Abstract
Background
Materials and Methods
Results
Conclusion
Keywords
1. Introduction
- Longo U.G.
- Silva S.
- Perdisa F.
- Salvatore G.
- Filardo G.
- Berton A.
- et al.
- Longo U.G.
- Silva S.
- Perdisa F.
- Salvatore G.
- Filardo G.
- Berton A.
- et al.
- Tribe K.L.
- Lapsley H.M.
- Cross M.J.
- Courtenay B.G.
- Brooks P.M.
- March L.M.
- Artz N.
- Elvers K.T.
- Lowe C.M.
- Sackley C.
- Jepson P.
- Beswick A.D.
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.
2. Materials and methods
2.1 Systematic literature search

Population | Intervention | Comparison | Outcome |
---|---|---|---|
Adults with total knee replacement | Supervised rehabilitation | Unsupervised rehabilitation | Mobility (6MWT, TUG)Patient-reported outcomes (pain, function)Range of Motion (knee extension and knee flexion) |
Database | Search terms |
---|---|
PubMed | TITLE-ABS (“total knee replacement*”) OR (“total knee arthroplasty*”) AND (rehab*) AND NOT (hip) |
SCOPUS | TITLE-ABS (“total knee replacement*”) OR (“total knee arthroplasty*”) AND (rehab*) AND NOT (hip) |
Cochrane | #1 MeSH descriptor: [Arthroplasty, Replacement, Knee] explode all trees] #2 MeSH descriptor: [Rehabilitation] explode all trees #3 #1 AND #2 |
2.2 Eligibility criteria and data extraction
- Ko V.
- Naylor J.M.
- Harris I.A.
- Crosbie J.
- Yeo A.E.T.
- McConnell S.
- Kolopack P.
- Davis A.M.
- Roos E.M.
- Lohmander L.S.
2.3 Quality assessment, risk of bias and evidence synthesis
2.4 Statistical analysis
3. Results
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.
Author (year) | Design and Aim | Participants | Rehabilitation protocol | Outcomes and follow-up | Results |
---|---|---|---|---|---|
Bini et al. (2017) | RCT To compare physical therapy delivered through an asynchronous video-based tool to traditional in-person outpatient PT following routine TKA. | 28 patients with TKA (design of implant and name of commercial product not reported) Super group (n = 15) - Mean age: 63.6 - Gender; 9 M / 6F Unsuper group (n = 13) -Age: 62.9 - Gender: 6 M / 7F | Both group followed a pre-operative education class and a single posto-operative care protocol Super group: Conventional outpatient rehabilitation Unsuper group: Home program using an application with remote video on mobile (asynchronous). A therapist remotely monitors progress and changes the schedule (not in real time) | FU: 3-month post-surgery (24 weeks) OUTCOME:- VAS (Visual Analogue Scale) - KOOS -PS - Veterans-RAND Physical Component Score (VR-12 PCS) - Veterans-RAND Mental Component Score (VR-12 MCS) | Clinical outcomes following asynchronous telerehabilitation administered over the web and through a hand-held device were not inferior to those achieved with traditional care. |
Büker et al. (2014) | RCT To determine the functional differences between TKA patients who were treated with supervised physiotherapy or a standardized home program and perform a cost analysis | 34 patients with TKA (ligament-preserving TKA, name of commercial product not reported) Super group (n = 18) - Mean age: 64,25 ± 3,86 - Gender: 2 M/16F - BMI: 35,44 ± 7,6 Unsuper group (n = 16) - Mean age: 64,08 ± 6,25 - Gender: 1 M/15F - BMI: 28,81 ± 5,37 | Super group: patients in supervised physiotherapy participated in a total of 20 sessions of a physiotherapy and rehabilitation program 5 days a week for 4 weeks. The program included: knee joint ROM exercises, strengthening exercises for the knee and hip, 20 min of application of moist heat, and 20 min of conventional transcutaneal electrical nerve stimulation (TENS) application. Unsuper group: patients performed home exercise for an hour a day, 5 days a week, for 4 weeks. Home exercises included arrangement of knee joint motion limit, restoration of knee and hip muscle power. | FU: at 3, 6, 12, 24 months post-operatively OUCOME: -VAS -Beck Depression Scale -Knee flexion and extension ROM -WOMAC -SF-36 | No difference between the patients performing supervised or unsupervised with respect to the effects on functional status. A home exercise program can be used patients with TKA, which can also reduce health-care spending. |
Correia et al (2018) | RCT To compare the clinical outcomesof a home-based program using a novel digital biofeedback system for home-based physical rehabilitation (SWORD) against conventional in-person home-based rehabilitation after TKA. | Fifty-nine patients with TKA (design of implant and name of commercial product not reported) Super group (n = 29) - Age: 70 ± 7.2 - Gender: 71 % F / 29 % M - BMI: 30.8 ± 5.4 Unsuper group (n = 30) - Age: 67.3 ± 6.8 - Gender: 84.2 % F / 15.8 % M - BMI: 31 ± 4.5 | Super group: Conventional rehabilitation group, each patient had 24 face-to-face sessions consisting in soft tissue massages, active assisted mobilization, open kinetic chain (OKC) exercise, gait training, strengthening exercises and ice pack application for the first 2 weeks; 3 to 6 weeks closed kinetic chain (CKC) exercises and gait training without external support were added; 7–8 weeks eccentric and weight bearing exercises including steps exercise were added. Unsuper group: Unsupervised rehabilitation program was carried out with the use of a digital biofeedback system for home-based physical rehabilitation and remote monitoring. Each patient had 3 face-to-face contacts with the therapist (on deployment, 4 weeks into the rehabilitation program and on termination). The rehabilitation program consisted in OKC exercise, strengthening exercises and ice pack application for the first 2 weeks; 3 to 6 weeks exercise with steps, CKC exercise, standing exercise without support; 7–8 weeks, eccentric and multidirectional exercises were added. | FU: 8 weeks post-surgery OUTCOME:-TUG (Time Up and Go) - Knee flexion and extension ROM -KOOS Pain | The study demonstrated a superiority of the unsupervised group for all outcomes. Independent-home based rehabilitation after TKA with the digital biofeedback system is feasible, safe and effective. |
Crawford et al. (2021) | RCT To determine the non-inferiority of a smartphone-based exercise educational care management system after primary knee arthroplasty compared with a traditional in-person physiotherapy rehabilitation model. | 345 patients with TKA (design of implant and name of commercial product not reported) Super group (n = 185) - Mean age: 64.5 ± 8.9 - Gender: 75 M / 110F - Mean BMI: 31 ± 3 6.5 - Unsuper group TKA (n = 160) - Mean age: 63.2 ± 8.6 - Gender: 54 M / 106F - Mean BMI: 32.2 ± 6.4 | Super group: conventional outpatient rehabilitation sessions (3 times/week for 4 weeks). Unsuper group: application-based program using smartphone/smartwatch and MyMobility smartphone platform (3 times / day, 6 days / week for 6 weeks). | FU: 1 month and 3 months post-surgery OUTCOME: -KOOS -TUG - Knee flexion ROM - EQ-5D-5L -Single Leg Stance | The use of the unsupervised care platform demonstrated similar early outcomes to traditional care models, while requiring significantly less postoperative physiotherapy visits. |
Fleischmann et al. (2019) | RCT To compare the efficacy of an unsupervised home exercise program, through an interactive web-based program or a printed paper manual, with the routine prescription of outpatient PT services after primary, unilateral TKA | 290 patients with TKA (cemented posterior stabilized or cruciate retaining TKA, name of commercial product not stated) Super group (n = 97) - Age: 65 - Gender: 47M50F - BMI: 31 Unsuper group (n = 193) was divided into:1) Web PT (n = 96) -Age: 65 - Gender: 47 M / 49 / F - BMI: 312) paper PT (n = 97) -Age: 66 - Gender: 48 M / 49F - BMI: 30 | Super group: outpatient PT group received formal outpatient PT supervised by a licensed therapist with two to three weekly sessions for 4 to 8 weeks after surgery. Unsuper group: the web PT and paper PT groups followed an 8-week unsupervised home exercise program using either an interactive web-based platform (FORCE Therapeutics, New York, NY, USA) or a printed PT manual that was provided to patients before discharge. Both unsupervised home-based PT programs recommended the same weekly exercises, which were to be performed three times daily and graduated from week to week. | FU: 4–6 weeks and 6 months post-operatively. OUTCOME: - Knee flexion ROM - KOOS | Unsupervised home exercise is an effective and adequate rehabilitation strategy for selected patients undergoing primary, unilateral TKA |
Han et al. (2015) | RCT To determine whether the home exercise program (HEP) is not inferior to usual care in terms of self-reported pain and physical function, knee ROM, walking ability, and safety at 6 weeks. | 390 patients with TKA (cemented posterior stabilized or cruciate retaining TKA, name of commercial product not stated) Super group (n = 196) -Mean age: 65.4 ± 6.0 -Gender: 92 M / 104F -BMI: 32.2 ± 6.3 Unsuper group (n = 194) - Mean age: 64.1 ± 6.5 - Gender: 88 M/ 106F - BMI: 32.2 ± 5.5 | Super group: postoperative rehabilitation recommended by hospital or orthopedic surgeon. Super group mostly involved access to clinic-based outpatient physiotherapy for the 6 weeks after discharge from the orthopedic ward. Unsuper group: the patients allocated to the HEP received 1 session of instruction from a physiotherapist prior to hospital discharge and received a written copy of the HEP and instructions regarding effective icing. Brief weekly telephone calls were made thereafter to monitor adherence and evaluate readiness to commence the intensive exercise. Rehabilitation protocol consisted in weeks 1–2: 6 exercises to increase full active and passive ROM in sitting and supine positions; weeks 3–6 focused on 6 functional and weight-bearing exercises to increase ROM and maintain muscle strength. Patients were asked to complete 10 repetitions of each exercise, 3 times daily | FU: 6 weeks. Post-operatively OUTCOME: -WOMAC -Knee flexion and extension ROM −50-Foot Walk Time (50-FWT) | Delivery of a monitored HEP is not inferior in terms of WOMAC pain and physical function, knee ROM, walking speed, to access to clinic-based usual care physiotherapy during the first 6 weeks after hospital discharge among patients with TKA. |
Ko et al. (2013) | RCT To determine whether center-based, one-to-one physical therapy provides superior outcomes compared with group-based therapy or a simple monitored home-based program in terms of functional and physical recovery and health-related quality of life after TKA | 249 patients with TKA (cement fixation used for all participants; posterior stabilizing, cruciate retaining and additional patellar resurfacing were seurgeon-dependent. Name of commercial product not stated) Super group (n = 169) Divided into:1-to-1 Therapy (n = 85) -Mean age: 67 ± 9 -Gender: 32 % M/ 68 % F -BMI: 33 ± 6 Group-based Therapy (n = 84) -Mean age: 68 ± 9 -Gender: 40 % M/ 60 % F -BMI: 34 ± 6 Unsuper group (n = 80) -Mean age: 67 ± 8 -Gender: 39 % M/ 61 % F -BMI: 32 ± 5 | Super group 1-to-1: 12 physiotherapy sessions with a physiotherapist over a 6 weeks period. Group-based: 12 group sessions over a 6-week period. Unsuper group: Participants attended two individual sessions at one of the participating physical therapy departments. At the first session, participants were instructed on the home-based exercise program and received an instructional DVD and a booklet with fortnightly exercise progressions. The second session occurred two weeks after: the therapist documented any adverse signs and symptoms and reviewed and modified the program as required. | FU: 2 10, 26, 52 weeks post-operatively OUTCOME: -WOMAC Function -WOMAC Pain −6MWT -OKS (Oxford Knee Score) -Knee flexion and extension ROM | One-to-one therapy does not provide superior self-reported or performance-based outcomes compared with group-based therapy or a home program, in the short term and the long term after TKA. |
Kramer et al. (2003) | RCT To compare a clinic-based rehabilitation program delivered in outpatient physical therapy clinics against home-based rehabilitation monitored by a physical therapist via periodic telephone calls, on disease-specific, joint-specific, and functional outcome measures after TKA | 160 patients with TKA (Genesis - Smith and Nephew Orthopaedics, Memphis, TN; and AMK - DePuy, Warsaw, IN) Super group (n = 80) -Mean age: 68,2 ± 6,9 -Gender: 33 M/47F Unsuper group (n = 80) -Mean age: 68,6 ± 7,8 -Gender: 36 M/44F | All patients received booklets, which included written and pictorial descriptions of each exercise and educational information on using ice, controlling swelling, walking, and ROM. They were instructed to complete the common home exercises 3 times daily until their 12-week follow-up. Super group: In addition to the common home exercises, patients in the clinic-based group were required to attend outpatient physical therapy between weeks 2 to 12 after surgery, for as many as two sessions per week, for 1 hour per session. Unsuper group: A physical therapist telephoned each patient in the home-based group at least once during Weeks 2 to 6 and once during Weeks 7 to 12 after surgery to ask whether the patient was having any problems with the exercises, to remind them of the importance of completing the exercises, and to provide advice on wound care, scar treatment, and pain control. | FU: at 12 weeks and 52 weeks post-operatively OUTCOME: -WOMAC -KOOS Pain -Medical Outcomes Study Short Form – 36 (SF-36) , −30-seconds Stair Test −6MWT -Knee Rating Scale -Knee Flexion ROM | Prior to surgery there were no significant differences between groups (p > 0.01). Pain before surgery, as measured by the Knee Society clinical rating scale, was significantly greater than that at 12 and 52 weeks after surgery (p 0.01), while there was no statistically significant difference (p 0.01) between pain scores at 12 and 52 weeks. After primary total knee arthroplasty, patients who completed a standardized home exercise program performed similarly during the first 52 weeks after surgery, regardless of whether they participated in a clinic-based or a home-based rehabilitation program |
Naylor et al. (2015) | RCT To determine whether patients who present with more mobility limitation at the commencement of rehabilitation after TKA, benefit more if they receive closer supervision during their rehabilitation | 233 patients with TKA (design of implant and name of commercial product not reported) Super group (n = 159) Divided into:1) One-to-one PT (n = 78)2) Group based PT (n = 81) Further divided according to the 6MWT into:a) Low performer (LP) (n = 89) - Mean age: 68.5 ± 8.2 - Gender: 58 M / 31F - BMI: 33.8 ± 6.3b) High performer (HP) (n = 70) - Mean age: 65.8 ± 9.4 - Gender: 43 M / 27F - BMI: 32.9 ± 5.8 Unsuper group (n = 74) Further divided according to the 6MWT into:a) LP (n = 36) - Mean age: 65.7 ± 9.5 - Gender: 23 M / 13F - BMI: 31.1 ± 5.8b) HP (n = 38) - Mean age: 67.5 ± 8.5 - Gender: 23 M / 15F - BMI: 31.5 ± 4.4 | Super group: Distinct in “One-To-One” and “Group Based” Participants in the one-to-one or group-based programmes were prescribed an exercise-based home programme in addition to the supervised sessions to be conducted twice per week for 6 weeks. Exercise: brisk walking, exercise at parallel bars, stretching; Sit down and getting up from chair; step-ups using a step; knee flexion, stationary cycling, arm ergometry; stairs retraining; balance mat; marching; obstacle walking; upper and lower body movement exercises; general stretches including quadriceps, hamstring and calf stretches. Unsuper group:Patients in the unsupervised group were given the same home programme, to be conducted 4 times per week. Home programme participants were assessed twice by a physical therapist; at the beginning of formalized rehabilitation (2 weeks post-surgery) and at 4 weeks post-surgery. They were subsequently monitored via a telephone assessment at 6-weeks post-surgery. Exercise: brisk walking, sit down and getting up from chair, semi-squat without support, with weighted backpack (up to 5 kg), Step-ups using a step or bounded telephone books, support permitted with weighted backpack (up to 5 kg); calf raises; arm raises; standing knee flex, single leg standing, standing hip extension; shoulder range of motion in standing; walking, stationary cycling; quadriceps, hamstring and calf stretch. | FU: at 10, 26 and 52 weeks post-operatively OUTCOME: −6MWT (% of the targeted prediction model) -WOMAC Function -WOMAC Pain | Individuals manifesting comparatively poor mobility at the commencement of physiotherapy may recover their mobility, but not perceived function, more quickly if streamed to supervised therapy. Patients who, at entry to physiotherapy rehabilitation after TKA, is unable to walk more than 40 % of their 6MWT target, may benefit more through enrolment in a supervised exercise programme, while those who manage to achieve this target or better seem to be just as successful with a lower level of supervision. |
Prvu Bettger et al. (2020) | RCT To examine costs and clinical noninferiority of a virtual PT program compared with traditional PT care after TKA. | 287 patients with TKA (design of implant and name of commercial product not reported) Super group (n = 144) -Mean age: 65,1 ± 9,2 -Gender: 65,4% F -BMI: 31,9 ± 5,9 Unsuper group (n = 143) -Mean age: 65,4 ± 7,7 -Gender: 59,6% F -BMI: 31,6 ± 5,7 | Super group: Patients undergo traditional outpatient or home rehabilitation following their care team’s recommendations for all preoperative and postoperative medical and rehabilitative care. Unsuper group:Patients undergo rehabilitation using the Virtual Exercise Rehabilitation Assistant (VERA; Reflexion Health) . Patients had a video visit with their telehealth therapist in the week after hospital discharge and weekly to review progress and to revise the therapy regimen accordingly. | FU: at 6 and 12 weeks post-operatively OUTCOME: -KOOS -Knee flexion and extension ROM (only at 6 weeks) | Virtual PT with telerehabilitation for skilled clinical oversight significantly lowered 3-month health-care costs after TKA while providing similar effectiveness of traditional PT. Virtual PT with clinical oversight should be considered for patients managed with TKA. |
Xu et al. (2021) | RCT To compare aself-developed, home-based, enhanced knee flexion exercise (KFEH) program, which involved the use of a low stool) and an exercycle, against standard supervised physiotherapy. | 106 patients with TKA (Posteriorcruciate stabilizing prostheses; name of commercial product not reported) Super group (n = 51) - Mean age: 67,3 ± 6,9 - Gender: 8 M/43F - BMI: 21,5 ± 1,6 Unsuper group (n = 55) - Mean age: 68,4 ± 8,4 - Gender: 11 M/44F - BMI: 21,2 ± 2,5 | Super group: patients participated in a total of 24 sessions of a physiotherapy and rehabilitation program 2 days/week for the first 7 weeks, followed by 1 day/month for the remaining 10 months of the year. Exercises: knee joint ROM exercises andstrengthening exercises (including quadriceps setting exercise, straight leg raising exercise, stationary cycling, training strengthand length were individually designed) for the knee joint after 20 min of application of moist heat and 20 min of transcutaneous electrical nerve stimulation. Unsuper group: the program consisted of quadriceps femoris sets, hamstring sets, ankle pumps, terminal knee extension with weight, straight leg raises with weight in the supine and side-lying positions, cycling, and prone, hip, and knee flexion–extension with weight in supine, knee flexion–extension with weight in prone, and in sitting, static stretching exercises for hamstrings and gastrosoleus muscles, as well as a low stool-assisted knee joint bending exercise. Doctors in the team will guide patients through phone calls or WeChat to correct patient actions, answer patient questions once a week. | FU: at 1 week and at 1, 3, 6 and 12 months post-operatively. OUTCOME: -VAS for pain -WOMAC Function -Knee flexion ROM -Knee Society Score | The self-developed home-based enhanced knee flexion exercise program resulted in better ROM at early discharge. VAS, KSS, and WOMAC scores, and complication rates during the 12-month follow-up period were non-inferior to supervised PT. Has also been verified the efficiency and cost-effectiveness of using a home-based program for TKA rehabilitation. |
3.1 Characteristics and quality of included studies

3.2 Pain
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.

3.3 Physical function
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.

3.4 Knee range of motion
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.

- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.

3.5 Mobility

- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.

3.6 Evidence synthesis
Outcomes | No. of participants (studies) | Certainty of the Evidence (GRADE) | Anticipated absolute effects (95 % CI) Mean value with Unsupervised PT | MD With Supervised PT Rehabilitation (95 % CI) |
---|---|---|---|---|
At short-term (6–12 weeks) | ||||
Pain (WOMAC pain; VAS) | 1324 (6 RCTs) | ⊕⊕○○ Lowa,b | N.E. | 0.2 points (0.03 to 0.37 points)* |
Function (WOMAC function) | 1012 (5 RCTs) | ⊕⊕⊕○ Moderatec | The function ranged from 22.4 to 39.9 points | 0.88 points (-4.25 to 6 points) |
Mobility (6MWT) | 376 (2 RCTs) | ⊕⊕○○ Lowe,f | The 6MWT ranged from 340 to 386.5 meters | −13.67 meters (-35.61 to 8.26 meters) |
At mid-term (24–26 weeks) | ||||
Pain (WOMAC pain; VAS) | 651 (5 RCTs) | ⊕⊕○○ Lowc,d | N.E. | −0.06 points (-0.22 to 0.1 points)* |
Function (WOMAC function) | 622 (4 RCTs) | ⊕⊕⊕○ Moderatec | The function ranged from 15.2 to 35.6 points | −1.59 points (-4.31 to 1.13 points) |
Mobility (6MWT) | 249 (1 RCT) | ⊕⊕○○ Lowe,g | The mean 6MWT was 401.5 meters | 3.84 meters (–22.81 to 30.48 meters) |
At long-term (52 weeks) | ||||
Pain (WOMAC pain; VAS) | 622 (4 RCTs) | ⊕⊕○○ Lowc,d | N.E. | 0 points (-0.16 to 0.17 points)* |
Function (WOMAC function) | 622 (4 RCTs) | ⊕⊕⊕○ Moderatec | The function ranged from 9.1 to 35.9 points | 0.84 points (-1.82 to 3.5 points) |
Mobility (6MWT) | 376 (2 RCTs) | ⊕⊕○○ Lowe,f | The 6MWT ranged from 400 to 425 meters | −26.1 meters (-47.62 to −4.59 meters) |
4. Discussion
- Xu T.
- Yang D.
- Liu K.
- Gao Q.
- Lu H.
- Qiao Y.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.
- Correia F.D.
- Nogueira A.
- Magalhães I.
- Guimarães J.
- Moreira M.
- Barradas I.
- et al.
- Longo U.G.
- Ciuffreda M.
- D’Andrea V.
- Mannering N.
- Locher J.
- Denaro V.
5. Conclusion
Declaration of Competing Interest
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