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Integrative analyses of mendelian randomization and bioinformatics reveal casual relationship and genetic links between COVID-19 and knee osteoarthritis.

BACKGROUND: Clinical and epidemiological analyses have found an association between coronavirus disease 2019 (COVID-19) and knee osteoarthritis (KOA). Infection with COVID-19 may increase the risk of developing KOA. OBJECTIVES: This study aimed to investigate the potential causal relationship between COVID-19 and KOA using Mendelian randomization (MR) and to explore the underlying mechanisms through a systematic bioinformatics approach. METHODS: Our investigation focused on exploring the potential causal relationship between COVID-19, acute upper respiratory tract infection (URTI) and KOA utilizing a bidirectional MR approach. Additionally, we conducted differential gene expression analysis using public datasets related to these three conditions. Subsequent analyses, including transcriptional regulation analysis, immune cell infiltration analysis, single-cell analysis, and druggability evaluation, were performed to explore potential mechanisms and prioritize therapeutic targets. RESULTS: The results indicate that COVID-19 has a one-way impact on KOA, while URTI does not play a causal role in this association. Ribosomal dysfunction may serve as an intermediate factor connecting COVID-19 with KOA. Specifically, COVID-19 has the potential to influence the metabolic processes of the extracellular matrix, potentially impacting the joint homeostasis. A specific group of genes (COL10A1, BGN, COL3A1, COMP, ACAN, THBS2, COL5A1, COL16A1, COL5A2) has been identified as a shared transcriptomic signature in response to KOA with COVID-19. Imatinib, Adiponectin, Myricetin, Tranexamic acid, and Chenodeoxycholic acid are potential drugs for the treatment of KOA patients with COVID-19. CONCLUSIONS: This study uniquely combines Mendelian randomization and bioinformatics tools to explore the possibility of a causal relationship and genetic association between COVID-19 and KOA. These findings are expected to provide novel perspectives on the underlying biological mechanisms that link COVID-19 and KOA.

Humans

Extended Reality Interventions for Osteoarthritis of the Knee and Recovery After Total Knee Arthroplasty: Systematic Review and Meta-Analyses.

BACKGROUND: Nonpharmacologic interventions are important for treating knee pain due to osteoarthritis or after total knee arthroplasty (TKA), and extended reality (XR) technology may enhance treatments for these indications. OBJECTIVE: This systematic review aimed to evaluate XR interventions for pain due to knee osteoarthritis (KOA) or for recovery after TKA. METHODS: Databases were searched through May 2023 and updated in December 2025. Eligible trials evaluated XR interventions to treat KOA pain or after TKA. We classified interventions by depth of immersion and clinical mechanism. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria to determine the certainty of evidence for prioritized outcomes. Meta-analyses were performed when ≥3 studies evaluated similar comparisons, outcomes, and time points. RESULTS: Eligible trials addressed KOA (k=12) or recovery after TKA (k=9). Sample sizes ranged from 36 to 306 participants, and most studies had a follow-up of ≤3 months. Nineteen studies assessed pain-related functioning and pain intensity, and 5 assessed adverse events (AEs). For KOA, 10 studies examined interactive digital rehabilitation (IDR), and 2 examined virtual reality (VR)-digitally augmented exercise (DAE). IDR for KOA may result in better pain-related functioning (low certainty of evidence [COE]; pooled standardized mean difference [SMD] -0.59, 95% CI -1.11 to -0.06; prediction interval [PI] -1.72 to 0.55; k=5) and lower pain intensity at 6-8 weeks (low COE; pooled SMD -0.46, 95% CI -0.92 to 0.00; PI -1.39 to 0.47; k=4). VR-DAE for KOA (k=2) produced inconsistent results (very low COE). For post-TKA studies, 5 examined IDR, 2 examined VR-DAE, 1 examined VR-distraction, and 1 examined VR-psychoeducation. Post-TKA IDR may result in better pain-related functioning (low [k=4] and moderate COE [k=1]) but little to no difference in pain intensity (low-moderate COE; pooled SMD at 3-4 months -0.12, 95% CI -0.75 to 0.52; PI -1.63 to 1.27; k=3). VR-psychoeducation probably results in lower pain at 4 weeks (moderate COE; k=1), and VR-distraction may result in 6 months (low COE; k=1), whereas VR-DAE produced mixed findings (k=2; very low COE). IDR was not associated with AEs, and VR may not be associated with AEs for KOA (high and low COE), though AE reporting was uncommon (k=5) and evidence was very uncertain for post-TKA. CONCLUSIONS: IDR may augment treatment for KOA and post-TKA recovery, and VR may benefit post-TKA rehabilitation. This review is the first to stratify by level of immersion, clinical mechanism, and follow-up duration and to systematically evaluate AEs. IDR may be ready for integration into KOA care, while use after TKA needs more evidence. Randomized controlled trials with implementation outcomes could determine how XR interventions can be used for KOA, whereas trials evaluating efficacy and AEs are needed before their use for post-TKA.

Humans

The causal relationship between antihypertensive drugs and knee osteoarthritis: A drug target Mendelian randomization study.

Recently studies have revealed a robust association between hypertension and knee osteoarthritis (KOA), with patients likely to suffer from both conditions. We employed Mendelian randomization (MR) analysis to assess the impact of antihypertensive medications on KOA, aiming to offer clinical guidance for concomitant drug therapy and identify potential therapeutic targets for KOA. We obtained exposure instruments (instrumental variables) by locating Single-nucleotide polymorphisms related to systolic blood pressure near drug target genes. We then conducted Mendelian randomization analyses between the exposure data and genome-wide association studies data on KOA to evaluate the impact of antihypertensive drugs on KOA. We observed a significant association between decreased expression of the SLC12A2 target gene and a reduced risk of KOA (odds ratio: 0.915, 95% confidence interval: 0.869-0.964, P&#x2005;<&#x2005;.001). In this study, we find that SLC12A2 inhibitors can have a beneficial effect on KOA, and that the SLC12A2 gene may be a potential therapeutic target for KOA. These findings suggest that when treating patients with both hypertension and KOA, clinicians may consider prioritizing the use of SLC12A2 inhibitors.

Humans

Causal association of menstrual reproductive factors on the risk of osteoarthritis: A univariate and multivariate Mendelian randomization study.

OBJECTIVE: Several observational studies have revealed a potential relationship between menstrual reproductive factors (MRF) and osteoarthritis (OA). However, the precise causal relationship remains elusive. This study performed Mendelian randomization (MR) to provide deeper insights into this relationship. METHODS: Utilizing summary statistics of genome-wide association studies (GWAS), we conducted univariate MR to estimate 2 menstrual factors (Age at menarche, AAM; Age at menopause, AMP) and 5 reproductive factors (Age at first live birth, AFB; Age at last live birth, ALB; Number of live births, NLB; Age first had sexual intercourse, AFSI; Age started oral contraceptive pill, ASOC) on OA (overall OA, OOA; knee OA, KOA and hip OA, HOA). The sample size of MRF ranged from 123846 to 406457, and the OA sample size range from 393873 to 484598. Inverse variance weighted (IVW) method was used as the primary MR analysis methods, and MR Egger, weighted median was performed as supplements. Sensitivity analysis was employed to test for heterogeneity and horizontal pleiotropy. Finally, multivariable MR was utilized to adjust for the influence of BMI on OA. RESULTS: After conducting multiple tests (P<0.0023) and adjusting for BMI, MR analysis indicated that a lower AFB will increase the risk of OOA (odds ratio [OR] = 0.97, 95% confidence interval [CI]: 0.95-0.99, P = 3.39&#xd7;10-4) and KOA (OR = 0.60, 95% CI: 0.47-0.78, P = 1.07&#xd7;10-4). ALB (OR = 0.61, 95% CI: 0.45-0.84, P = 2.06&#xd7;10-3) and Age AFSI (OR = 0.66, 95% CI: 0.53-0.82, P = 2.42&#xd7;10-4) were negatively associated with KOA. In addition, our results showed that earlier AMP adversely affected HOA (OR = 1.12, 95% CI: 1.01-1.23, P = 0.033), and earlier ASOC promote the development of OOA (OR = 0.97, 95% CI: 0.95-1.00, P = 0.032) and KOA (OR = 0.58, 95% CI: 0.40-0.84, P = 4.49&#xd7;10-3). ALB (OR = 0.98, 95% CI: 0.96-1.00, P = 0.030) and AFSI (OR = 0.98, 95% CI: 0.97-0.99, P = 2.66&#xd7;10-3) also showed a negative association with OOA but they all did not pass multiple tests. The effects of AAM and NLB on OA were insignificant after BMI correction. CONCLUSION: This research Certificates that Early AFB promotes the development of OOA, meanwhile early AFB, ALB, and AFSI are also risk factors of KOA. Reproductive factors, especially those related to birth, may have the greatest impact on KOA. It provides guidance for promoting women's appropriate age fertility and strengthening perinatal care.

Humans

Intramuscular Fat Infiltration and Knee Osteoarthritis: A Systematic Review and Meta-Analysis.

BACKGROUND: Intramuscular fat infiltration (IMFI) is considered to be closely associated with knee osteoarthritis (KOA); however, its overall association, muscle-specific involvement, and clinical relevance remain unclear. OBJECTIVE: To quantify the association between IMFI and KOA, identify affected muscle groups, and evaluate prognostic value. METHODS: We searched PubMed, Web of Science, Scopus, and Embase up to December 2025 for observational studies. Two reviewers independently screened, extracted data, and assessed bias (NOS/JBI). Pooled standardized mean differences (SMDs) were calculated using random-effects models, with subgroup and sensitivity analyses. RESULTS: Seventeen studies were included. IMFI was significantly higher in KOA patients than controls (SMD&#xa0;=&#xa0;0.63, 95% CI 0.41-0.85, I2&#xa0;=&#xa0;84.7%). Anatomically, the anterior thigh muscles (rectus femoris, vastus lateralis, vastus medialis) demonstrated a significant pooled effect (SMD&#xa0;=&#xa0;0.96, 95% CI 0.66-1.25, I2&#xa0;=&#xa0;3.2%) and showed the strongest pooled association, whereas posterior, medial, and composite measures did not demonstrate significant associations. At the individual muscle level, a single study reported a notable association for the semimembranosus (SMD&#xa0;=&#xa0;1.25, 95% CI 0.57-1.93); however, this finding is based on limited evidence and requires confirmation in future studies. Subgroup by imaging modality: CT demonstrated a significant association (SMD&#xa0;=&#xa0;0.59, 95% CI 0.28-0.90), while MRI and ultrasound did not show significant associations. Elevated IMFI was also associated with reduced muscle strength, higher KOA incidence, structural progression, and increased knee replacement risk. CONCLUSION: A moderate positive association exists between IMFI and KOA, with notable muscle-specific heterogeneity. Anterior thigh muscles show the strongest pooled association, whereas individual muscle findings require further confirmation. These findings suggest that IMFI may represent a promising potential marker warranting further prospective investigation for risk stratification, though causality and its role in modifying disease progression remain to be established.

Humans

CoLchicine for Treatment of OsteoArthritis of the Knee (CLOAK): Clinical and biochemical outcomes from a three-month double-blind, placebo-controlled study.

OBJECTIVE: Knee osteoarthritis (KOA) causes pain and progressive disability, but pharmacologic treatments are limited. Colchicine inhibits inflammation that might modulate KOA, but efficacy trials have yielded mixed results. We tested whether colchicine, without concurrent NSAIDs, improved KOA pain, function, synovial effusion size, and OA-associated inflammatory serum biomarkers. METHODS: Participants with symptomatic KOA and radiographic Kellgren-Lawrence grades 2/3 were randomized to receive three months of daily colchicine or placebo in a double-blind manner, with no concurrent NSAID use. The primary outcome was between-group change in visual analog score (VAS) for index knee pain. Secondary outcomes included changes in Knee Osteoarthritis Outcome Scores (KOOS), size (depth in millimeters) of sonographically-identified effusions, acetaminophen use, and changes in OA-related serum biomarkers. RESULTS: From baseline to end of study of 120 enrolled participants, no significant differences were observed in improvement of VAS pain, KOOS scores or effusion size. Subsets of participants with more severe VAS pain, worse radiographic disease, or higher hsCRP or serum urate levels at baseline also showed no significant clinical benefit from colchicine compared to placebo. In contrast to the clinical outcomes, colchicine treatment was associated with significant or trending improvement in multiple OA-related serum biomarkers including hsCRP and &#x3b2;-NGF (p < 0.05) and PGE2, IL-1ra, IL-8, and VEGF (p < 0.16). CONCLUSION: This double-blind placebo-controlled trial of colchicine for KOA failed to demonstrate improvement in pain, function, or synovial effusion size in comparison to placebo at three months. Early improvement in OA-associated inflammatory biomarkers suggests a possible longer-term clinical benefit. Clinical Trials Registration No NCT03913442.

Humans

The effect of ultrafiltration on dialysance. Mathematical theory and experimental verification.

It is known that convective transport (ultrafiltration, QF) augments diffusive transport. This augmentation achieves great importance as solute molecular weight increases. Previous mathematical treatments of dialysance (D) have provided the relationship between D and blood flow rate (QB), dialysate flow rate (QD), and dialyzer membrane surface area permeability product (KoA), in the limit of QF = 0. The authors derived the relationship between D (defined as D') and QB, QD, and KoA for the general case of QF greater than or equal to 0: D' = X-Y/In X/Y . [(1-ó) QF + KoA] for X = X(D', QF, QD) = 1 - [D'/QD + QF] Y = Y(D', QF, QB) = D'-QB/QF-QB ó = the Staverman reflection coefficient. This equation demonstrates an approximate linear increase in D' as QF increases. Experimental verification is provided by in vivo studies of dialysis patients in which the dialysance of vancomycin doubles as QF is increased from 0 to 50. Because D' varies linearly with QF, this allows for the determination of KoA and ó. Using the Cobe 500HG Hemophan membrane, KoA for vancomycin was determined to be 6.54 and ó = 0.88.

Diffusion

Efficacy of high-intensity laser therapy versus ultrasound therapy in patients with knee osteoarthritis: a randomized controlled trial.

PURPOSE: High-intensity laser therapy (HILT) and ultrasound (US) are widely used for knee osteoarthritis (KOA), but comparative efficacy data remain scarce. This study compared HILT and US as exercise adjuncts in patients with KOA. METHODS: In this single-center, assessor-blinded RCT, 66 adults with KOA were randomized 1:1 to HILT or US twice weekly for 6&#xa0;weeks as exercise adjuncts. The primary outcome was WOMAC total score change from baseline to 12&#xa0;weeks post-treatment (minimum important change [MIC]&#x2009;=&#x2009;10 points, applied as an approximation). Secondary outcomes included VAS, OKS, KOOS, and EQ-5D-5L. RESULTS: In ITT analysis (N&#x2009;=&#x2009;66), the HILT group achieved a mean WOMAC reduction of 40.0 vs 8.2 points (adjusted between-group difference: -27.7 points, 95% CI:&#x2009;-&#x2009;39.0 to&#x2009;-&#x2009;16.5; p&#x2009;<&#x2009;0.001, partial &#x3b7;2&#x2009;=&#x2009;0.277). At 12&#xa0;weeks post-treatment, greater improvements across all secondary outcomes were observed in exploratory analyses (p&#x2009;&#x2264;&#x2009;0.012). Furthermore, HILT maintained therapeutic effects up to 12&#xa0;weeks post-treatment, whereas the US group experienced a gradual loss of post-treatment gains. CONCLUSION: HILT combined with exercise produced greater short-term improvements in WOMAC total score than US in patients with KOA, with exploratory findings suggesting consistent benefits in pain, function, and quality of life, and with benefits maintained up to 12&#xa0;weeks after the last treatment session.

Humans

Optimization of dialysate flow and mass transfer during automated peritoneal dialysis.

The purpose of this study was to evaluate the effect of patient position on the mass transfer area coefficient (KoA) and to characterize drain/fill profiles in an effort to enhance efficiency of automated peritoneal dialysis. Over 100 exchanges were performed in 38 stable peritoneal dialysis patients to either determine the small solute KoA in the supine versus upright position or to characterize fill/drain profiles. The KoA for all solutes tested was significantly greater in the supine position compared with the upright position (P < 0.05). Fill profiles revealed the fill rate to be a function of fill height (P < 0.001) and patient position (supine > upright [P < 0.001]). Analysis of drain flow rate versus time revealed an initial segment of high outflow (350 +/- 89 mL/min) followed by an abrupt transition to a segment characterized by slow drainage (36 +/- 21 mL/min). The first segment of drain only took 5.6 +/- 2.3 minutes (42% of the total drain time); in that time, 83% +/- 10% of the dialysate was drained. The transition volume (volume of dialysate remaining at the time the transition occurs, excluding residual volume) correlated with body surface area (R = 0.52, P < 0.01). In conclusion, automated peritoneal dialysis treatment (including intermittent peritoneal dialysis, which may be done in the upright position) should be done in the supine position to optimize the KoA, and shortening drain time to include only the initial segment of high outflow will improve the efficiency and convenience of therapy.

Automation

The role of lymphatic drainage in peritoneal mass transfer.

Peritoneal lymphatic drainage has recently been shown to be a contributing factor to both clearance and fluid removal patterns during continuous ambulatory peritoneal dialysis. In this report peritoneal transport equations are derived and compared and contrasted with existing models that ignore this term. It was found that for solutes for which the sieving coefficient may be assumed to equal unity, such as urea and creatinine, the values of the mass transfer area coefficient (KoA) are overestimated by the value of the lymphatic drainage rate. In this instance, corrected KoA may be obtained simply by subtracting lymphatic flow rate from the KoA calculated by traditional methods. For larger solutes, such as beta 2-microglobulin, for which the sieving coefficient may be assumed to equal zero, the value of mass transfer coefficient was underestimated to varying degrees; however, for values of lymphatic drainage rate less than 60 ml/h the effect will not be clinically measurable. A theoretical model is used to plot the dependence of net fluid removal on peritoneal lymphatic flow, glucose KoA, and hydraulic permeability. Reduction in net ultrafiltered volume, and hence estimation of transperitoneal ultrafiltration, is directly proportional to accumulated lymphatic drainage.

Creatinine

Efficacy and Safety of Celecoxib Combined With Jintiange Capsules for the Treatment of Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND Knee osteoarthritis (KOA) poses a substantial global health burden, and conventional nonsteroidal anti-inflammatory drug (NSAID) therapy with celecoxib is hindered by adverse effects. This study evaluated the efficacy and safety of combining celecoxib with Jintiange capsules, a synthetic tiger bone formulation used in traditional Chinese medicine (TCM), to manage symptomatic KOA. MATERIAL AND METHODS This 12-week, randomized, double-blind, placebo-controlled trial enrolled 120 patients with KOA (age &#xf0b3;40 years; visual analog scale [VAS] score 4-7). Participants received celecoxib (200 mg/day tapered to 100 mg/day) combined with either Jintiange capsules (3.6 g/day) or placebo. The primary outcome was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score. Secondary outcomes included WOMAC subscale scores (pain, function, and stiffness), VAS scores, and adverse drug reaction reports. RESULTS The experimental group demonstrated a 23.5-point (37.8%) reduction in WOMAC total score from baseline (P<0.001); the control group showed a 13.2-point (21.6%) reduction (P<0.001). The experimental group achieved 51.6% improvement in the WOMAC pain subscale (P<0.001), whereas the control group showed 33.3% improvement (P<0.001). Relative to the control group, the experimental group demonstrated a greater reduction in VAS score (P<0.001). Combined TCM-NSAID therapy produced significantly greater pain relief and functional improvement than NSAID monotherapy. CONCLUSIONS Celecoxib combined with Jintiange capsules provided clinically meaningful improvements in pain relief and functional outcomes relative to celecoxib monotherapy in patients with KOA. These findings support integration of TCM with conventional pharmacotherapy for osteoarthritis management.

Humans

The phenotype and gene frequencies of human platelet specific antigens among Chinese in Taiwan.

Human platelet specific antigens (HPA) were serologically typed among 48 to 567 samples of blood from Chinese in Taiwan by using the mixed passive hemag-glutination method (MPHA). The prevalence found was: HPA-la (P1A1), > 99.9% (48/48); HPA-2b (Koa or Siba), 9.0% (51/567); HPA-3a (Baka), 84.8% (481/567); HPA-4a (Yukb), > 99.9% (567/567); HPA-4b (Yuka), 0.5% (3/567); HPA-5b (Br(a)), 32.6% (185/567); and Nak(a), 98.4% (558/567). The gene frequencies for these antigens were: HPA-la (P1A1), > 0.999; HPA-2b (Koa or Siba), 0.046; HPA-3a (Bak(a)), 0.611; HPA-4a (Yukb), 0.997; HPA-4b (Yuka), 0.003; HPA-5b (Br(a)), 0.179; and Nak(a), 0.874. The distribution of HPA's for Chinese differ from those for Caucasians and for Japanese. When compared to Caucasians, Chinese show a higher prevalence of HPA-la (P1A1), higher prevalence of HPA-5b (Br(a)), lower prevalence of HPA-2b (Koa or Siba) and lower prevalence of HPA-3a (Baka). Both Chinese and Japanese have a very high prevalence rate of HPA-la (P1A1), ie. close to 100%. However, the prevalence of HPA 2-2b (Koa or Siba) and HPA-4b (Yuka) is slightly lower in Chinese than in Japanese; and, the prevalence rate for HPA-3a (Baka) is slightly higher in Chinese than in Japanese.

Antigens, Human Platelet

Association of TCF7L2 and LEPR gene variants (rs7903146 and rs1137101) with primary knee osteoarthritis in a northern Mexican Mestizo population.

INTRODUCTION: There is a growing interest in the study of Obesity, Diabetes, and their genetic polymorphisms for the risk of developing osteoarthritis. This study analyzed the associations among the rs1137101 LEPR gene and rs7903146 polymorphisms TCF7L2 gene with primary knee osteoarthritis in a population from northern Mexico. METHODS: We conducted a case-control study with 438 Mexican Mestizo participants, selected non-randomly by convenience. We included age, diabetes, and body mass index for analysis. The presence of the TCF7L2 (n&#x2009;=&#x2009;236) and LEPR (n&#x2009;=&#x2009;405) gene genotypes was determined using real-time PCR with the rhAmpTM SNP Assay methodology. We performed comparisons between groups using the chi-square test, Fisher&#xb4;s exact test, the Mann-Whitney U test, and adjusted regression model analysis. RESULTS: The CC genotype of the rs7903146 &#x200b;&#x200b;polymorphism was significantly associated as risk factor with obesity (p&#x2009;=&#x2009;0.043; OR 2.021, CI 1.023 - 3.989) and CT genotype as a protective factor (p&#x2009;=&#x2009;0.016, p&#x2009;=&#x2009;0.013, and p&#x2009;=&#x2009;0.008); the CC genotype was significantly associated with primary KOA as a risk factor (p&#x2009;=&#x2009;0.040; OR 2.061, CI 1.034 - 4.107) and the CT genotype as a protective factor (p&#x2009;=&#x2009;0.039, and p&#x2009;=&#x2009;0.041; OR 0.480, CI 0.237 - 0.970). No association was found between the genotypes for LEPR rs1137101 and KOA. CONCLUSION: This study suggests a possible role for the rs7903146 &#x200b;&#x200b;polymorphism of the TCF7L2 gene, in the risk of primary KOA and obesity. We suggest conducting additional studies with a larger population sample, including other polymorphisms of the same genes in different ethnic groups, to corroborate the findings shown in this study. Key Points &#x2022; We observed significant associations for obesity and primary knee osteoarthritis in the presence of the rs7903146 CC and CT genotypes.

LEPR