Marc Darrow, MD., JD.
Over the years we have seen a lot of people with knee problems. Many of them with problems of the patellar tendon. They have had many treatments including using painkillers and anti-inflammatories, cortisone injections, physical therapy, rest, some of the them wear big braces on their knees some try kineziotaping. They are doing a consult with us because they are still looking for help. Can Platelet Rich Plasma Therapy help them? After an email or a phone call we assesses the person’s situation. If we feel they are a realistic candidate for treatment, they come in for a consultation where we can do an examination and come up with a healing program.
- PRP treatments involve collecting a small amount of your blood and spinning it in a centrifuge to separate the platelets from the red cells. The collected platelets are then injected back into the injured area to stimulate healing and regeneration. PRP utilizes the blood’s platelets and their healing and tissue repair factors.
Patellar tendinopathy is commonly referred to by the more lay terms as “Jumper’s Knee” or “Tennis Knee” because this type of chronic injury is seen obviously in jumping athletes and tennis players. The term basketball knee may also apply as this injury is caused by wear and tear of playing basketball on hard surfaces. So too tennis players. Most tennis players play on the painted cement court.
When knee pain begins, most people self-treat via instructions from the internet.
When knee pain begins, most people self-treat via instructions from the internet. They will ICE and COMPRESS the knee with tape or braces. Some will ELEVATE their knee when laying down or sitting in a chair. Much fewer will REST. By now you will probably recognize the familiar RICE anagram or Rest, Ice, Compression, and Elevation as the first line of knee pain treatments along with anti-inflammatory medications found “over-the-counter.”
As the person’s knee worsens they will make their first doctors appointment. Here their doctor may advise them to Rest, Ice, Compress and elevate again. This time the doctor may offer the person a stronger medication. Still failing to resolve their knee pain, the doctor then may move onto stronger medication, a cortisone injection, or physical therapy. Some people will get all these treatments.
A June 2020 study (1) from Stanford University focused on additional treatment options for the two most common causes of front of the knee pain, patellofemoral pain syndrome, and patellar tendinopathy.
Here they discuss tape, brace, and Prolotherapy, PRP and Stem Cell injections
- Recent studies of bracing and taping have found them to be helpful for patients in the short-term management of pain and improving function.
- Injections remain a commonly used treatment for musculoskeletal conditions; however, the evidence for their use in patellofemoral pain and patellar tendinopathy is limited. The use of platelet-rich plasma (PRP), sclerosing (sometimes referred to as Prolotherapy), or stem cell injections is an exciting new area in the treatment of patellar tendinopathy.
I point out this study because many of the people that come into our office have heard something similar in their orthopedist’s office. Wear a brace if it helps, there is no evidence that PRP or stem cells can help you. So the first thing many of the people who eventually come to visit is ask is, “Is there any research on PRP or stem cells for patellofemoral pain syndrome, and patellar tendinopathy?” I also want to point out that these same people who come visit us are people who have been on anti-inflammatories, wrap up their legs in ace bandages, ice, may have had a cortisone injections and nothing is really helping. They are here because for some of them are willing to take a chance on PRP or stem cells.
We will get to the research below on these injections.
General questions and research on patellar tendinopathy
In this section I want to answer some general questions before we move onto the injection research.
A November 2023 paper (19) sums up the medical treatment options currently for patients by stating: “There are a wide variety of treatment and rehabilitation options available, the majority of which are non-operative, such as eccentric exercises, cryotherapy, platelet-rich plasma (PRP) injections, and anti-inflammatory strategies. If conservative treatment fails, surgery is the next most preferable step. Even though there are many surgical treatment methods, there is no clear evidence on what is the most effective approach to address patellar tendinopathy.”
Physical therapy and exercise for Patellar tendinopathy
A May 2022 study (2) suggests that “Despite a dearth of studies on preventative interventions for athletes with Patellar tendinopathy, resistance training may be a useful prophylactic method. Eccentric, heavy slow and isometric resistance training have been found to be feasible and clinically beneficial in-season. There are a lack of studies showing that extracorporeal shock wave therapy offers any additional benefit over resistance training in competing athletes. Patellar strapping and taping may offer short-term pain relief during training and competition.”
A March 2023 study (3) compared whether ultrasound-guided dry needling during conventional physical therapy would provide more treatment benefits than conventional physical therapy alone in patients with jumper’s knee.
In this study, 96 patients diagnosed jumper’s knee were randomly assigned to receive ultrasound-guided dry needling and conventional physical therapy or to receive conventional physical therapy alone. When surveyed about pain and function at four weeks post treatment, both both groups reported improvement in signs of jumper’s knee but the improvement in ultrasound-guided dry needling combined with conventional physical therapy was more significant. The researchers also reported improvement in the visual knee structure or improvement in ultrasonographic features.
A November 2023 study (18) wrote: “In patients with patellar tendinopathy, physical test results including strength and flexibility in the lower limb, jump performance, and pain levels during pain-provoking tests were not identified as prognostic factors for patient-reported outcomes after exercise therapy. Similarly, changes in physical test results were not associated with changes in patient-reported outcomes after adjustments. These results do not support using physical test results to estimate prognosis or monitor treatment response.”
In this study, the researchers were assessing whether the commonly used physical tests that “aid the clinical diagnosis, assess the prognosis, and monitor treatment,” matched up with patient-reported outcomes after exercise therapy. What the researchers found was that improvement in ability to exercise as measured by clinician physical testing and pain eliciting palpitation did not match the patient-reported outcomes for their ability to play or return to sport. There was a disconnect between what the clinicians thought and what the patient thought about the patient’s ability to return to play.
Extracorporeal shock wave therapy
An October 2022 study (4) extracorporeal shockwave therapy is a safe and non-invasive treatment for patellar tendinopathy. Contrary to surgical intervention, this form of therapy is not related to major complications or side effects; also, the patients do not need to take time off work. However, our meta-analysis did not reveal significant differences between ESWT and control groups with respect to (standardized pain, function and disability) scores for long-term outcomes. Hence, no definite conclusions on extracorporeal shockwave therapy efficacy for jumper’s knee can be drawn.”
PRP research on patellar tendinopathy
There is limited research as well in the role of PRP in helping patients with patellar tendinopathy. However a 2017 study (6) stated: “These limited studies are encouraging and indicate that PRP injections have the potential to promote the achievement of a satisfactory clinical outcome, even in difficult cases with chronic refractory tendinopathy after previous classical treatments have failed.” One of the studies reviewed was a study from researchers in the Netherlands. In this study, outcomes of patients with patellar tendinopathy treated with platelet-rich plasma injections (PRP) were evaluated to determine whether certain characteristics, such as activity level or previous treatment affected the results. What they found was: “After PRP treatment, patients with patellar tendinopathy showed a statistically significant improvement. In addition, these improvements can also be considered clinically meaningful.”
For many years, as stated above, people would ask, where is the research when it comes to PRP and patellar tendinopathy? For many years there was was indeed limited research in the role of PRP in helping patients with patellar tendinopathy. But whatever research was coming out, appeared to be beneficial.
A 2014 study in The American journal of sports medicine (5) offered these results and assessments:
- “Chronic patellar tendinopathy is one of the most common overuse knee disorders. Platelet-rich plasma (PRP) appears to be a reliable nonoperative therapy for chronic patellar tendinopathy.”
In this study a total of 28 athletes (17 professional, 11 semiprofessional) with chronic patellar tendinopath refractory to nonoperative management were prospectively included for ultra-sound guided pure PRP injections into the site of the tendinopathy. The same treating physician at a single institution performed three consecutive injections 1 week apart, with the same PRP preparation used. Tendon healing was assessed with MRI at 1 and 3 months after the procedure.
Results:
- Patients showed significantly improved at the 2-year follow-up.
- Twenty-one of the 28 athletes returned to their pre-symptom sporting level at 3 months (range, 2-6 months) after the procedure.
- Follow-up MRI assessment showed improved structural integrity of the tendon at 3 months after the procedure and complete return to normal structural integrity of the tendon in 16 patients (57%).
- Seven patients did not recover their presymptom sporting level (among them, 6 were considered treatment failures): 3 patients returned to sport at a lesser level, 1 patient changed his sport activity (for other reasons), and 3 needed surgical intervention.
Conclusion:
In this study, application of 3 consecutive ultrasound-guided PRP injections significantly improved symptoms and function in athletes with chronic patellar tendinopathy and allowed fast recovery to their pre-symptom sporting level. The PRP treatment permitted a return to a normal architecture of the tendon as assessed by MRI.
Is PRP no better than a placebo? “IT’S UNCLEAR.”
One of the problems in understanding if PRP works for patellar tendinopathy is that empirically, doctors have seen good results. However, there is very little research to support this. In May 2022 a paper in The Journal of family practice (8) wrote:
Does platelet-rich plasma (PRP) injections improve patellar tendinopathy symptoms? “IT’S UNCLEAR. High-quality data have not consistently established the effectiveness of platelet-rich plasma (PRP) injections to improve symptomatic recovery in patellar tendinopathy, compared to placebo (strength of recommendation A), based on 3 small randomized controlled trials. The 3 small randomized controlled trials included only 111 patients, total. One found no evidence of significant improvement with PRP compared to controls. The other 2 studies showed mixed results, with different outcome measures favoring different treatment groups and heterogeneous results depending on follow-up duration.”
In 2023 the efficacy of PRP varies depending on patient characteristics, disease severity, and the specific administration methodology
A September 2023 paper in the European journal of orthopaedic surgery & traumatology (20) PRP has demonstrated promising results in promoting cellular remodeling and accelerating the healing process in the jumper’s knee. It shows potential benefits in pain reduction, improved function, and accelerated recovery. However, the efficacy of PRP varies depending on patient characteristics, disease severity, and the specific administration methodology.
Platelet-rich plasma injection in the treatment of patellar tendinopathy
A May 2022 paper (9) compared PRP injection with other ‘active treatment’ interventions (‘Non-PRP’ injection and ‘No-injection’ treatments) or ‘No-active treatment’ interventions. To do this the researchers examined eight published studies. They suggest “assessment of these studies revealed that there were no significant differences in pain relief, functional outcomes, and quality of life in the short, medium, and long term between PRP injection and Non-PRP injection interventions. Similarly, comparison of PRP injection to the No-active treatment intervention showed no differences in short- and medium-term pain relief. However, when PRP injection was compared to the No-injection treatment intervention extracorporeal shock wave therapy , the former was found to be more effective in terms of pain relief in the medium term and long term and functional outcomes in the medium term and long term. Conclusions: “In terms of pain relief and functional outcomes, the PRP injection did not provide significantly greater clinical benefit than Non-PRP injections in the treatment of patellar tendinopathy. However, in comparison with ESWT, there was a significant benefit in favor of PRP injection.”
PRP is effective for patellar tendinopathy
However an April 2022 (10) also reviewed the previous research and said this: “Four studies investigated the efficacy of PRP injection on various outcome measures of patellar tendinopathy. All the selected studies reported a significant positive impact of PRP injection on patellar tendinopathy symptoms.” The researchers also noted “significantly improved” pain and functional scores at the 6- and 12-month follow-up assessments. Another study “reported that PRP accelerated the recovery compared to dry needling in a short-term follow-up. However, this benefit dissipated over time.” Further PRP showed better outcomes in short-term, medium-term, and long-term follow-ups compared to normal saline injection. The researchers here as well concluded there is not enough published research, stating: “However, because of the limited number of studies and the disparities in the study populations and protocols, it is not possible to make a firm conclusion on the efficacy of these injection methods, and these results should be inferred with care.”
A September 2023 study (11) “PRP has demonstrated promising results in promoting cellular remodeling and accelerating the healing process in the jumper’s knee. It shows potential benefits in pain reduction, improved function, and accelerated recovery. However, the efficacy of PRP varies depending on patient characteristics, disease severity, and the specific administration methodology. Establishing standardized PRP preparation and administration protocols are necessary to optimize its effectiveness.”
An August 2023 paper (12) “Platelet-rich plasma (PRP) injections PRP injections have been shown to be an effective treatment option for chronic PT. PRP injections with US guidance enable infiltration into the tendon with great accuracy. This treatment stimulates soft tissue healing and improves tendon healing and remodeling. (Research) suggest that multiple PRP injections could be the best option for patients with severe symptoms, or when other conservative treatments fail to alleviate chronic PT. Patients with chronic PT and no previous treatment who received PRP injections had significantly better results in comparison to patients with chronic PT for the same duration, and previous failing therapies such as ethoxysclerol, corticosteroid and surgical treatment.”
Women make for a larger percentage of patellar tendinopathy than previous thought.
A June 2022 paper (13) writes: “Patellar tendinopathy is one of the most common musculoskeletal problems associated with sport. While commonly perceived as a predominantly male problem, recent epidemiological studies revealed that it also affects a large number of sport-active women . . . Women represent only a minority of patients studied for this topic (this paper) showed a gender blindness in sports medicine when investigating a common problem like patellar tendinopathy.”
UCLA doctors present a case history
Doctors at UCLA presented this September 2021 case history (14). It tells the story of a 19-year-old FEMALE Division-1 collegiate soccer player who came to the training room with a slowly developing and worsening onset right front knee pain. According to the case: “The pain started while she was doing rehabilitation following a right anterior cruciate ligament (ACL) reconstruction using a contralateral patellar tendon autograft. She has point tenderness over her right medial proximal patellar tendon, and she describes pain that worsens with repetitive loading of her knee during activities such as squats and running. She is diagnosed with patellar tendonitis via diagnostic ultrasound and starts physical therapy with a specific focus on eccentric and concentric loading of the quadriceps. She fails to improve following 3 months of compliant physical therapy and is frustrated by her continued pain. ” The patients was recommended to PRP injections. “Using ultrasound guidance, the athlete underwent a patellar tendon LP-PRP injection without the use of local anesthetic. She was restricted from lower body activities for 2 weeks to allow tissue recovery. She then resumed her rehabilitation program with a focus on eccentric loading in addition to her post-ACL reconstruction exercise regimen. At 15-month follow-up, she was ready to play in the season opener for her collegiate team.”
Leukocyte-poor platelet-rich plasma
In a September 2023 paper, (15) researchers, doing a follow up to previously reported research, assessed the feasibility of offering leukocyte-poor platelet-rich plasma (the “anti-inflammatory” PRP preparation) to patients with patellar tendinopathy as compared to or prior to treatment with bone marrow-derived mesenchymal stem cells. In their previous paper, the study authors noted that the bone marrow-derived mesenchymal stem cells treatment only group “showed improved tendon structure and regeneration of the gap (damaged / tear) area when compared with treatment using leukocyte-poor platelet-rich plasma.” The leukocyte-poor platelet-rich plasma group (10 patients), displayed no tendon regeneration at the 6-month follow-up, was subsequently moved over to bone marrow-derived mesenchymal stem cells treatment with to see if structural improvement would occur.
The end results of this study were summed up this way by the authors: “The 12-month follow-up outcomes after both groups of patients received bone marrow-derived mesenchymal stem cells treatment indicated that biological treatment was safe, there were no adverse effects, and the participants showed a highly statistically significant clinical improvement, as well as an improvement in tendon structure on MRI. Preinjection of leukocyte-poor platelet-rich plasma yielded no advantages.”
Bone marrow stem cell therapy
Bone marrow stem cell therapy is the injection, into a damaged joint and surrounding area, of stem cells drawn from the patient’s own bone marrow. Stem cells are “de-differentiated pluripotent” cells, which mean that they continue to divide to create more stem cells; these cells eventually “morph” into the tissue needing repair—for our purposes, collagen, bone, and cartilage.
A December 2018 study examined the role of mesenchymal stem cells in the treatment of tendinopathies.(16) The investigators of this study wrote: “Although (research) attention was mainly focused on their (the stem cell’s) ability to differentiate (change into needed repair cells) and to directly participate to the regeneration process in the past, mesenchymal stem cells have more recently been demonstrated to have further and probably more important therapeutic functions in response to injury like immune modulation and trophic (promoting cellular growth) activities. That is why that they have been defined as “drugstores”. Indeed, they can home in on sites of inflammation or tissue injury and they start to secrete immunomodulatory and trophic agents such as cytokines and growth factors aimed to re-establish physiological homeostasis in response to that environment. (In simpler terms act as an anti-inflammatory and pro-healing agent). So, either as direct player in the process or/and bioactive molecules “drugstores”, mesenchymal stem cells may enhance tissue repair and regeneration and thereby restore normal joint homeostasis.” This research does suggest further studies to validate these positive findings.
A well referenced and cited study from 2012 (17) followed eight mid-20s aged athletes with chronic patellar tendon degeneration. These patients received bone marrow stem cell therapy. The stem cells were taken from the patient’s iliac bone crest and injected into the problem knee. These patients were then followed for 5 years to measure the long-term results of the treatment. Here were the published results:
- “At 5-year followup, statistically significant improvement was seen for most clinical scores.
- Seven of eight patients said they would have the procedure again if they had the same problem in the opposite knee and were completely satisfied with the procedure.
- Seven of 8 patients thought that the results of the procedure were excellent. According to our results, (bone marrow stem cells should be) considered as a potential therapy for those patients with chronic patellar tendinopathy refractory to nonoperative treatments.”
Surgery
A September 2023 study (21) found good success with patellar tendinopathy surgery. “Although the majority of patients with patellar tendinopathy can be treated nonoperatively, operative management may be indicated for recalcitrant cases.” The researchers here “hypothesized that surgical management would lead to clinically important improvements in patient-reported outcomes (PROs) with high rates of return-to-sport and return-to-sports at the same level.”
The researchers examined the medical records of patients. They found 1,238 total knees undergoing surgery for patellar tendinopathy. Their records showed “clinically and statistically significant improvements after surgery. The overall return-to-sport rate following operative management was 89.8% of athletes returning to the same level of activity.”
When surgery fails
A March 2021 paper (22) examined 22 athletes (age about 25) who had undergone revision surgery after the failure of the first patellar tendinopathy surgery. There was about 15 months on average between the two surgeries. At about a 30 month follow up, patients were seen to have returned to training about 9 months after the revision surgery. “Fifteen patients (68.2%) returned to competition within a mean of 11.6 months. Of these 15 patients, a further 2 had decreased their performance, and 2 more had abandoned sports participation by the final follow-up. The overall rate of complications was 18.2%. One patient (4.5%) had a further revision procedure.”
As stated at the top of this article. We have been offering regenerative medicine injections for almost 25 years. Empirical and in office data shows a benefit for many. Will these treatments work for everyone? No. Email me with the form below so we can assess whether or not these treatments would be viable for you.
References
1 Sisk D, Fredericson M. Taping, Bracing, and Injection Treatment for Patellofemoral Pain and Patellar Tendinopathy [published online ahead of print, 2020 Jun 4]. Curr Rev Musculoskelet Med. 2020;10.1007/s12178-020-09646-8. doi:10.1007/s12178-020-09646-8
2 Burton I. Interventions for prevention and in-season management of patellar tendinopathy in athletes: A scoping review. Physical Therapy in Sport. 2022 Mar 7.
3 Sharif F, Ahmad A, Gilani SA. Effectiveness of ultrasound guided dry needling in management of jumper’s knee: a randomized controlled trial. Scientific Reports. 2023 Mar 23;13(1):4736.
4 Stania M, Król T, Marszałek W, Michalska J, Król P. Treatment of Jumper’s Knee with Extracorporeal Shockwave Therapy: A Systematic Review and Meta-Analysis. Journal of Human Kinetics. 2022 Oct 1;84(1):124-34.
5 Charousset C, Zaoui A, Bellaiche L, Bouyer B. Are multiple platelet-rich plasma injections useful for treatment of chronic patellar tendinopathy in athletes? a prospective study. The American journal of sports medicine. 2014 Apr;42(4):906-11.
6 Shahid M, Kundra R. Platelet-rich plasma (PRP) for knee disorders. EFORT Open Reviews. 2017 Feb 1;2(2):28-34.
7 Filardo G, Di Matteo B, Kon E, Merli G, Marcacci M. Platelet-rich plasma in tendon-related disorders: results and indications. Knee Surgery, Sports Traumatology, Arthroscopy. 2018 Jul;26(7):1984-99.
8 Wolfenden E, Vukelic B, DeMarco M, Knox J, Ose D. Does platelet-rich plasma improve patellar tendinopathy symptoms? J Fam Pract. 2022 May;71(4):188-189. doi: 10.12788/jfp.0402. PMID: 35730711.
9 Barman A, Sinha MK, Sahoo J, Jena D, Patel V, Patel S, Bhattacharjee S, Baral D. Platelet-rich plasma injection in the treatment of patellar tendinopathy: a systematic review and meta-analysis. Knee surgery & related research. 2022 Dec;34(1):1-5.
10 Nuhmani S, Ahsan M, Bari MA, Malhotra D, Al Muslem WH, Alsaadi SM, Muaidi QI. Patellar Tendinopathy—Does Injection Therapy Have a Role? A Systematic Review of Randomised Control Trials. Journal of clinical medicine. 2022 Apr 3;11(7):2006.
11 Bosco F, Giai Via R, Giustra F, Ghirri A, Cacciola G, Massè A. Platelet-rich plasma for jumper’s knee: a comprehensive review of efficacy, protocols, and future directions. European Journal of Orthopaedic Surgery & Traumatology. 2023 Sep 5:1-6.
12 Theodorou A, Komnos G, Hantes M. Patellar tendinopathy: an overview of prevalence, risk factors, screening, diagnosis, treatment and prevention. Archives of Orthopaedic and Trauma Surgery. 2023 Aug 4:1-1.
13 Mondini Trissino da Lodi C, Landini MP, Asunis E, Filardo G. Women Have Tendons… and Tendinopathy: Gender Bias is a “Gender Void” in Sports Medicine with a Lack of Women Data on Patellar Tendinopathy—A Systematic Review. Sports Medicine-Open. 2022 Dec;8(1):1-8.
14 Fahy KE, Miller EM, Kobayashi Y, Gottschalk AW. Efficacy of Platelet-Rich Plasma on Symptom Reduction in Patellar Tendinopathy. The Ochsner Journal. 2021;21(3):232.
15 Soler R, Rodas G, Rius-Tarruella J, Alomar X, Balius R, Ruíz-Cotorro Á, Masci L, Maffulli N, Orozco L. Safety and Efficacy of Bone Marrow–Derived Mesenchymal Stem Cells for Chronic Patellar Tendinopathy (With Gap> 3 mm) in Patients: 12-Month Follow-up Results of a Phase 1/2 Clinical Trial. Orthopaedic Journal of Sports Medicine. 2023 Sep 8;11(9):23259671231184400.
16 Abat F, Alfredson H, Cucchiarini M, Madry H, Marmotti A, Mouton C, Oliveira JM, Pereira H, Peretti GM, Spang C, Stephen J, van Bergen CJA, de Girolamo L. Current trends in tendinopathy: consensus of the ESSKA basic science committee. Part II: treatment options. J Exp Orthop. 2018 Sep 24;5(1):38. doi: 10.1186/s40634-018-0145-5. PMID: 30251203; PMCID: PMC6153202.
17 Pascual-Garrido C,et al. Treatment of chronic patellar tendinopathy with autologous bone marrow stem cells: a 5-year-followup. Stem Cells Int. 2012;2012:953510. doi: 10.1155/2012/953510. Epub 2011 Dec 18.
18 Deng J, Breda SJ, Eygendaal D, Oei EH, de Vos RJ. Association Between Physical Tests and Patients-Reported Outcomes in Athletes Performing Exercise Therapy for Patellar Tendinopathy: A Secondary Analysis of the JUMPER Study. The American Journal of Sports Medicine. 2023 Nov;51(13):3523-32.
19 Theodorou A, Komnos G, Hantes M. Patellar tendinopathy: an overview of prevalence, risk factors, screening, diagnosis, treatment and prevention. Archives of Orthopaedic and Trauma Surgery. 2023;143(11):6695.
20 Bosco F, Giai Via R, Giustra F, Ghirri A, Cacciola G, Massè A. Platelet-rich plasma for jumper’s knee: a comprehensive review of efficacy, protocols, and future directions. European Journal of Orthopaedic Surgery & Traumatology. 2023 Sep 5:1-6.
21 Cognetti DJ, Sheean AJ, Arner JW, Wilkerson D, Bradley JP. Surgical management of patellar tendinopathy results in improved outcomes and high rates of return to sport: a systematic review. The Journal of Knee Surgery. 2022 Sep 26.
22 Maffulli N, Oliva F, Maffulli GD, Migliorini F. Failed surgery for patellar tendinopathy in athletes: midterm results of further surgical management. Orthopaedic Journal of Sports Medicine. 2021 Mar 26;9(3):2325967121994550.
23. Gosens T, Den Oudsten BL, Fievez E, van ‘t Spijker P, Fievez A. Pain and activity levels before and after platelet-rich plasma injection treatment of patellar tendinopathy: a prospective cohort study and the influence of previous treatments.Int Orthop. 2012 Apr 27. [Epub ahead of print]
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