Salvatore Russo, Stefano Landiand Paolo Landa

Management of knee osteoarthritis in Italy. A cost-utility analysis of Platelet-Rich-Plasma dedicated kit versus Hyaluronic acid for the intra-articular treatment of knee OA

Working Paper n. 8/2017August 2017

ISSN: 2239-2734

This Working Paper is published   under the auspices of the Department of Management at Università Ca’ Foscari Venezia. Opinions expressed herein are those of the authors and not those of the Department or the University. The Working Paper series is designed to divulge preliminary or incomplete work, circulated to favour discussion and comments. Citation of this paper should consider its provisional nature.

Management of knee osteoarthritis in Italy. A cost-utility analysis of Platelet-Rich-Plasmadedicated kit versus Hyaluronic acid for the intra-articular treatment of knee OA.

Salvatore Russo Stefano Landi Paolo Landa

salvus@unive.it stefano.landi@unive.it P.Landa@exeter.ac.uk

Department of Management Department of Management Medical School

Ca’ Foscari University Venice Ca’ Foscari University Venice University of Exeter

(May 2017)

Abstract:

Background. Osteoarthritis (OA) is a chronic and degenerative pathology that affects joints inparticular hands, knees, hip and lower back. It is one of the main causes of disability in most ofadvanced economy countries. Its prevalence and incidence are increasing for the ageing ofpopulation and the presence of risk factors. OA burden of disease implies high costs of care and ithas an important social impact. Although more high-quality evidence is needed, recent studiesindicate that intra-articular Platelet-Rich Plasma (i.a. PRP) injections can relieve pain, improvingknee function and quality of life, especially in younger patients and mild OA cases.

Objectives. The aim of this work is to develop a preliminary economic evaluation of i.a. PRPtherapy in the treatment of knee OA. The comparator adopted is the Hyaluronic acid (HA) whichrepresents the standard therapy. Both therapies can reduce pain and can help the patient todelay the total knee replacement (TKR) surgical intervention.

Methods. A Cost-Utility Analysis (CUA) was performed using a decision tree model. Outcomes arereported in terms of Quality Adjusted Life Year (QALY), while costs are reported in Euro (€)currency. The adopted perspective is the National Healthcare System. Deterministic andprobabilistic sensibility analyses are reported to evaluate the robustness of results underuncertainty.

Results. The i.a. PRP-based therapy is cost-effective with respect to HA. Future clinical studiesshould provide more evidence on the major effectiveness and considering a longer patient

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follow-up there could be the delay of TKR, reducing consequently the eventual prosthesis revisionand reducing costs of knee OA for National Healthcare System.

Keywords: materiality, integrated report, accounting

JEL Classification Numbers: C63, D61, I1

Correspondence to:

Stefano

Landi

Institution: Università Cà Foscari Venezia, Dipartimento di Management,

Address: Fondamenta, S. Giobbe, 873,

Zip code: 30121

City: Venezia

Country: Italy

Tel/fax/mobile: 346 3287572 stefano.landi@unive.it

1. Introduction

Osteoarthritis (OA) is a chronic and degenerative pathology that affects joints in particular hands,knee, hip and lower back resulting in joint inflammation with associated pain, stiffness and loss ofmovement. Its onset is linked to several risk factors such as age, gender, ethnicity, workingactivity and overweight1-4. Its incidence is higher in the population older than 60 years-old, forwhom prevalence is estimated 10% worldwide5-9.

OA is a disease associated to older age and obesity. The increasing of these two populationcharacteristics will lead to significant rises in OA prevalence. Considering Disability Adjusted LifeYears (DALYs) over the period 1990-2010, OA burden of disease has grown at a faster pace thanmusculoskeletal diseases (64% vs 45%). In western countries the number of total jointarthroplasty, which can be considered as the final stage of OA (knee and hip OA), is growing 10-11.According to Italian Health Ministry, OA resulted to be the 7 th out of 283 diagnosis for ClinicalClassifications Software (CCS) for number of hospital discharges from hospital data collected in2014. Hospital discharges for OA in Italy were 127,000, close to the 2% of the discharges with an

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average hospital stay of 7.5 days12. Moreover in Italy during 2014 were performed around170,000 arthroplasty surgeries with an increasing rate of 4.2%13. As far as it concerns knee jointsubstitution, around 65,000 surgeries were performed with an annual increasing rate of 7.2%13.The increasing incidence of total joint arthroplasty consequently rose OA prevalence. OA diseasehas a significant impact on patient quality of life causing pain, stiffness and decreased jointfunctionality, leading to reduction of social life and partial loss of work productivity.

The burden of OA is correlated to a high economic impact in terms of both direct health-relatedcosts and indirect costs. The presence of several studies on cost-of-illness does not allow to havea clear view of cost related to OA. In western countries, where the prevalence is higher, the totalcosts relating to treatment for OA are estimated at between 1% and 2.5% of Gross DomesticProduct (GDP) 14. A recent systematic review concludes that the social cost of OA could bebetween 0.25% and 0.50% of a country’s GDP15.

OA costs may vary considerably between countries and population. A Canadian study estimateddirect health related costs in Canadian dollars (CAD) $2,233 per patient per year16, while a Dutchstudy found indirect costs due to loss of productivity of €722 (with median €217) per patient permonth17. In Italy annual total costs per patient have been estimated €3,000 (€1,300 as directhealth-related costs and €1,700 as indirect costs adjusted in 2013)18. A review of 32 cost-of-illnessstudies states that the weighted average annual cost per patient living with knee and hip OA is €11,100, € 9,500 and € 4,400 for total, direct and indirect costs, respectively19 .

The main direct health-related cost driver is the total joint arthroplasty20. The steady increasing,year after year, of surgery incidence lead costs to grow20-21 for the next future10-11.

The continuous need in terms of limited use of resources and budget restriction put underpressure the national healthcare systems where organizations have to find out how to manageand restrain the growth of costs or to find alternative solutions to reduce them. A possiblestrategy to adopt consists in the reduction of the pathology progression in order to delay thesurgery22-24. As stated in one of the latest report of European Society for Clinical and EconomicAspects of Osteoporosis and Osteoarthritis (ESCEO), the intra-articular treatment isrecommended after the failure of conservative treatments, between the drug therapies and thesurgery25. Hyaluronic acid (HA) and platelet-rich-plasma (PRP) are the two intra-articular (IA)infiltration therapies used between these two phases to delay the surgical intervention whenpatients failed to respond to first drug therapy, usually corticosteroids.

Intra-articular Therapies: Platelet-Rich-Plasma and Hyaluronic Acid

HA is an important viscoelastic component of the synovial fluid present inside the joints withlubricant and cushioning properties. When a patient is affected by OA, the concentration andmolecular weight of HA get lower, losing its properties. From the clinical practice it is shown thatan infiltration of HA in the joint can restore temporarily the patient’s health, giving him relief.

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Several clinical studies show the HA efficacy in knee OA treatment26-29, moreover HA has a longerlasting effect with respect to corticosteroids infiltrations 25,30. Considering direct costs and costsassociated to potential side effects, in literature has been reported the cost-effectiveness of HAcompared to oral Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), physical therapy and assistivedevices31. HA has been used for several years and it is considered a standard treatment in intra-articular therapy for knee OA.

PRP is a non-transfusion use blood component, used to treat pathologies with topical use or IAinjections. It is collected from patient’s blood and used on the same patient, for this reason it isconsidered as a safe practice32-33. The PRP treatment efficacy is shown in several studies, inparticular in the first years of treatment 33-38.

PRP is produced by the centrifugation of whole blood yielding a concentration of platelets abovebaseline levels. The benefits can be due to the platelet-derived growth factors introduced intothe knee. These growth factors present in the platelet, when introduced in the knee, act inchondrocytes to promote cartilage matrix synthesis, increasing cell growth and migration, andfacilitating protein transcription. The release of platelet-derived factors directly at the site ofcartilage disease and stimulates the natural healing cascade with the regeneration of tissue andfurther mediate the anti-inflammatory response39. In recent literature six studies compare HAand PRP effectiveness and in all of them was reported that PRP has major effectiveness than HAfor knee OA treatment33, 40-45. The results of three meta-analyses confirm the major effectivenessof PRP46-49.

The production of PRP needs a specific medical device and a longer time process, leading thetherapy to be more costly than the comparator (HA). For this preliminary economic evaluation weconsider as PRP device the Regen kit BCT-1©, manufactured by Regenlab (Switzerland). Thepreparation of PRP starts taking a small blood sample from a patient’s vein (around 8 ml), thensample is put in the BCT-1 kit tube that contains an anticoagulant to prevent the activation of theplatelets and a cell selector gel that permits separation of red cells from other bloodcomponents. The BCT-1 tube is then submitted to a centrifugation at a speed of 1500 g-force(3400 RPM), which enables to obtain three components: red blood cells trapped under the gel,Platelet-Poor-Plasma (PPP) and PRP settled on the surface of the gel. By a gently inverting theBCT-1 tube several times, it is possible to re-suspend cellular deposit in the supernatant andobtain PRP (about 4 ml). Then PRP is ready for use, collected by a sterile syringe it is injected intothe patient’s joint36, 50.

The objective of the present study is to assess a preliminary economic evaluation in terms ofcost-utility of the intra-articular PRP therapy with respect to HA, considering the standard of carefor patients with moderate to severe knee pain due to OA and who failed to respond to firsttherapies with corticosteroids.

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2. Materials and methods

2.1 Study design

A decision tree model has been developed to evaluate the choice between PRP and HA for OAknee disease for Italian health system, considering costs and clinical benefits of both therapies.Results are reported in terms of Incremental Cost-Effectiveness Ratio (ICER). The outcomemeasure adopted for the analysis is EuroQoL (QALY). The perspective of the study is the ItalianNational Health System, as suggested by Italian Health Technology Assessment (HTA) guidelines.Since most clinical studies report a one year follow-up and there are no evidences on a longerperiod, the time horizon considered in the model is one year.

The decision tree is one of the models used in decisional analysis to perform economicevaluations, especially for short term time horizon. The decision tree represents two or morestrategic choices, defined by the initial branches which depart from the main node. Each branchrepresents one of the possible paths that could be undertaken while following a certain strategy.Each branch leads to a node, in which you find another event from which other branches departup to a final leaf node. To each leaf node are associated the costs to bear during the path fromroot to leaf nodes and the relative outcome.

In the model developed the root node of the tree represents the choice between the twotherapies (PRP and HA) for the knee OA treatment. From this choice depart several paths andtreatments that the patient could be submitted at. For both the therapies the first node splits thepath in two, according to the positive or negative response of patient to the therapy. The decisiontree model is shown in Figure 1.

Fig. 1 Cost-effectiveness model of PRP vs HA

At the root node it is wondered which could be the best choice between using PRP or HA for kneeOA. In case PRP is chosen, it will have a certain effectiveness (pEffPRP) which will lead to thecorresponding values of cost and benefit. The development of the HA branch is similar to PRPbranch previously described.

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2.2 Model parameters

Resources use and costs

There are several types of HA that have different volumes and price features. The productchanges according to the number of possible injections, concentration, volume and molecularweight. Given the high variety in the choice of HA, it has been decided to compute the averagecost of a therapeutic cycle of every product by using the information available in the individualpackage leaflets (number of injections, molecular weight etc.). We took into account all the pricesof the HA in Italy51 and then, given the NHS perspective, all the average prices to public werereduced by 50% to obtain a value similar to the one generally applied for public hospitals. Theaverage cost of the therapy of HA for Health Local Authority (ASL) is €82.62, with a standarddeviation of € 16.4 (IC 95%. € 116.2 - 49).

The cost of the PRP treatment used for this study refers to the kit needed to produce it, and notto the product itself (autologous blood). In this analysis we refer to the price applied to a HealthLocal Authority in Tuscany Region (Area Vasta Centro of Tuscany Region) that obtained the kitthrough an official tender notice of the Regenkit BCT-1. The Regenkit BCT-1 used as reference forour analysis costs € 40 per i.a. injection52.

Besides the i.a. injection, the production of PRP implies several preparation steps (as previouslydescribed) and need longer times for elaboration, 11 minutes for PRP against 2 minutes for HA.These important differences in the delivery of the two therapies are considered in the model. Theduration of the PRP preparation process and the cost per minute have been obtained byinterview to clinicians and the Hospital Managers of the Local Health Authorities of hospitalblood transfusion centers in Veneto region. The HA treatment needs only the i.a. injection time,while the PRP treatment needs two minutes for the plasma withdrawal from the patient, around7 minutes for the centrifugation and the other operations previously cited and finally 2 minutesfor the injection that are in common for both therapies. Finally, for Italian current standards ismandatory to perform the processing of blood components with the presence of a hematologistmedical doctor, this presence increases the cost of PRP treatment.

General costs were not inserted in the analysis because there is no significant difference for thetwo therapies and they do not affect the results. The number of injections included for a PRPtherapeutic cycle is three, as reported in the most recent meta-analysis46, 47, 49. The number ofinjections relative to HA treatment varied with different molecular weight and type, so in thismodel we assume the average cost of the overall treatment that is the average of the cost of allinjections of every HA treatment.

In table 1 are reported the model parameters for costs and outcomes. For each parameter arereported the value, the range of variation for Deterministic Sensitivity Analysis (DSA), distributionof probability used for Probabilistic Sensitivity Analysis (PSA) and the related data source. As

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reported in previous literature, for costs was adopted Gamma distribution and for outcomes wasadopted Uniform distribution.

Direct costs (€)Parameters Value (€) Range Distribution Data source

Min MaxMedical Doctor/minute (€) 1,28 - - USSL 1 Belluno, Veneto RegionPRP process costs for single injection (about 9 minutes)

11.61

RegenKit BCT-1 Cost 40 20 60 Gamma ESTAV, Area Vasta Centro, Tuscany Region

PRP therapeutic cycle cost(3 i.a. RegenKit BCT-1)

154.83 134.83 174.83

HA therapeutic cycle cost 82.62 49 116 Gamma www.terapiainfiltrativa.it Discounted prices for Nhs structures (50%)

Effectiveness

Parameters Outcome (QALY)

Range Distribution ReferencesMin Max

HA Therapy 0,677 0,654 0,703 Uniform Raeissadat et al, 2015Wailoo et al, 2014

PRP Therapy 0,736 0,718 0.772 Uniform Raeissadat et al, 2015Wailoo et al, 2014

Therapies not effective 0,556 0.523 0.584 Uniform Raeissadat et al, 2015Wailoo et al, 2014

Tab. 1 Costs and effectiveness: input parameters including parameters for sensitivity analysis.

Clinical data source and utility values

The previous studies on both therapies report effectiveness in terms of WOMAC scale (WesternOntario & Mc Master University Arthritis Index) that represents an illness specific measure ofoutcome widely adopted for lower extremity symptoms and function.

Illness specific scales are very sensitive to changes in patients’ conditions and are accurate inevaluating improvement of related to a specific treatment for a certain disease. On the otherhand they are not useful to make comparison among treatments out of the context of a certainpathology or disease. The general health status profiles are less sensitive, but allow to analyzeand compare results also out of the context of a certain disease. A variety of generic preference-based measures have been developed, the most commonly used questionnaires include theEuroQol (EQ)-5D-5L, the Short Form 6D (SF-6D) and the Health Utilities Index (HUI)53. Illnessspecific scales can be transformed in QALYs using mapping techniques. In this analysis WOMACscores are converted in QALYs using the conversion procedure developed by Wailoo53, which usea multiple regression model derived from a study where patient health states are both expressedin terms of WOMAC and EQ-5D-5L. The model predict Health Related Quality of Life (HRQoL)using demographic variables, WOMAC pain, stiffness and function subscales.

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Among the studies selected in the meta-analyses only two reported the information useful tomap WOMAC in QALYs44-45,60,61. The scenario considered in this study is defined by the lessfavorable for the PRP in terms of benefits44. The values and the interval of QALYs reported are inline or conservative with respect to other published studies40, 42-48.

The clinical effectiveness is shown in several studies, with a response rate that ranges between70% and 90% for both of the treatments26-27, 37-38. For our analysis was chosen to set theprobability of clinical effectiveness at 80% for both of the therapies.

Sensitivity analysis

Deterministic and probabilistic sensitivity analyses have been conducted to assess the impact ofthe uncertainty of the parameters, costs and outcomes values used in the model. DSA has beendeveloped considering the variation of model parameters. In detail one way DSA has beendeveloped for every parameter where a range of minimum and maximum values are reported.PSA was performed developing 10,000 scenarios using a Monte Carlo simulation to assess theuncertainty around the ICER and the probability of the PRP therapy to be cost-effective atdifferent given cost per QALYs thresholds (Willingness to Pay, WTP). Each model input parameterwas represented by a probability distribution that describes the variability and the distributionunder uncertainty. The outcome values have been modelled with uniform distribution while forcosts was adopted Gamma distribution55. For the parameters cited in literature where it was notestimated any standard error, it was assumed a general standard error of 25% of the meanvalue56.

5. Results

In cost-utility analysis there is not a dominance of the therapy with respect to the other one, theICER relative to PRP introduction with respect to HA is €1,524.15/QALY. This means that to gain ayear lived in perfect health for a patient with OA knee disease, the additional cost of PRP is€1,524.15 with respect to HA treatment.

The DSA was performed considering the variations of any parameters of the model (Table 2) andrepresented by a Tornado Diagram (Figure 3). The analysis shows that the ICER is sensitiveaccording to the cost of the kit used to produce the PRP, the number of injections, the HAeffectiveness and the HA therapeutic cycle cost.

Parameter for Tornado Analysis Min Max

Regenkit BCT-1 Cost € 20.00 € 60.00

PRP Number of injections 2 4PRP therapeutic cycle cost € 40.00 € 240.00HA effectiveness 0.654 0.703PRP effectiveness 0.718 0.772HA therapeutic cycle cost € 49.00 € 116.00Probability PRP Effective 0.7 0.9Probability PRP Effective 0.7 0.9

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PRP Time process (in minutes) 7 13Table 2: Input values for DSA.

Fig.3 Tornado Diagram for DSA

A further analysis was performed in order to show the variation of ICER when the parameters assume the relative minimum and maximum value. The ICER varies according to the relative effectiveness of therapy, less is effective the therapy of PRP, higher is the ICER value (€2,193.29/QALY), while less is the effectiveness of HA therapy and lower is the ICER value (€1,096.65/QALY). ICER also varies according to the cost of the therapy, the more expensive is the PRP therapy, higher is the ICER value(€2,795.34/QALY) and the more expensive is the HA therapy, lower is the ICER value (€816.95/QALY). The results are reported in table 3.

ParametersICER

(€/QALY)

Effectiveness PRP Min 2,193.29

Max 946.58

Effectiveness HA Min 1,096.65

Max 2,725.50

HA therapeuticcycle cost

Min 2,236.44

Max 816.95

PRP therapycycle cost

(RegenKit BCT-1)

Min 252.97

Max 2,795.34

Tab. 3 Results of one-way sensitivity analysis, Costs and effectiveness parameters.

A PSA was developed through a Monte Carlo considering a high number of scenarios. The Cost-Effectiveness Acceptability Curve (CEAC) reported in Figure 4 shows that, considering uncertaintyof parameter, costs and outcomes and considering a conservative WTP threshold of €10,000, PRPtherapy is cost-effective for the 78.6% of scenarios. The asymptotic tendency of CEAC to 83% isrepresented by three main factors: short term horizon used in the evaluation and the relative

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differences in terms of improvement on outcome and costs between the two strategies. Theseresults are also confirmed in Figure 5 where is shown the Cost-Effective distribution of resultingfrom the Monte Carlo simulation. If we consider a WTP of €30,000 the PRP is cost-effective in81.1% of the scenarios. Finally the results show that PRP is advisable as therapy for the Italianhealth system for the OA knee disease and the relative ICER is under the WTP threshold.

Fig. 4 Cost-effectiveness acceptability curve of PRP vs HA.

Fig. 5 Distribution of Cost-effective scenarios of PRP vs HA.

6. Discussion

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PRP and HA are therapies able to give relief to patients affected by OA, and to potentially reduce,or at least delay, the surgical intervention to replace the joint25-31, 33-44. Several studies show thatPRP is more effective than HA33, 40-48. No economic analysis of PRP in the treatment of knee OAhas previously been reported. Therefore, the authors consider it significant to develop this study,as first economic evaluation of this therapy for knee OA. Results obtained from the analysis showthat for patient with a mild to severe knee OA, considering a time horizon of 1 year in ItalianHealthcare System context, PRP therapy is cost-effective with respect to HA. Even if the PRPproduction process implies additional costs, this therapy can be considered cost-effective underthe Italian Healthcare System perspective. In Italy the cost-effectiveness threshold has range ofvalues that varies from € 25,000.00 – € 40,000.00 per QALY gained558, 59. A threshold around €30,000.00/QALY is commonly accepted and applied to health economic evaluations60. Evenconsidering a more conservative WTP threshold (€ 10,000.00/QALY) PRP is cost-effective. It isworth noting that in our analysis we considered only direct health-related costs. The study didnot consider, for example, cost due to loss of productivity and social life activities. Given therelative major effectiveness of PRP, including social costs could favored even more PRP therapy.

These results can be considered robust and accurate although we assumed some limitation in themodel assumption Firstly the reported cost-effectiveness ratio may be influenced in relation withthe method used to convert WOMAC scores in QALYs, as some bias can be given by thecharacteristic of population. Moreover the evidence shows that the use of PRP leads to clinicalimprovements in pain and knee functionality, but there are still several questions about the bestway to use it (volume, number of injections, centrifugation method) and about the possibledifferent effects of PRP on specific Kellgren and Lawrence (KL) grades of knee OA48. Secondly achronic disease should be evaluated in a longer period of time. The lack of clinical evidences onlonger-term follow up does not allow to use a decisional model more accurate for the chronicillness on a long term. In author’s opinion this first economic evaluation should stimulate widerworks on the topic. In particular the new clinical studies should do be oriented to analyze alonger time horizon. The economic impact of TKR in NHS is an important variable to take intoaccount for the economic evaluation for the introduction of new therapies for knee OA,especially considering that the number of TKR is growing every year in several countries. A moreeffective therapy for knee OA can delay of some years TKR and this delay could lead to reduce thetotal OA economic impact on Healthcare Systems. This aspect will be considered in the future fora more detailed economic evaluation.

7. Conclusion

Although more high-quality evidence is needed, recent studies indicate that i.a. platelet richplasma injections are promising for relieving pain, improving knee function and quality of life,especially in younger patients, and in mild OA cases. On the other hand PRP has a higher costthan HA, for this reason it was important to make a first cost-utility analyses. In conclusion,despite the limits explained, the i.a. PRP-based therapy seems to be cost-effective with regard to

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the i.a. HA therapy, considering one year scenario. Future clinical studies should provide moreevidence on the major effectiveness and in particular evaluates PRP effectiveness in a longerperiod of time, in particular with reference to the delay of TKR. The major effectiveness of PRP, inaddition to quality-of-life improvement, could delay TKR and therefore reduce also eventualprosthesis revision, reducing the total costs of the knee OA and the economic burden forHealthcare Systems. In this scenario where the number of TKR and the OA economic burden inwestern countries is increasing, this analyses can be of great support for better resourceallocation in the future.

Acknowledgement

This research was supported by University Ca’ Foscari Venezia. We want to thank Dr Lucia Beinatfor the useful help on clinical data collection.

Conflict of interest statement

On behalf of all authors, the corresponding author states that there is no conflict of interest.

DECLARATION SECTION

Ethics approval and consent to participate

Not applicable, Ethical approval was not required for this study.

Availability of data and material

The datasets generated and/or analyzed during the current study are not publicly available due

ownership issues but are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This research was supported by University Cà Foscari Venezia.

Authors' contributions

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SR, PL and SL conceptualized this paper and determined the research plan. SR was responsible for

research coordination and recruitment of the data. SL carried out the literature review on the topic.

SL completed the statistical analyses with the methodological support of PL. All authors read and

approved the final manuscript.

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