion size), X-ray (joint space width), and clinical (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain score) data. Participants who received IACI experienced a transient and significantly greater rate of loss of the meniscal thickness (p = 0.006) and joint space width (p = 0.011) in the knee medial compartment in the year they received the injection, compared to controls. No significant effect of the IACI was found on the rate of cartilage loss nor on any other knee structural changes or WOMAC pain post-treatment. In conclusion, a single IACI in knee OA was shown to be safe with no negative impact on structural changes, but there was a transient meniscal thickness reduction, a phenomenon for which the clinical relevance is at present unknown.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32521015

RESUMO

OBJECTIVE: The objective of this study was to investigate whether diacerein has comparable efficacy with celecoxib in pain reduction for treatment in symptomatic knee OA patients. METHODS: This randomized double-blind multicentre non-inferiority trial evaluated diacerein vs celecoxib treatment in patients with Kellgren-Lawrence grade 2-3 and pain scoring ≥4 (10-cm VAS). Patients were randomized to 6 months of treatment with diacerein 50 mg (n = 187) once daily for 1 month and twice daily thereafter, or celecoxib 200 mg (n = 193) once daily. The primary outcome was the change in WOMAC pain score (0-50 cm) at 6 months, and the secondary outcomes were WOMAC sub-scores, VAS pain score, and the OMERACT-OARSI responder rate. RESULTS: In the per protocol population, the adjusted mean change from baseline in the WOMAC pain score was -11.1 ( 0.9) with diacerein (n = 140) and -11.8 (0.9) with celecoxib (n = 148). The intergroup difference was 0.7 (95% CI: -1.8, 3.2; P = 0.597), meeting the non-inferiority margin. Supportive analysis of the intention-to-treat population gave similar results. Other outcomes showed no significant difference between treatment groups. The incidence of treatment-related adverse events was low and balanced between groups, but a greater incidence of diarrhoea occurred with diacerein (10.2% vs 3.7%). Diarrhoea was considered mild-to-moderate in all but one case with complete resolution. CONCLUSIONS: Diacerein was non-inferior to celecoxib in reducing knee OA pain and improving physical function. Diacerein also demonstrated a good safety profile. TRIAL REGISTRATION: A multicentre study on the effect of DIacerein on Structure and Symptoms vs Celecoxib in Osteoarthritis is a National Institutes of Health (NCT02688400) and European Clinical Trial Database (2015-002933-23) registered phase III (Canada) or IV (Europe) study.

9.
Sci Rep ; 10(1): 9993, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561782

RESUMO

OBJECTIVE: The infrapatellar fat pad (IPFP) has been associated with knee osteoarthritis onset and progression. This study uses machine learning (ML) approaches to predict serum levels of some adipokines/related inflammatory factors and their ratios on knee IPFP volume of osteoarthritis patients. METHODS: Serum and MRI were from the OAI at baseline. Variables comprised the 3 main osteoarthritis risk factors (age, gender, BMI), 6 adipokines, 3 inflammatory factors, and their 36 ratios. IPFP volume was assessed on MRI with a ML methodology. The best variables and models were identified in Total-cohort (n = 678), High-BMI (n = 341) and Low-BMI (n = 337), using a selection approach based on ML methods. RESULTS: The best model for each group included three risk factors and adipsin/C-reactive protein combined for Total-cohort, adipsin/chemerin; High-BMI, chemerin/adiponectin HMW; and Low-BMI, interleukin-8. Gender separation improved the prediction (13-16%) compared to the BMI-based models. Reproducibility with osteoarthritis patients from a clinical trial was excellent (R: female 0.83, male 0.95). Pseudocodes based on gender were generated. CONCLUSION: This study demonstrates for the first time that the combination of the serum levels of adipokines/inflammatory factors and the three main risk factors of osteoarthritis could predict IPFP volume with high reproducibility, with the superior performance of the model accounting for gender separation.

10.
Curr Rheumatol Rep ; 22(7): 27, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32435959

RESUMO

PURPOSE OF REVIEW: The propose of this viewpoint is to improve or facilitate the clinical decision-making in the management/treatment strategies of arthritis patients through knowing, understanding, and having access to an interactive process allowing assessment of the patient disease outcome in the future. RECENT FINDINGS: In recent years, the time series (TS) concept has become the center of attention as a predictive model for making forecast of unseen data values. TS and one of its technologies, the interrupted TS (ITS) analysis (TS with one or more interventions), predict the next period(s) value(s) of a given patient based on their past and current information. Traditional TS/ITS methods involve segmented regression-based technologies (linear and nonlinear), while stochastic (linear modeling) and artificial intelligence approaches, including machine learning (complex nonlinear relationships between variables), are also used; however, each have limitations. We will briefly describe TS/ITS, provide examples of their application in arthritic diseases; describe their methods, challenges, and limitations; and propose a combined (stochastic and artificial intelligence) procedure in post-intervention that will optimize ITS modeling. This combined method will increase the accuracy of ITS modeling by profiting from the advantages of both stochastic and nonlinear models to capture all ITS deterministic and stochastic components. In addition, this combined method will allow ITS outcomes to be predicted as continuous variables without having to consider the time lag produced between the pre- and post-intervention periods, thus minimizing the prediction error not only for the given data but also for all possible future patterns in ITS. The use of reliable prediction methodologies for arthritis patients will permit treatment of not only the disease, but also the patient with the disease, ensuring the best outcome prediction for the patient.

11.
Arthritis Rheumatol ; 72(9): 1524-1533, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32336048

RESUMO

OBJECTIVE: Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the formation of prostaglandin D2 (PGD2 ), which has important roles in inflammation and cartilage metabolism. We undertook this study to investigate the role of L-PGDS in the pathogenesis of osteoarthritis (OA) using an experimental mouse model. METHODS: Experimental OA was induced in wild-type (WT) and L-PGDS-deficient (L-PGDS-/- ) mice (n = 10 per genotype) by destabilization of the medial meniscus (DMM). Cartilage degradation was evaluated by histology. The expression of matrix metalloproteinase 13 (MMP-13) and ADAMTS-5 was assessed by immunohistochemistry. Bone changes were determined by micro-computed tomography. Cartilage explants from L-PGDS-/- and WT mice (n = 6 per genotype) were treated with interleukin-1α (IL-1α) ex vivo in order to evaluate proteoglycan degradation. Moreover, the effect of intraarticular injection of a recombinant adeno-associated virus type 2/5 (rAAV2/5) encoding L-PGDS on OA progression was evaluated in WT mice (n = 9 per group). RESULTS: Compared to WT mice, L-PGDS-/- mice had exacerbated cartilage degradation and enhanced expression of MMP-13 and ADAMTS-5 (P < 0.05). Furthermore, L-PGDS-/- mice displayed increased synovitis and subchondral bone changes (P < 0.05). Cartilage explants from L-PGDS-/- mice showed enhanced proteoglycan degradation following treatment with IL-1α (P < 0.05). Intraarticular injection of rAAV2/5 encoding L-PGDS attenuated the severity of DMM-induced OA-like changes in WT mice (P < 0.05). The L-PGDS level was increased in OA tissues of WT mice (P < 0.05). CONCLUSION: Collectively, these findings suggest a protective role of L-PGDS in OA, and therefore enhancing levels of L-PGDS may constitute a promising therapeutic strategy.

12.
JAMA ; 323(15): 1456-1466, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32315057

RESUMO

Importance: A proof-of-principle study suggested that intravenous zoledronic acid may reduce knee pain and the size of bone marrow lesions in people with knee osteoarthritis, but data from large trials are lacking. Objective: To determine the effects of intravenous zoledronic acid on knee cartilage volume loss in patients with symptomatic knee osteoarthritis and bone marrow lesions. Design, Setting, and Participants: A 24-month multicenter, double-blind placebo-controlled randomized clinical trial conducted at 4 sites in Australia (1 research center and 3 hospitals). Adults aged 50 years or older with symptomatic knee osteoarthritis and subchondral bone marrow lesions detected by magnetic resonance imaging (MRI) were enrolled from November 2013 through September 2015. The final date of follow-up was October 9, 2017. Interventions: Intravenous infusion with either 5 mg of zoledronic acid in a 100-mL saline solution (n = 113) or a placebo saline solution (n = 110) at baseline and 12 months. Main Outcomes and Measures: The primary outcome was absolute change in tibiofemoral cartilage volume assessed using MRI over 24 months (the minimum clinically important difference [MCID] has not been established). Three prespecified secondary outcomes were change in knee pain assessed by a visual analog scale (0 [no pain] to 100 [unbearable pain]; MCID, 15) and the Western Ontario and McMaster Universities Osteoarthritis Index (0 [no pain] to 500 [unbearable pain]; MCID, 75) over 3, 6, 12, 18, and 24 months and change in bone marrow lesion size over 6 and 24 months (the MCID has not been established). Results: Of 223 participants enrolled (mean age, 62.0 years [SD, 8.0 years]; 52% were female), 190 (85%) completed the trial. Change in tibiofemoral cartilage volume was not significantly different between the zoledronic acid group and the placebo group over 24 months (-878 mm3 vs -919 mm3; between-group difference, 41 mm3 [95% CI, -79 to 161 mm3]; P = .50). No significant between-group differences were found for any of the prespecified secondary outcomes, including changes in knee pain assessed by a visual analog scale (-11.5 in the zoledronic acid group vs -16.8 in the placebo group; between-group difference, 5.2 [95% CI, -2.3 to 12.8]; P = .17), changes in knee pain assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (-37.5 vs -58.0, respectively; between-group difference, 20.5 [95% CI, -11.2 to 52.2]; P = .21), and changes in bone marrow lesion size (-33 mm2 vs -6 mm2; between-group difference, -27 mm2 [95% CI, -127 to 73 mm2]; P = .60) over 24 months. Adverse events were more common with zoledronic acid than with placebo (96% vs 83%, respectively) and consisted mainly of acute reactions (defined as symptoms within 3 days of administration of infusion; 87% vs 56%). Conclusions and Relevance: Among patients with symptomatic knee osteoarthritis and bone marrow lesions, yearly zoledronic acid infusions, compared with placebo, did not significantly reduce cartilage volume loss over 24 months. These findings do not support the use of zoledronic acid in the treatment of knee osteoarthritis. Trial Registration: anzctr.org.au Identifier: ACTRN12613000039785.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Doenças da Medula Óssea/tratamento farmacológico , Cartilagem Articular/efeitos dos fármacos , Osteoartrite do Joelho/tratamento farmacológico , Ácido Zoledrônico/uso terapêutico , Idoso , Conservadores da Densidade Óssea/administração & dosagem , Medula Óssea/patologia , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/diagnóstico por imagem , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/patologia , Falha de Tratamento , Ácido Zoledrônico/administração & dosagem
13.
Aging (Albany NY) ; 12(3): 2880-2896, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32012117

RESUMO

The adipokine adipsin is an emerging mediator of human osteoarthritis (OA) progression. Here, we investigated its in vivo role in the development of spontaneous OA in aging mice. We compared articular knee joint morphology, histology in knee cartilage, synovial membrane, subchondral bone, meniscus, and anterior cruciate ligament (ACL); and chondrogenesis in the ACL from adipsin-deficient (Df-/-) and wild-type (Df+/+) 20-week- and 20-month-old mice. Serum levels of a panel of adipokines, inflammatory factors, and metalloproteases known to be implicated in OA were investigated. Data first revealed that the early manifestation of OA appeared in the ACL of 20-week-old mice, progressing to severe alterations in the 20 month-old wild-type mice. Further results demonstrated that adipsin-deficiency protected the articular tissues from spontaneous OA progression and triggered significantly higher serum levels of the adipokines adiponectin and FGF-21 while lowering levels of the inflammatory factor interleukin 6 (IL-6) in both young and old mice. This work further underlines the clinical relevance of adipsin as a novel therapeutic approach of human OA. Moreover, this study shows the potential beneficial effect of the adipokine FGF-21 against OA, and provides support for this factor to be a new biomarker and/or target of primary OA therapeutic avenues.

14.
Comput Methods Programs Biomed ; 189: 105315, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31972347

RESUMO

BACKGROUND AND OBJECTIVE: The interrupted time-series (ITS) concept is performed using linear regression to evaluate the impact of policy changes in public health at a specific time. Objectives of this study were to verify, with an artificial intelligence-based nonlinear approach, if the estimation of ITS data could be facilitated, in addition to providing a computationally explicit equation. METHODS: Dataset were from a study of Hawley et al. (2018) in which they evaluated the impact of UK National Institute for Health and Care Excellence (NICE) approval of tumor necrosis factor inhibitor therapies on the incidence of total hip (THR) and knee (TKR) replacement in rheumatoid arthritis patients. We used the newly developed Generalized Structure Group Method of Data Handling (GS-GMDH) model, a nonlinear method, for the prediction of THR and TKR incidence in the abovementioned population. RESULTS: In contrast to linear regression, the GS-GMDH yields for both THR and TKR prediction values that almost fitted with the measured ones. These models demonstrated a low mean absolute relative error (0.10 and 0.09 respectively) and high correlation coefficient values (0.98 and 0.78). The GS-GMDH model for THR demonstrated 6.4/1000 person years (PYs) at the mid-point of the linear regression line post-NICE, whereas at the same point linear regression is 4.12/1000 PYs, a difference of around 35%. Similarly for the TKR, the linear regression to the datasets post-NICE was 9.05/1000 PYs, which is lower by about 27% than the GS-GMDH values of 12.47/1000 PYs. Importantly, with the GS-GMDH models, there is no need to identify the change point and intervention lag time as they simulate ITS continually throughout modelling. CONCLUSIONS: The results demonstrate that in the medical field, when looking at the estimation of the impact of a new drug using ITS, a nonlinear GS-GMDH method could be used as a better alternative to regression-based methods data processing. In addition to yielding more accurate predictions and requiring less time-consuming experimental measurements, this nonlinear method addresses, for the first time, one of the most challenging tasks in ITS modelling, i.e. avoiding the need to identify the change point and intervention lag time.

15.
Rheumatology (Oxford) ; 59(6): 1288-1295, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31580450

RESUMO

OBJECTIVE: To examine whether the presence of bulge sign or patellar tap was associated with frequent knee pain, progression of radiographic OA (ROA) and total knee replacement (TKR). METHODS: This study included 4344 Osteoarthritis Initiative participants examined at baseline for bulge sign and/or patellar tap. The clinical signs were categorized as no (none at baseline and 2 years), resolved (present at baseline only), developed (present at 2 years only) and persistent (present at both time points). Frequent knee pain and progression of ROA over 4 years and TKR over 6 years were assessed. Binary logistic regression was used to examine the associations. RESULTS: A total of 12.7% of participants had bulge sign only, 2.0% had patellar tap only and 3.3% had both. A positive baseline bulge sign was associated with an increased risk of frequent knee pain [OR 1.31 (95% CI 1.04, 1.64), P = 0.02] and TKR [OR 1.47 (95% CI 1.06, 2.05), P = 0.02]. Developed bulge sign was associated with an increased risk of frequent knee pain [OR 1.75 (95% CI 1.34, 2.29), P < 0.001] and progressive ROA [OR 1.67 (95% CI 1.11, 2.51), P = 0.01]. Persistent bulge sign was associated with an increased risk of frequent knee pain [OR 1.60 (95% CI 1.09, 2.35), P = 0.02], progressive ROA [OR 1.84 (95% CI 1.01, 3.33), P = 0.045] and TKR [OR 2.13 (95% CI 1.23, 3.68), P = 0.007]. Patellar tap was not examined for its association with joint outcomes due to its low prevalence. CONCLUSION: The presence of bulge sign identifies individuals at increased risk of frequent knee pain, progression of ROA and TKR. This provides clinicians with a quick, simple, inexpensive method for identifying those at higher risk of progressive knee OA who should be targeted for therapy.


Assuntos
Articulação do Joelho/fisiopatologia , Osteoartrite do Joelho/diagnóstico , Exame Físico/métodos , Idoso , Progressão da Doença , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/fisiopatologia , Índice de Gravidade de Doença
16.
Arthritis Care Res (Hoboken) ; 72(6): 778-786, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31008553

RESUMO

OBJECTIVE: To examine whether joint line tenderness and patellofemoral grind from physical examination were associated with cartilage volume loss, worsening of radiographic osteoarthritis, and the risk of total knee replacement. METHODS: This study examined 4,353 Osteoarthritis Initiative participants. For each measurement of joint line tenderness and patellofemoral grind, the patterns were defined as no (none at baseline and at 1 year), fluctuating (present at either time point), and persistent (present at both time points). Cartilage volume loss and worsening of radiographic osteoarthritis over 4 years were assessed using magnetic resonance imaging and radiographs, and total knee replacement over 6 years was assessed. RESULTS: A total of 35.0% of participants had joint line tenderness, and 15.8% had patellofemoral grind. Baseline patellofemoral grind, but not joint line tenderness, was associated with increased cartilage volume loss (1.08% per year versus 0.96% per year; P = 0.02) and an increased risk of total knee replacement (odds ratio [OR] 1.55 [95% confidence interval (95% CI) 1.11-2.17]; P = 0.01). While the patterns of joint line tenderness were not significantly associated with joint outcomes, participants with persistent patellofemoral grind had an increased rate of cartilage volume loss (1.30% per year versus 0.90% per year; P < 0.001) and an increased risk of total knee replacement (OR 2.10 [95% CI 1.30-3.38]; P = 0.002) compared with those participants without patellofemoral grind. CONCLUSION: Patellofemoral grind, but not joint line tenderness, may represent a clinical marker associated with accelerated cartilage volume loss over 4 years and an increased risk of total knee replacement over 6 years. This simple clinical examination may provide clinicians with an inexpensive way to identify those at higher risk of disease progression who should be targeted for surveillance and management.


Assuntos
Osteoartrite do Joelho/fisiopatologia , Articulação Patelofemoral/fisiopatologia , Exame Físico/estatística & dados numéricos , Idoso , Artroplastia do Joelho/estatística & dados numéricos , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/epidemiologia , Osteoartrite do Joelho/cirurgia , Articulação Patelofemoral/diagnóstico por imagem , Radiografia , Estados Unidos/epidemiologia
17.
Arthritis Res Ther ; 21(1): 224, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694709

RESUMO

BACKGROUND: Identification of the optimal treatment for a given patient is of paramount importance. This is of particular relevance in osteoarthritis (OA) because of the high prevalence of the disease, extensive heterogeneity of the disease, and need for long-term treatment. The aim of the study was to examine whether serum lysophosphatidylcholines (lysoPCs) to phosphatidylcholines (PCs) ratio can predict clinical response to licofelone and naproxen treatments in symptomatic knee OA patients. METHODS: One hundred fifty-eight OA patients who completed the study according to protocol (ATP) of a previous 24-month clinical trial cohort comparing the effect of licofelone vs. naproxen in symptomatic knee OA patients were included. Symptomatic responses to either treatments were classified according to the OARSI-OMERACT criteria based on the WOMAC scores at 24 months. Total concentrations of PCs and lysoPCs were measured in the serum samples collected before the initiation of the treatments, and the lysoPCs to PCs ratio was calculated. Student's t test was utilized to compare the difference in the ratio of lysoPCs to PCs between the symptomatic responders and non-responders. Logistic regression was utilized to adjust for the potential confounders. Receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff of the ratio for prediction. RESULTS: Data showed that 61.4% of the patients symptomatically responded to licofelone and naproxen and 38.6% were deemed as therapeutic failures (non-responders). There was no difference in responders between licofelone and naproxen (p = 0.87). Responders had a significantly higher lysoPCs to PCs ratio than non-responders (0.097 ± 0.003 vs. 0.085 ± 0.003; p = 0.006). Patients with a ratio greater than the optimal cutoff of 0.088 had 2.93 times more likely to respond to licofelone and naproxen (p = 0.002). CONCLUSIONS: Serum lysoPCs to PCs ratio is a marker for response to licofelone and naproxen and may aid in the personalized treatment to knee OA.


Assuntos
Lisofosfatidilcolinas/sangue , Naproxeno/uso terapêutico , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/tratamento farmacológico , Fosfatidilcolinas/sangue , Pirróis/uso terapêutico , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Inibidores de Ciclo-Oxigenase/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
18.
Clin Rheumatol ; 38(12): 3557-3566, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31478110

RESUMO

INTRODUCTION/OBJECTIVE: Knee alignment and anterior cruciate ligament (ACL) injury are risk factors for knee osteoarthritis (OA). The objective was to examine interactions between knee alignment and ACL status on cartilage volume loss in participants with or at risk of knee OA. METHOD: Participants were from the Osteoarthritis Initiative, a longitudinal cohort study. Data were from baseline and 24- and 72-month follow-up visits. Participants with knee OA (progression subcohort) or at risk of knee OA (incidence subcohort) that had partial or full ACL tears (OA-ACL group; n=66) or an intact ACL (OA-only group, n=367) were selected. Femur-tibia angles from radiographs quantified knee alignment. Changes in tibial and femoral cartilage volumes were measured using magnetic resonance imaging. Hierarchical linear models examined if knee alignment, presence of ACL, and their interaction were related to cartilage volume loss after accounting for other variables. RESULTS: Interactions between alignment and ACL status were significantly related to cartilage volume loss in the lateral plateau (ß=-20.19, 95% confidence interval [CI]=-34.65 to -5.73) and lateral condyle (ß=-23.64, 95%CI=-43.06 to -4.23). Valgus alignment was related to lateral compartment cartilage loss in the OA-ACL group, but not in the OA-only group. Varus alignment was related to cartilage loss in the medial plateau (ß=7.49, 95%CI=0.17 to 14.80) and medial condyle (ß=19.70, 95%CI=5.96 to 33.44) in both groups. CONCLUSION: The impact of knee alignment on knee OA initiation and progression varies based on ACL status. Initial lateral compartment damage or changes in joint kinematics after ACL rupture might account for these findings.Key Points• The relationship between knee alignment and lateral compartment cartilage loss depended on the status of the anterior cruciate ligament in participants with knee osteoarthritis or at risk for knee osteoarthritis.• Valgus alignment was related to lateral compartment cartilage loss in participants with a deficient anterior cruciate ligament.• Varus alignment was related to medial compartment cartilage loss regardless of the status of the anterior cruciate ligament.


Assuntos
Lesões do Ligamento Cruzado Anterior/complicações , Articulação do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/etiologia , Idoso , Lesões do Ligamento Cruzado Anterior/patologia , Progressão da Doença , Feminino , Humanos , Articulação do Joelho/patologia , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Estudos Prospectivos
19.
Sci Rep ; 9(1): 9648, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273319

RESUMO

To identify serum biomarker(s) for predicting knee cartilage volume loss over time, we studied 139 knee osteoarthritis (OA) patients from a previous 24-month clinical trial cohort. Targeted metabolomic profiling was performed on serum collected at baseline. The pairwise metabolite ratios as proxies for enzymatic reaction were calculated and used in the analysis. Cartilage volume loss between baseline and 24 months was assessed quantitatively by magnetic resonance imaging (MRI). Data revealed an association between the serum ratio of lysophosphatidylcholine 18:2 (lysoPC 18:2) to phosphatidylcholine 44:3 (PC44:3) and the cartilage volume loss in the lateral compartment (ß = -0.21 ± 0.04, p = 8.53*10-7) and with joint degradation markers, COMP (r = 0.32, p = 0.0002) and MMP1 (r = 0.26, p = 0.002). The significance remained after adjustment for age, sex, BMI, diabetes, hypertension, dyslipidemia, and the treatment taken in the original study. As the ratio indicated the over activation of the conversion pathway of PC to lysoPC catalyzed by phospholipase A2 (PLA2), we assessed and found that a specific PLA2, PLA2G5, was significantly increased in human OA cartilage and synovial membrane (85% and 19% respectively, both p < 0.04) compared to controls, and its overexpression correlated with IL-6 (r = 0.63, p = 0.0008). Our data suggest that the serum lysoPC 18:2 to PC44:3 ratio is highly associated with a greater risk of cartilage volume loss of the knee and warrants further investigation in an independent cohort.


Assuntos
Cartilagem Articular/patologia , Articulação do Joelho/patologia , Lisofosfatidilcolinas/metabolismo , Osteoartrite do Joelho/patologia , Fosfatidilcolinas/metabolismo , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Cartilagem Articular/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Articulação do Joelho/metabolismo , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite do Joelho/metabolismo , Membrana Sinovial/metabolismo
20.
Arthritis Res Ther ; 21(1): 127, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126352

RESUMO

OBJECTIVE: To examine whether metformin use was associated with knee cartilage volume loss over 4 years and risk of total knee replacement over 6 years in obese individuals with knee osteoarthritis. METHODS: This study analysed the Osteoarthritis Initiative participants with radiographic knee osteoarthritis (Kellgren-Lawrence grade ≥ 2) who were obese (body mass index [BMI] ≥ 30 kg/m2). Participants were classified as metformin users if they self-reported regular metformin use at baseline, 1-year and 2-year follow-up (n = 56). Non-users of metformin were defined as participants who did not report the use of metformin at any visit from baseline to 4-year follow-up (n = 762). Medial and lateral cartilage volume (femoral condyle and tibial plateau) were assessed using magnetic resonance imaging at baseline and 4 years. Total knee replacement over 6 years was assessed. General linear model and binary logistic regression were used for statistical analyses. RESULTS: The rate of medial cartilage volume loss was lower in metformin users compared with non-users (0.71% vs. 1.57% per annum), with a difference of - 0.86% per annum (95% CI - 1.58% to - 0.15%, p = 0.02), after adjustment for age, gender, BMI, pain score, Kellgren-Lawrence grade, self-reported diabetes, and weight change over 4 years. Metformin use was associated with a trend towards a significant reduction in risk of total knee replacement over 6 years (odds ratio 0.30, 95% CI 0.07-1.30, p = 0.11), after adjustment for age, gender, BMI, Kellgren-Lawrence grade, pain score, and self-reported diabetes. CONCLUSIONS: These data suggest that metformin use may have a beneficial effect on long-term knee joint outcomes in those with knee osteoarthritis and obesity. Randomised controlled trials are needed to confirm these findings and determine whether metformin would be a potential disease-modifying drug for knee osteoarthritis with the obese phenotype.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Obesidade/complicações , Osteoartrite do Joelho/patologia , Idoso , Cartilagem Articular/patologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/etiologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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