Placenta-Derived Products Demonstrate Good Safety Profile and Overall Satisfactory Outcomes for Treating Knee Osteoarthritis: A Systematic Review of Clinical Evidence.

PURPOSE: To summarize the available evidence regarding the clinical application of placenta-derived products to treat knee osteoarthritis (OA), underlining the differences existing among products, their preparation methods, and the clinical results reported so far. METHODS: A research on PubMed, Cochrane, and Google Scholar databases was performed. The following inclusion criteria for relevant articles were used: (1) randomized controlled trials (RCTs), prospective and retrospective studies, on humans; (2) written in English; (3) published in indexed journals in the last 10 years (2011-2022); and (4) dealing with the use of placenta-derived products for the treatment of knee OA. Exclusion criteria were articles written in other languages; animals or in vitro trials; reviews; and trials analyzing other applications of placenta-derived products not related to knee OA. RESULTS: In total, 16 studies were included in the present systematic review. Five studies investigated placenta-derived products as an augmentation during surgical procedures, whereas 11 studies were focused on the injective approach only. Of these, only 4 were RCTs and were all from the injective approach group. Potential risk of bias was carried out using Cochrane Risk of Bias 2 tool for RCTs and a modified Coleman approach for nonrandomized studies, revealing for both an overall insufficient quality. Clinical outcomes reveal excellent safety profile and notable efficacy, despite the different types of products used and different administration methods adopted. CONCLUSIONS: Placental products showed a good safety profile and overall satisfactory outcomes for the treatment of knee OA. LEVEL OF EVIDENCE: Level IV, systematic review of Level II, III and IV studies.

Combined subchondral and intra-articular injections of bone marrow aspirate concentrate provide stable results up to 24 months.

PURPOSE: The aim of this study was to evaluate the clinical and imaging findings up to 24 months of follow-up in patients treated with combined subchondral and intra-articular bone marrow aspirate concentrate (BMAC) injections for the treatment of knee osteoarthritis (OA). METHODS: Thirty consecutive patients (19 males, 11 females) aged between 40 and 75 years (mean age 56.4 ± 8.1 years) with unilateral symptomatic knee OA (Kellgren-Lawrence 2-3) were included in the study. Patients were treated with combined intra-articular and subchondral bone BMAC injections (total 9 ml) under fluoroscopic control. IKDC subjective score, VAS for pain, KOOS, and EQ-VAS were prospectively evaluated up to 24 months. Radiographs were performed at baseline and at 24 months after the procedure. MRI was evaluated with the WORMS score at baseline, 6-12 months, and 24 months of follow-up. The statistical analysis was performed using SPSS v.19.0 and for all tests p < 0.05 was considered significant. RESULTS: No major complications and a 13% failure rate were reported. The IKDC subjective score remained stable from 62.6 ± 19.4 at 12 months to 63.4 ± 17.1 at 24 months (both p < 0.0005 compared to baseline, 40.5 ± 12.5). Similar improvements were reported for all KOOS subscales, while EQ-VAS did not report any significant improvement. VAS pain worsened from 3.0 ± 1.9 at 12 months to 4.4 ± 1.8 at the final follow-up (p = 0.0001), although remaining lower compared to the baseline value of 6.3 ± 1.8 (p = 0.002). The radiographic evaluation did not reveal signs of improvement or deterioration of the OA grade. The MRI findings showed a worsening in marginal osteophytes and synovitis, but a significant reduction of bone marrow edema at 24 months (p < 0.0005). CONCLUSION: Combined intra-articular and subchondral BMAC injections provided clinical and imaging benefits up to 24 months for the treatment of symptomatic knee OA, with durable clinical results, a low failure rate, and a significant reduction of bone marrow edema.

Early application of extracorporeal shock wave therapy improves pain control and functional scores in patients undergoing total knee arthroplasty: a randomized controlled trial.

PURPOSE: The use of biophysical stimuli produced by extracorporeal shock wave therapy (ESWT) can improve the rehabilitation treatment of patients undergoing total knee arthroplasty (TKA). The aim of our study is to evaluate the short-term efficacy of early postoperative ESWT in combination with physiotherapy in terms of pain reduction and motor function recovery of patients undergoing TKA and compare it with conventional physiotherapy treatment. METHODS: Fifty-six patients undergoing TKA were enrolled in the study from January 2019 to February 2020. Patients received two sessions of physiotherapy daily, with (experimental group) or without (control group) four sessions of ESWT within seven days after surgery. Patients were prospectively evaluated at baseline and at post-operative day two and seven. Assessment included active knee range of motion (aROM), timed up and go (TUG) test, visual analogue scale (VAS) for pain, and Borg scale. RESULTS: Fifty patients completed the study. Both treatments proved to be effective in reducing pain and improving the knee range of motion and functional scores at seven days after surgery: the aROM in the ESWT group was 36.8 ± 11.0 grades (p < 0.001), while in control group was 19.8 ± 7.8 grades (p < 0.001). TUG, VAS, and BORG scores showed a similar trend. Comparative analysis revealed superior clinical results for the experimental group in all the outcomes, in particular aROM (96.0 ± 5.40 vs. 81.20 ± 11.01, p < 0.001) and TUG test (17.4 ± 5.61 vs. 21.24 ± 5.88, p < 0.001), at day seven after surgery. CONCLUSION: Early application of ESWT in addition to physiotherapy can positively influence the rehabilitation process after TKA. The treatment proved to be well tolerated and safe. Preliminary results demonstrated better pain control and functional scores compared to physiotherapy alone.

Intra-Articular Injection of Botulinum Toxin for the Treatment of Knee Osteoarthritis: A Systematic Review of Randomized Controlled Trials.

The purpose of the present paper was to review the available evidence on intra-articular botulinum toxin (BTX) injection in the treatment of knee osteoarthritis and to compare it to other conservative treatment options. A systematic review of the literature was performed on the PubMed, Scopus, Cochrane Library, Web of Science, Pedro and Research Gate databases with the following inclusion criteria: (1) randomized controlled trials (RCTs), (2) written in the English language, and (3) published on indexed journals in the last 20 years (2001-2021) dealing with the use of BTX intra-articular injection for the treatment of knee OA. The risk of bias was assessed using the Cochrane Risk of Bias tool for RCTs. Nine studies involving 811 patients in total were included. Patients in the control groups received different treatments: conventional physiotherapy, hyaluronic acid injection or prolotherapy or a combination thereof in 5 studies, steroid infiltrative therapy (triamcinolone) in 1 study, placebo in 2, and local anesthetic treatment in 1 study. Looking at the quality of the available literature, two of the included studies reached "Good quality" standard, three were ranked as "Fair", and the rest were considered "Poor". No major complications or serious adverse events were reported following intra-articular BTX, which provided encouraging pain relief, improved motor function, and quality of life. Based on the available data, no clear indication emerged from the comparison of BTX with other established treatments for knee OA. The analysis of the available RCTs on BTX intra-articular injection for the treatment of knee OA revealed modest methodological quality. However, based on the data retrieved, botulinum toxin has been proven to provide good short-term outcomes, especially in patients with pain sensitization, by modulating neurotransmitter release, peripheral nociceptive transduction, and acting on the control of chronic pain from central sensitization.

Ozone Therapy versus Hyaluronic Acid Injections for Pain Relief in Patients with Knee Osteoarthritis: Preliminary Findings on Molecular and Clinical Outcomes from a Randomized Controlled Trial.

Ozone therapy (OT) is used for the treatment of multiple musculoskeletal disorders. In recent years, there has been a growing interest in its use for the treatment of osteoarthritis (OA). The aim of this double-blind randomized controlled trial was to evaluate the efficacy of OT compared with hyaluronic acid (HA) injections for pain relief in patients with knee OA. Patients with knee OA for at least three months were included and randomly assigned to receive three intra-articular injections of ozone or HA (once a week). Patients were assessed at baseline and at 1, 3, and 6 months after the injections for pain, stiffness, and function using the WOMAC LK 3.1, the NRS, and the KOOS questionnaire. Out of 55 patients assessed for eligibility, 52 participants were admitted to the study and randomly assigned into the 2 groups of treatment. During the study, eight patients dropped out. Thus, a total of 44 patients, reached the endpoint of the study at 6 months. Both Group A and B consisted of 22 patients. At 1-month follow-up after injections, both treatment groups improved statistically significantly from baseline in all outcomes measured. At 3 months, improvements remained similarly consistent for Group A and Group B. At 6-month follow-up, the outcomes were comparable between the 2 groups, showing only a worsening trend in pain. No significant differences were found between the two groups in pain scores. Both therapies have proven to be safe, with the few recorded adverse events being mild and self-limiting. OT has demonstrated similar results to HA injections, proving to be a safe approach with significant effects on pain control in patients affected by knee OA. Due to its anti-inflammatory and analgesic effects, ozone might be considered as a potential treatment for OA.

A single step, centrifuge-free method to harvest bone marrow highly concentrated in mesenchymal stem cells: results of a pilot trial.

PURPOSE: The aims of the present study were: (1) to characterize the bone-marrow aspirate (BMA) obtained with a centrifuge-free process, employing a dedicated aspiration device; (2) to test the in vitro efficacy of BMA in a model of cartilage inflammation; and (3) to report the preliminary clinical results in a small cohort of patients affected by knee OA. METHODS: Ten patients (4 M, 6 W; mean age: 51.9 ± 9.2 yy) affected by mild to moderate unicompartmental knee OA (KL grade 2-3) were treated by intra-articular and subchondral injections of BMA obtained by a centrifuge-free process. To evaluate the effectiveness of the device in harvesting mesenchymal stem cells (MSCs), samples of the obtained BMA were tested by flow cytometry before and after subculture; BMA ability to counteract inflammation was also tested in an in vitro model of cartilage cell inflammation, evaluating the expression of MMP1, MMP3, TGFß and TIMP-1 by real-time PCR. Patients were also evaluated up to two years' follow-up by using: VAS for pain, IKDC-subjective and KOOS scores. RESULTS: The laboratory analysis showed that BMSCs accounted for 0.011% of BMA cells, similar to what had been expected in native bone marrow. The paracrine activity of BMA was able to reduce in vitro the catabolic response of human chondrocyte, as shown by the decrease in metalloproteases concentration and increase in anti-inflammatory mediators. Moreover, the clinical evaluation showed significant improvements in all scores adopted, with stable results up to two years. CONCLUSION: The present data showed the effectiveness of the study device to harvest pure bone marrow with minimal peripheral blood contamination. The relevant content of MSCs resulted in the ability to counteract the catabolic cascade through a paracrine action. The clinical outcomes in patients affected by unicompartmental knee OA were encouraging in terms of pain reduction and functional improvement up to mid-term evaluation.

Navigating around the Current Options to Preserve and Regenerate Meniscus: A Long Journey Still to Be Pursued.

The beginning of meniscal surgery was attributed to Annadale at the end of the 19th century: interestingly, he performed the first documented surgical repair of the meniscus [...].

Gender-Related Aspects in Osteoarthritis Development and Progression: A Review.

Osteoarthritis (OA) is a common degenerative joint disease treated mostly symptomatically before approaching its definitive treatment, joint arthroplasty. The rapidly growing prevalence of OA highlights the urgent need for a more efficient treatment strategy and boosts research into the mechanisms of OA incidence and progression. As a multifactorial disease, many aspects have been investigated as contributors to OA onset and progression. Differences in gender appear to play a role in the natural history of the disease, since female sex is known to increase the susceptibility to its development. The aim of the present review is to investigate the cues associated with gender by analyzing various hormonal, anatomical, molecular, and biomechanical parameters, as well as their differences between sexes. Our findings reveal the possible implications of gender in OA onset and progression and provide evidence for gaps in the current state of art, thus suggesting future research directions.

Editorial Commentary: Minimally Invasive Strategies for Osteoarthritis: From Platelets to Mesenchymal Stem Cells.

The range of biological agents to treat osteoarthritis is in constant expansion, and recent trials suggest that amnion-derived products (such as umbilical cord stem cells or amniotic allograft suspension) may provide significant symptomatic relief and functional improvement compared with traditional injectables. Anyway, in many countries, stringent limitations exist on the manipulation and homologous use of placenta-derived products, and therefore, collecting more data is mandatory to endorse their use for musculoskeletal diseases in a safe and clearly regulated way. More in general, an increasing interest toward orthobiology has been observed in recent years, which led to the introduction in clinical practice of many minimally invasive strategies to treat osteoarthritis, from platelet-rich plasma to mesenchymal stem cells. On the basis of this trend, which involves physicians from different specialties, it would be fundamental to have clear guidelines establishing the correct use of these products in the setting of clinical routine not only to safely provide patients the most advanced therapeutic options but also to protect our practice from potential legal issues.

Editorial Commentary: Platelet-Rich Martini or Vodka Hyaluronate? The Dilemma of Drink Selection for the Modern Orthopaedic Surgeon.

The number of options for intra-articular treatment of osteoarthritis has been growing over the years, and currently a wide range of injectables is available, from "traditional" products such as corticosteroids and hyaluronic acid (HA) to biologic agents like platelet-rich plasma (PRP) and mesenchymal stem cells. Although the ultimate goal is to exert a modulation on the intra-articular environment, these substances act through different mechanisms of action. The combination of different products may have a rationale in taking advantage of complementary actions, but the "additive" effect and the safety should be demonstrated before any recommendation of use. Recently, the combination of HA and PRP has been tested in some clinical trials, with outcomes apparently superior to those of HA and PRP alone. This strategy may open a new scenario for the future, provided that we put scientific evidence before the pressure of the market, especially when dealing with cell-based approaches, which, although very attractive for patients, still need solid data to support their use as injectables.

Subchondral and intra-articular injections of bone marrow concentrate are a safe and effective treatment for knee osteoarthritis: a prospective, multi-center pilot study.

PURPOSE: Subchondral bone is becoming a treatment target for knee OA patients, with promising early findings on the use of bone marrow aspirate concentrate (BMAC). The aim of this prospective, multi-centric pilot study was to evaluate safety as well as clinical and MRI outcomes of a combined approach of intra-articular and subchondral BMAC injections. METHODS: Thirty patients (19 men, 11 women, 56.4 ± 8.1 years) with symptomatic knee OA were treated with a combination of an intra-articular and two subchondral BMAC injections (femoral condyle and tibial plateau). Patients were evaluated at baseline and at 1-3-6-12 months of follow-up with the IKDC subjective, VAS, KOOS, and EQ-VAS scores. The MRI evaluation was performed with the WORMS score. RESULTS: No major complications were reported and only two patients were considered treatment failures, requiring a new injective or surgical treatment. The IKDC subjective score improved significantly from 40.5 ± 12.5 to 59.9 ± 16.1 at 3 months, 59.1 ± 12.2 at 6 months, and 62.6 ± 19.4 at 12 months (p < 0.0005). A similar improvement was reported for VAS pain and all KOOS subscales at all follow-ups, while EQ-VAS did not show any significant improvement. The MRI analysis showed a significant bone marrow edema reduction (p = 0.003), while the remaining WORMS parameters did not show any significant changes. CONCLUSION: The pilot evaluation of this combined BMAC injective treatment showed safety and positive outcome up to 12 months of follow-up in patients with symptomatic knee OA associated with subchondral bone alterations. These findings suggest that targeting both subchondral bone and joint environment can provide promising results, and that BMAC can be a valid option for this combined approach to treat knee OA.

Ultrasound-guided periradicular oxygen-ozone injections as a treatment option for low back pain associated with sciatica.

BACKGROUND: The social impact and economic burden of low back pain are well known among the medical community. A novel therapeutic approach is represented by oxygen-ozone therapy, whose anti-inflammatory effects could be especially useful in patients with herniated discs. The most common administration is through a palpation-guided injection technique, although the use of ultrasound guidance could allow a more precise delivery of the therapeutic substance close to the nerve root. AIM OF THE STUDY: To describe the clinical outcomes following US-guided periradicular injection of oxygen-ozone as a treatment option for low back pain associated to sciatica in patients affected by symptomatic L5-S1 disc herniation. CONCLUSION: Ultrasound-guided periradicular injection of oxygen-ozone in L5-S1 herniation is a safe and effective minimally invasive treatment, able to improve both low back and radiating pain.

Drug Delivery Systems for the Treatment of Knee Osteoarthritis: A Systematic Review of In Vivo Studies.

Many efforts have been made in the field of nanotechnology to improve the local and sustained release of drugs, which may be helpful to overcome the present limitations in the treatment of knee OA. Nano-/microparticles and/or hydrogels can be now engineered to improve the administration and intra-articular delivery of specific drugs, targeting molecular pathways and pathogenic mechanisms involved in OA progression and remission. In order to summarize the current state of this field, a systematic review of the literature was performed and 45 relevant studies were identified involving both animal models and humans. We found that polymeric nanoparticles loaded with anti-inflammatory drugs (i.e., dexamethasone or celecoxib) are the most frequently investigated drug delivery systems, followed by microparticles and hydrogels. In particular, the nanosystem most frequently used in preclinical research consists of PLGA-nanoparticles loaded with corticosteroids and non-steroidal anti-inflammatory drugs. Overall, improvement in histological features, reduction in joint inflammation, and improvement in clinical scores in patients were observed. The last advances in the field of nanotechnology could offer new opportunities to treat patients affected by knee OA, including those with previous meniscectomy. New smart drug delivery approaches, based on nanoparticles, microparticles, and hydrogels, may enhance the therapeutic potential of intra-articular agents by increasing the permanence of selected drugs inside the joint and better targeting specific receptors and tissues.

Robot-Assisted Gait Training in Patients with Multiple Sclerosis: A Randomized Controlled Crossover Trial.

Background and Objectives: Gait disorders represent one of the most disabling aspects in multiple sclerosis (MS) that strongly influence patient quality of life. The improvement of walking ability is a primary goal for rehabilitation treatment. The aim of this study is to evaluate the effectiveness of robot-assisted gait training (RAGT) in association with physiotherapy treatment in patients affected by MS in comparison with ground conventional gait training. Study design: Randomized controlled crossover trial. Materials and Methods: Twenty-seven participants affected by MS with EDSS scores between 3.5 and 7 were enrolled, of whom seventeen completed the study. They received five training sessions per week over five weeks of conventional gait training with (experimental group) or without (control group) the inclusion of RAGT. The patients were prospectively evaluated before and after the first treatment session and, after the crossover phase, before and after the second treatment session. The evaluation was based on the 25-foot walk test (25FW, main outcome), 6 min walk test (6MWT), Tinetti Test, Modified Ashworth Scale, and modified Motricity Index for lower limbs. We also measured disability parameters using Functional Independence Measure and Quality of Life Index, and instrumental kinematic and gait parameters: knee extensor strength, double-time support, step length ratio; 17 patients reached the final evaluation. Results: Both groups significantly improved on gait parameters, motor abilities, and autonomy recovery in daily living activities with generally better results of RAGT over control treatment. In particular, the RAGT group improved more than control group in the 25FW (p = 0.004) and the 6MWT (p = 0.022). Conclusions: RAGT is a valid treatment option that in association with physiotherapy could induce positive effects in MS-correlated gait disorders. Our results showed greater effectiveness in recovering gait speed and resistance than conventional gait training.

Editorial Commentary: Bone Tunnel Grafting for Two-Stage Anterior Cruciate Ligament Revision and the Meaning of Life for an Arthroscopic Surgeon.

Accurate bone tunnel filling in a 2-staged anterior cruciate ligament revision is indubitably fundamental for a successful outcome. Bone autograft is commonly employed and it is usually harvested from the iliac crest: this requires longer surgical time, and donor-site morbidity following bone harvest is a well-known problem. Therefore, strategies to minimize or abolish it have been attempted: the use of allografts may seem promising, but their use is associated with high costs and strict regulatory limitations. Bony substitutes instead represent a new and potentially effective solution: they could help surgeons to fill bone tunnels in an easier and faster way that elicits satisfactory lamellar bone formation within the tunnels, and their use is associated with fewer postoperative complications, such as pain and local hematoma. Evidence from literature suggests that this approach could provide significant advantages over traditional autograft harvesting, with comparable outcomes in terms of bone formation and integration, allowing a correct tunnel placement during revision surgery.

Oxygen-Ozone Therapy for the Treatment of Knee Osteoarthritis: A Systematic Review of Randomized Controlled Trials.

PURPOSE: To review the available literature on the application of oxygen-ozone therapy (OOT) in the treatment of knee osteoarthritis (KOA) to understand its therapeutic potential and to compare it with other conservative treatment options. METHODS: A systematic review of the literature was performed on the PubMed, Cochrane, Embase, ResearchGate, and PedRo Databases, with the following inclusion criteria: (1) randomized controlled trials (RCTs), (2) written in English, (3) published on indexed journals in the last 20 years (1998-2018), (4) dealing with the use of ozone intra-articular injection for the treatment of KOA. The risk of bias was assessed by the Cochrane Risk of Bias tool for RCTs. RESULTS: Eleven studies involving 858 patients in total (629 female and 229 male) were included. Patients in the control groups received different treatments: placebo in 1 trial; hyaluronic acid in 2 studies; hyaluronic acid and PRP in 1 trial; corticosteroids in 4; and hypertonic dextrose, radiofrequency, or celecoxib + glucosamine in the remaining 3 trials. In looking at the quality of the available literature, we found that none of the studies included reached "good quality" standard, 2 were ranked as "fair," and the rest were considered "poor." No major complications or serious adverse events were reported following intra-articular OOT, which provided encouraging pain relief at short term. On the basis of the available data, no clear indication emerged from the comparison of OOT with other established treatments for KOA. CONCLUSIONS: The analysis of the available RCTs on OOT for KOA revealed poor methodologic quality, with most studies flawed by relevant bias, thus severely limiting the possibility of drawing conclusions on the efficacy of OOT compared with other treatments. On the basis of the data available, OOT has, however, proven to be a safe approach with encouraging effects in pain control and functional recovery in the short-middle term. LEVEL OF EVIDENCE: Systematic review of Level I and III studies.

Reconstruction of Large Osteochondral Defects Using a Hemicondylar Aragonite-Based Implant in a Caprine Model.

PURPOSE: To investigate the safety and regenerative potential of a hemicondylar aragonite-based scaffold in the reconstruction of large osteochondral lesions occupying an extensive portion of the medial femoral condyle in a goat model. METHODS: Eight Saanen goats were treated by the implantation of an aragonite-based scaffold (size: 19 × 8 × 8 mm) on a previously prepared hemicondylar osteochondral defect located in the right medial femoral condyle of the knee. Goats were euthanized after 12 months and the specimens underwent X-ray imaging, macroscopic, micro-computed tomography, histology, and immunohistochemistry evaluations to assess subchondral bone and cartilage regeneration. RESULTS: In all 8 goats, no adverse event or persistent inflammation was observed. The evaluations performed showed integration of the scaffold, which almost completely resorbed at 12 months. In all animals, no signs of osteoarthritis progression were seen. Concurrent regeneration of the osteochondral unit was observed, with trabecular bone tissue replacing the implant and restoring the subchondral layer, and the formation of an overlying hyaline cartilage surface, well integrated within the surrounding native tissue, also was observed. CONCLUSIONS: The use of the hemicondylar biphasic aragonite-based implant in the treatment of osteochondral defects in the goat model proved to be technically feasible and safe. The scaffold degraded and was replaced by regenerated tissue within the 12-month study period, restoring the osteochondral unit both at the level of the cartilaginous layer and the subchondral bone. CLINICAL RELEVANCE: The present animal study describes a scaffold-based procedure for the treatment of large condylar defects, which often require massive allograft or unicompartmental replacement. The aragonite-based implant promoted a regeneration of both cartilage and subchondral bone, and its use as a "biologic" unicondylar prosthesis might be feasible also in the clinical setting.

Meniscectomy-induced osteoarthritis in the sheep model for the investigation of therapeutic strategies: a systematic review.

PURPOSE: One of the major risk factors for OA is meniscectomy (Mx) that causes a rapid and progressive OA. Mx has been employed in various animal models, especially in large ones, to study preclinical safety and strategy effectiveness to counteract OA. The aim of the present study is to review in vivo studies, performed in sheep and published in the last ten years. METHODS: The search strategy was performed in three websites: www.scopus.com, www.pubmed.com, and www.webofknowledge.com, using "Meniscectomy and osteoarthritis in sheep" keywords. RESULTS: The 25 included studies performed unilateral total medial Mx (MMx), unilateral partial MMx, bilateral MMx, unilateral total lateral Mx (LMx), unilateral partial LMx, and bilateral LMx and MMx combined with anterior cruciate ligament transaction. The most frequently performed is the unilateral total MMx that increases changes in cartilage and subchondral bone more than the other techniques. Gross evaluations, histology, radiography, and biochemical tests are used to assess the degree of OA. The most widely tested treatments are related to scaffolds with or without mesenchymal stem cells. CONCLUSION: OA therapeutic strategies require the use of large animal models due to similarities with human joint anatomy. A protocol for future in vivo studies on post-traumatic OA is clarified.