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Intervention cost | contracture | The costs related to the intervention arm of the trial were summed to give the
total cost per participant (NHS costs). Where possible, unit costs for the UK
were applied (e.g. Personal Social Services Research Unit, British National
FormularySummary of all intervention costs.Resource use analysis is presented in Between-group analysis of resources and costs.The mean contracture cost for the treatment group was £817 while the costs for
the control group was £2298. This was statistically significant
(The change in Barthel Index scores between baseline and six months was lower in
the control group (mean 7.3 (SD 6.0)) compared to the treatment group (mean 8.1
(SD 5.0)). The mean difference was 0.8 and not statistically significant (95% CI
−1.5, 3.3, | PMC9912301 |
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Sensitivity Analysis | A one-way sensitivity analysis was undertaken to assess the extent of potential
changes in the main cost parameters and outcomes of the treatment using the mean
difference, lower and upper bounds of the confidence intervals for the Barthel
score (Table 3) and the Action Research Arm Test (Incremental cost of intervention using the Barthel score.Incremental cost of intervention using the Action Research Arm Test
(ARAT) score.When the base case results of the costs of the intervention are used with the
base case results of the Barthel scores, the cost per unit of improvement was
−£1240 indicating that the intervention costs less and is more effective.When the lower 5% bound of net cost (−£5867) is used with the upper 95% bound of
net utility (3.297), then the intervention is again seen as costing less and
more effective (−£1780) (see Table 3). When the base case results of the costs
of the intervention are used with the base case results of the Action Research
Arm Test scores, the cost per unit of improvement was −£450 indicating that the
intervention costs less and is more effective.When the lower 5% bound of net cost (−£5867) is used with the upper 95% bound of
net utility (10.71), then the intervention is again seen as costing less and
more effective (−£548) (see | PMC9912301 |
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Discussion | stroke, post-stroke spasticity, spasticity | STROKE | We have previously demonstrated that the early use of botulinum toxin reduced
spasticity and contractures after stroke and that the effects lasted for
approximately 12 weeks.This indicates that the early use of botulinum toxin for post-stroke spasticity can
be cost-saving to the NHS when assessed in terms of gain in the activity of daily
living (Barthel Index) and arm function (total Action Research Arm Test). This
result contrasts with previously reported cost-effectiveness data that suggested
that the base case incremental cost-effectiveness ratio for botulinum toxin type A
plus therapy was £93,500.The previous study measured response to treatment using the Modified
Ashworth Score (an invalidated measure of spasticity),The previous study treatment was initiated in patients who are likely to
have established spasticity and/or contractures (mean time to treatment
46 weeks post-stroke).The previous study primarily focused on improving function using a
combination of therapy and botulinum toxinIn the current study, all patients had an Action Research Arm Test of 0
to 2 at injection,This study is the first randomised-controlled study using botulinum toxin early to
analyse the potential cost-effectiveness of trying to manage contractures. It
provides data that suggests that the perceived expense of botulinum toxin early
after a stroke before any contractures have developed may help reduce health costs
longer term. Clinicians, often subconsciously, make decisions based on the cost of
treatment on a daily basis. This is a form of rationing services which clinicians
are often unaware they make. It is uncomfortable for clinicians who want to be
patient-centred but must balance this ideal, with remaining service-centred to
ensure patient flow through their service. We hope that this study helps to ease
just one of the many cost-based treatment decisions that clinicians must make.Treating spasticity early, in stroke patients at risk of contractures, with botulinum
toxin does not lead to a significant increase in cost associated with managing these
patients. Future-powered studies should now focus on the long-term
cost-effectiveness associated with treatment involving botulinum toxin and ensure
all social costs are included to allow for a more meaningful result. | PMC9912301 |
Clinical messages | contracture, spasticity | The early use of botulinum toxin, as soon as spasticity is identified,
appears to be cost-neutral.Mean contracture costs for the treatment group were £817 while the costs
for the control group were £2298 (Both base case results for cost per improvement of Barthel and Action
Research Arm Test scores indicate that the intervention costs less and
is more effective. | PMC9912301 |
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References | PMC9912301 |
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Background | malaria | MALARIA | In recent years, the downward trajectory of malaria transmission has slowed and, in some places, reversed. New tools are needed to further reduce malaria transmission. One approach that has received recent attention is a novel house-based intervention comprising window screening (S) and general house repairs to make the house more mosquito proof, together with EaveTubes (ET) that provide an innovative way of targeting mosquitoes with insecticides as they search for human hosts at night. The combined approach of Screening + EaveTubes (SET) essentially turns the house into a ‘lure and kill’ device. | PMC10161487 |
Methods | malaria, infection, malaria infection | MALARIA, INFECTION, MALARIA | This study evaluated the impact of SET on malaria infection prevalence in Côte d’Ivoire and compares the result in the primary outcome, malaria case incidence. Malaria infection prevalence was measured in a cross-sectional survey in 40 villages, as part of a cluster-randomised trial evaluating the impact of SET on malaria case incidence. | PMC10161487 |
Results | Infection | INFECTION | Infection prevalence, measured by rapid diagnostic test (RDT), was 50.4% and 36.7% in the control arm and intervention arm, respectively, corresponding to an odds ratio of 0.57 (0.45–0.71), | PMC10161487 |
Conclusions | malaria, infection, Infection | MALARIA, INFECTION, INFECTION | In addition to reducing malaria case incidence, house screening and EaveTubes substantially reduced malaria infection prevalence 18 months after installation. Infection prevalence may be a good metric to use for evaluating malaria interventions in areas of similar transmission levels to this setting. | PMC10161487 |
Trial registration | ISRCTN18145556, registered 1 February 2017. | PMC10161487 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12916-023-02871-1. | PMC10161487 |
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Keywords | PMC10161487 |
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Background | malaria, infection, deaths, malaria infection | MALARIA, INFECTION, PVC | Vector control has been credited with a large contribution to the decline in malaria cases and deaths in the past 15 years [One such tool is the In2Care® EaveTube. EaveTubes comprise PVC tubes which are inserted into a house at eave level and are closed off using an insecticide treated netted insert. EaveTubes exploit the preference of the anopheline mosquito to enter households at eave height [Initial entomological studies conducted in semi-field enclosures suggested that the combination of EaveTubes, closed eaves, and screened windows successfully reduced mosquito populations [The incidence of clinical malaria (new symptomatic malaria cases recorded in a population) is typically considered the gold standard measure of impact for malaria intervention trials [Measuring infection prevalence incurs vastly fewer cost implications for this type of evaluation compared to the measurement of incidence. Prevalence can be estimated through cross-sectional surveys at single time points which greatly reduces time, expense, and logistical burden. As part of the evaluation of the SET technology, we performed an endline cross-sectional survey to assess the impact on malaria infection prevalence in the study population 18 months post-installation of SET. This paper evaluates the impact of a vector control intervention on malaria infection prevalence using different diagnostics in a trial where SET resulted in a substantial reduction in malaria case incidence in the intervention clusters. | PMC10161487 |
Methods | PMC10161487 |
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Study site | malaria | MALARIA, MAY | The trial took place in 40 villages (clusters) within 50 km of the city of Bouaké, central Côte d’Ivoire. The study setting has moderate to high malaria transmission with seasonal transmission primarily occurring between May to November each year. There is a high level of pyrethroid resistance in the local anopheline vectors, as well as resistance to carbamates and organochlorides [ | PMC10161487 |
Trial overview | malaria, Febrile | MALARIA, MAY | The protocol and primary results for the trial have been previously published [The main epidemiological outcome of the trial was malaria case incidence. This was measured in a cohort of 50 children aged 6 months to 10 years per cluster. The cohorts were visited every 2 weeks during the transmission season (May to November) and once a month during the dry season (December to April). Febrile children were tested for malaria with an RDT and received treatment (artesunate-amodiaquine) if positive. The full analyses of the incidence data, as well as entomological and economic outcomes, have been published elsewhere [ | PMC10161487 |
Endline prevalence survey | malaria | MALARIA, MALARIA | An endline cross-sectional survey took place in November 2018, 18 months after the installation of SET. In contrast to the baseline survey where households were the sampling unit, compounds (ranging from 1 to 5 households) were randomly selected from census lists of each cluster, and individuals were tested until approximately 70 people per cluster had been sampled. Anyone over the age of 6 months was invited to be part of the study. Participants were tested using RDT (SD Bioline Malaria Ag P.f/Pan; Standard Diagnostics; Seoul, South Korea) and had a blood smear taken for microscopy analysis, regardless of symptoms of malaria. A short questionnaire was also administered to collect information on house structure, household assets, intervention use, and potential malaria symptoms.The prevalence survey had 80% power to detect a 40% reduction in prevalence between the control arm and the SET arm, assuming a 40% prevalence in the control arm and a coefficient of variation between clusters of 0.5. | PMC10161487 |
Statistical methods | HAND INFECTION | Descriptive statistics (proportions and means) and infection status associations were calculated with confidence intervals adjusting standard errors for clustering at the village level using the svy command in Stata. To assess the impact of the intervention, a mixed effect logit model with arm as a fixed effect and cluster included as a random effect was used to produce odds ratios using both the RDT and/or microscopy data. Impact was assessed separately for villages with more than 70% of houses with SET installed, compared to those with less than or equal to 70% coverage. Per protocol analyses involved comparison of children who lived in houses with SET installed with those in control clusters.To compare differences between the baseline and endline results (in children aged 6 months to 10 years only), an interaction between arm and survey was fitted to the mixed effect logistic model previously described.Incidence was calculated as described in detail in the main trial results paper [This study is registered as an International Standard Randomised Controlled Trial, ISRCTN18145556. | PMC10161487 |
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Results | PMC10161487 |
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Baseline survey results | malaria | MALARIA | In the baseline survey, 2559 children aged 6 months to 10 years from 1217 households were tested for malaria. The mean age of children tested was 5 years. Similar proportions of males and females were tested. The majority of children reported always using a bed net (76.8%), whilst 19% reporting never using a net. Children aged 5–10 years were more likely to report never using a net (22.6%), compared to 0–2 years (15.7%) or 2–5 years (16.5%). 73.2% (Population summary of participants in the baseline and endline survey by arm | PMC10161487 |
Endline survey results (18 months post-installation) | infection, Infection | INFECTION, INFECTION | For the endline survey, 2843 people from 275 compounds were included across the 40 clusters. The median age of participants was 12 years old (range: 6 months to 98 years). Net use was relatively high, with 72.5% of people reporting using a net the previous night, though this appeared lower in the intervention arm (68.0%) compared to the control arm (77.1%). The difference in net use across age groups was greater in the SET arm (ranging from 55% in 10–15 year olds to 76% in 50–100 year olds) compared to the control arm (ranging from 71% in 10–15 year olds to 84% in 0–5 year olds).In the endline survey, mean prevalence by cluster was 43.5% (95% CI: 23.7–66.2). Infection was highest in males (47.4% vs 40.8% in females) with the burden of infection highest in children aged 5–10 years (66.8%). Infection was highest in individuals living in households classified as the lowest SES category (46.9%, compared to 43.5% and 40.1% in the middle and higher categories). Infection was lower in those who reported using a net the previous night (41.0% compared to 50.0%). | PMC10161487 |
Impact of Screening and EaveTubes (SET) on infection prevalence measured by RDT | infection, malaria infection, Infection | INFECTION, HAND INFECTION, INFECTION | Infection prevalence was lower in the intervention arm (36.7%) compared to the control arm (50.4%), with 43% lower odds of infection in the SET arm compared to the control arm (odds ratio (OR) 0.57 (0.45–0.71), Infection prevalence in each cluster (open circles) by intervention arm. The mean of the cluster results and 95% confidence intervals are shown in the diamondsImpact of intervention on infection prevalence (measured using RDT)In the intervention clusters, there was a reduction in malaria infection prevalence for all age groups compared to those living in control clusters. Individuals reporting sleeping under a net the night before had lower infection prevalence in both arms. There was no evidence for an interaction between intervention arm and bed net use, suggesting that the benefit of living in a SET village was additional (not multiplicative) to the protection conferred by a bed net. However, individuals living in SET villages but not using a bed net had lower prevalence (42.8%) than those using a net in control villages (47.5%) with the biggest difference between those living in control villages and not using a net (60.2%) and those living in SET villages and using a net (33.8%).Due to the range of coverage of SET in the intervention clusters (32% to 100% of households), we assessed the impact of intervention coverage on malaria infection prevalence. Seven clusters had SET coverage of 70% or lower. At baseline, infection prevalence in the 7 lower coverage clusters was similar to infection prevalence in the 14 clusters which had > 70% coverage (infection prevalence of 72.3% (95% CI: 53.7–95.5) in clusters with coverage ≤ 70% and infection prevalence of 70.7% (95% CI: 48.4–88.5) in clusters with > 70% coverage). In the endline survey, clusters with ≤ 70% coverage had a mean infection prevalence of 43.4% (95% CI: 32.9–52.1) compared to a prevalence of 33.0% (95% CI: 23.7–56.3) in the clusters with coverage > 70%, suggesting a stronger effect of the intervention when coverage was higher. However, when comparing the lower coverage clusters to the control clusters, there was still evidence for a drop in prevalence in the lower coverage villages (OR 0.76 (95% CI: 0.60–0.95), Thirty-five (25%) of the households (297 individuals) sampled in the intervention arm did not have SET. Individuals living in these houses had comparable infection prevalence (37.4%) to those who did have the intervention (36.5%). When compared to individuals living in control villages, the impact of living in a SET cluster for those households without SET (OR 0.57 (0.40–0.83), | PMC10161487 |
Infection prevalence at endline compared to baseline (RDT) | infection, Infection | INFECTION, INFECTION | Infection prevalence in children aged 6 months to 10 years for each arm was compared between baseline and endline surveys to assess whether there was a reduction in either arm, with the caveats that the two surveys took place at different times of the year and had slightly different sampling methodologies. The interaction between study arm and survey was significant (Percentage reduction in infection prevalence between endline and baseline surveys compared to baseline prevalence. Each circle represents a cluster | PMC10161487 |
Comparison of diagnostics: RDT and microscopy | infection | INFECTION, CNS INFECTIONS | The majority of participants in the endline survey also had a blood smear taken for microscopy (Overall, 57.3% (707/1233) of positive RDT results were also positive by microscopy. Whilst age patterns of infection prevalence appeared similar for the two diagnostics, the agreement between the two was lowest in older participants (only 36.5% and 31.1% of positive RDT results were positive by microscopy in 25–50 year olds and 50–100 year olds respectively). Mean parasite density was also lower in infections in those age groups (< 2000 trophozoites per ml) compared to younger age groups (mean 36,384, 12,300, 3789, 6437 trophozoites per ml in 0–5, 5–10, 10–15, and 15–25 year olds, respectively). | PMC10161487 |
Infection prevalence (RDT) compared to incidence | malaria, infection | MALARIA, INFECTION | Cluster-level infection prevalence in the endline survey was associated with malaria case incidence measured in the child cohort at the end of the two years (Fig. Association between endline prevalence (all ages) and malaria case incidence in children aged 6 months to 10 years | PMC10161487 |
Discussion | malaria, infections, Infection | MALARIA, INFECTIONS, MALARIA, INFECTION | New paradigms of vector control tools are urgently needed if we are to continue the downward trajectory of malaria transmission that has been achieved over the past few decades. Housing modifications are a paradigm that has rarely been explored in cluster randomised trials. In this large trial, EaveTubes combined with house screening demonstrated a strong impact on malaria case incidence in Côte d’Ivoire [The endline prevalence survey took place at the end of the transmission season, 18 months after the intervention had been installed. Bed net trials in Tanzania have shown that an intervention’s impact on prevalence can differ substantially in accordance with the timing of the survey, which may be a reflection of seasonality of transmission, or the ageing of the intervention [Infection prevalence was highest in children aged between 5 and 10 years old in both arms at endline. Together with children aged 10–15 years, these children were the least likely to have slept under a net—a finding that has been seen elsewhere in malaria endemic settings [There were considerable discrepancies between the results of the RDTs and the results of the microscopy. One explanation for differences between the diagnostics could be that RDTs are still detecting circulating HRP-2 from previous infections; however, only a small proportion of participants reported receiving treatment for malaria in the previous 2 weeks, the majority of whom were either positive by RDT or both microscopy and RDT. Other potential reasons for discrepancies could be other circulating infections causing false positives in RDTs [One of the barriers to undertaking large scale trials, such as the Screening + EaveTubes trial in Côte d’Ivoire, is the limited number of funders who are willing or able to fund large cluster randomised control trials. Malaria case incidence can be an expensive and logistically challenging metric to collect, whereas prevalence is considerably cheaper to measure than incidence, due to the nature of the data collection (continuous monitoring of cohorts for incidence vs one off survey for prevalence). To illustrate efforts involved in active case detection for the incidence measure in this trial, the team undertook over 60,000 visits to approximately 2000 children over a 2-year period [ | PMC10161487 |
Conclusions | malaria, infection | MALARIA, INFECTION, HAND INFECTION | Epidemiological metrics are essential for a comprehensive evaluation of interventions and for those interventions to receive a recommendation from the WHO. In this high transmission setting, malaria case incidence and infection prevalence were similarly reduced in the SET intervention clusters, highlighting the usefulness of this intervention combination to reduce malaria transmission in this setting. Whilst the incidence measures collect interesting information regarding the differential impact over season and are likely the most useful metric in low transmission settings, infection prevalence may be a good option for more cheaply evaluating new products where transmission is moderate to high. | PMC10161487 |
Acknowledgements | This research was supported by a grant to the Pennsylvania State University from the Bill & Melinda Gates Foundation (OPP1131603). We thank our trial steering committee, the field staff, and the community health workers involved in the trial, the district health officials, and all the trial participants. | PMC10161487 |
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Authors’ contributions | JC, EDS, and SBA conceived and designed the study. EDS, JC, IK, and MBT conceived and designed the wider trial. CA, EDS, and SBA supervised the epidemiological field work. RN, AAK, and SBA advised on the study communities and coordination with local and national authorities. EDS coordinated the trial and oversaw data collection and management. JC, EDS, and CJA accessed and verified the epidemiological data. JC analysed the data. JC wrote the manuscript. All authors reviewed and approved the final manuscript. | PMC10161487 |
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Funding | The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. | PMC10161487 |
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Availability of data and materials | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10161487 |
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Declarations | PMC10161487 |
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Ethics approval and consent to participate | The trial was reviewed and approved by the Côte d’Ivoire Ministry of Health ethics committee (039/MSLS/CNER-dkn), the Pennsylvania State University’s Human Research Protection Program under the Office for Research Protections (STUDY00003899 and STUDY00004815), and the London School of Hygiene & Tropical Medicine ethical review board (11223). We obtained written and verbal informed consent from all trial participants or guardians for participants younger than 18 years. A trial steering committee monitored trial progress and adherence to protocol included a statement on ethics approval and consent (even where the need for approval was waived). | PMC10161487 |
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Consent for publication | Not applicable. | PMC10161487 |
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Competing interests | The authors declare they have no competing interests. | PMC10161487 |
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References | PMC10161487 |
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Background | pain | ACHILLES TENDINOPATHY | The Achilles tendon is the largest and strongest tendon in the human body. Achilles tendinopathy (AT) is a common clinical problem with Achilles overuse. Eccentric exercise is often used as an initial treatment for these patients. Most patients with AT experienced moderate to severe pain, limiting the incentive to perform eccentric exercise. It is difficult for them to complete eccentric exercise for 3 months consecutively to obtain significant improvements. Using PEMF as an adjunct, there could be immediate pain relief and improved response to eccentric exercise by modulating the mechanical properties of the Achilles tendon. Participants may experience less pain while performing eccentric exercises to increase compliance with the rehabilitation programme. | PMC10258964 |
Methods | This prospective randomised double-blinded, placebo-controlled trial aims to investigate the treatment effects of PEMF for participants with AT. All participants are randomised into two groups: the intervention group ( | PMC10258964 |
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Discussion | pain | AT is a common clinical condition affecting athletes and sedentary populations. It is essential to investigate treatment adjuncts to improve rehabilitation outcomes for these patients. This trial may demonstrate the effectiveness of PEMF in relieving pain, improving function, and restoring mechanical changes of the tendon in participants with AT. | PMC10258964 |
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Trial registration | ClinicalTrials.gov NCT05316961. Registered on 7th April 2022. | PMC10258964 |
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Keywords | PMC10258964 |
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Introduction | PMC10258964 |
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Background and rationale {6a} | tendinopathies, tendinopathy, pain | ACHILLES TENDINOPATHY, HAND SWELLING | The Achilles tendon is the largest and strongest tendon in the human body. Achilles tendinopathy (AT) is a common clinical problem with Achilles overuse; it is a clinical condition characterised by a combination of pain and swelling in the posterior leg and heel region. AT results from an altered tendon structure and mechanical properties. It impairs lower extremity function during activities of daily living and athletic capability [The number of Achilles tendon problems has risen in industrialised countries over the past decades [AT is treated by various interventions, including exercises, orthotics, laser therapy, manual soft-tissue mobilisation, extracorporeal shockwave therapy, injection therapies, surgical debridement, and tendon reconstruction. The treatment with the highest level of evidence is exercise rehabilitation. The exercise aims to provide a mechanical load to the tendon to promote remodelling, decrease pain, and improve calf muscle strength and lower leg function. The loading programmes have consisted of eccentric exercise, isolated concentric, or a combination of concentric and eccentric exercises. They have good reported results in controlled settings, but the effects are limited by poor compliance [Denaro et al. investigated the effects of pulsed electromagnetic fields on human tenocyte cultures. They assessed whether pulsed electromagnetic field therapy (PEMF) could represent a viable therapeutic option in tendon pathologies. A controlled laboratory study evaluated the effects of PEMF on an in vitro tenocyte ‘‘wound’’ closure model. Primary human tenocytes were isolated from healthy supraspinatus and quadriceps tendons. An in vitro cut was mechanically produced in tenocyte culture to mimic the failed healing response in tendinopathy. Compared with the control group, a significant decrease in the ‘‘wound’’ width was found after 12 and 24 h of PEMF exposure. Exposure to PEMF significantly accelerated cut closure 12 and 24 h after the injury. The results supported that PEMF could be a healing-promoting agent in tendon injury. This kind of exogenous stimuli could accelerate the intrinsic tendon healing process by acting directly on tenocytes, the basic cellular component of the tendon tissue, and synthesise collagen and all components of the extracellular matrix. These results provide the preliminary in vitro work and the basis to support the study of the in vivo effects of PEMF on tendinopathies [In addition, a parallel prospective study showed PEMF to reduce pain in patients with AT. Visual analogue scores for pain measurement decreased from 6.9 ± 1.3 at baseline to 3.6 ± 2.0 within 12 weeks [ | PMC10258964 |
Objectives {7} | tendons, pain | This study aims to investigate the clinical effectiveness of PEMF as a treatment adjunct to eccentric exercise in patients with AT. The objective is to establish whether PEMF plus eccentric exercise in people with AT will improve rehabilitation outcomes compared to eccentric exercise only. The second objective is to investigate the effects of PEMF on pain, functional outcomes, and mechanical and morphological properties of tendons among patients with AT. | PMC10258964 |
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Trial design {8} | This is a prospective randomised, double-blinded, placebo-controlled superiority trial with two parallel groups and a 1:1 allocation ratio to investigate the treatment effects of PEMF for participants with AT. All participants will be randomised into two groups: the intervention group ( | PMC10258964 |
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Methods: participants, interventions, and outcomes | PMC10258964 |
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Study setting {9} | This study will be conducted at the Prince of Wales Hospital in Hong Kong which is the teaching hospital of the Chinese University of Hong Kong. The assessment and intervention will be conducted at the Prince of Wales Hospital Sports Performance and Biomechanics Laboratory. | PMC10258964 |
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Eligibility criteria {10} | cognitive impairment, Achilles’ tendons, psychiatric, tenderness, hemiplegia, major injury, Fractures | ANKLE ARTHRITIS, DISORDERS | Participants will be recruited based on the inclusion and exclusion criteria (Table Inclusion and exclusion criteria (1) Age between 18 and 70 (2) Focal clinical signs of AT with localised tenderness on palpation of the Achilles tendon (3) Recurrent complaints in 1 or both Achilles’ tendons at rest and during exercise for the preceding 3 months (4) Structural changes of the tendon were confirmed via sonographic examination during the initial physical exam (5) Informed consent (1) History of major injury or surgery on the affected lower limb in the past year (2) Mental/physical limitations hindering participant’s ability to complete assessments including severe cognitive impairment and psychiatric disorders (3) With medical or musculoskeletal problems that could affect the ability to complete assessments and intervention (i.e. pre-existing ankle arthritis, hemiplegia, etc.) (4) With active electronic implants like pacemakers and defibrillators (5) Fractures of the trained body parts within the past 12 monthsAll of the researchers will obtain written consent from all participants before the commencement of this study. All eligible participants will be informed about this study and given the time they need to consider participation. The investigators of this study will answer all questions from the participants. Participants who are willing to participate should sign an informed consent form. The trial will be conducted in compliance with the Declaration of Helsinki and ICH-GCP. Clinical research ethics approval is obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Reference number: 2021.150). | PMC10258964 |
Additional consent provisions for collection and use of participant data and biological specimens {26b} | The written consent form consists of the consent provisions for collecting and using participant data. The researcher will keep the information collected for a maximum of 5 years after publication results in PhD thesis and scientific papers. The data collected will be published to the public and in peer-reviewed scientific papers anonymously. This study will not require the use of biological specimens. | PMC10258964 |
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Interventions | knee in flexion), pain | HEAT, RECRUITMENT | The intervention will be held at the Prince of Wales Hospital in Hong Kong. Participants in the intervention group will be exposed to PEMF treatment by a PEMF device (Quantum Tx, Singapore). The active PEMF does not produce heat or cause any sensation to the tissue, which allows the participants to be blinded to the treatment. Participants in the control group will receive a sham exposure with the same PEMF device. The diseased leg will be exposed to active or sham therapy for 10 min per session, and the treatment regime will run twice a week for 8 weeks, summing up 16 sessions of PEMF or sham exposure in total. The PhD candidate will be responsible to operate the PEMF machine and monitor the clinical condition of the participants. The PEMF supplier provides RFID cards generated using block randomisation to assign PEMF or sham treatment. Each participant will be allocated a unique RFID card recognisable by the PEMF machine. The PhD candidate will turn on the PEMF machine for all participants with the RFID cards. A biostatistician who does not participate in the recruitment of patients will oversee the randomisation. Hence, both participants and the research personnel are blinded, and participants will use the RFID to complete the assigned treatment without knowing which treatment they are receiving. Most participants do not report any perceivable sensations during PEMF treatment but a few participants report mild tingling or warm sensation.The procedure of PEMF treatment is shown as follows: The subject will be seated at a 90 degrees position on a chair. The solenoids of the PEMF device will be adjusted to be over the foot and ankle (Achilles tendon and lower calf muscle). The appliance options will be adjusted to 1 mT, 10 kHz on the diseased leg for 10 min. Sham pulsed electromagnetic field therapy and eccentric exercise will be used for the treatment in the sham group. The same PEMF device and the same set of eccentric exercise will be used for the control and experimental groups. Participants will not have perceivable sensations during active or sham PEMF treatment. Therefore, assessors and participants will be blinded to the PEMF applied. In addition to PEMF, all participants will perform eccentric exercise. The first step is stretching exercises for the calf muscles. The stretching is a static stretch of the gastrocnemius (knee in extension) and soleus (knee in flexion). The participants are instructed to hold these for at least 30 s and repeat each exercise three times. There will be a 1-min rest between each stretch. Three sets of 10 repetitions of the eccentric exercises will be carried out once daily for 6 weeks. After 6 weeks, the participants will be instructed to carry out three sets of 10 repetitions three times per week for 6 more weeks. The intensity of the exercise should be such that pain, or discomfort, is experienced in the last set of 10 repetitions. Every session ended with the same static stretch exercise as in step 1. Suppose a participant is unable to complete three sets of 15 repetitions. In that case, the participant is instructed to start with fewer repetitions and sets (a minimum of 2 groups of 10) and progress to the total amount as able [ | PMC10258964 |
Criteria for discontinuing or modifying allocated interventions {11b} | pain | ADVERSE EFFECTS | The treatment will be stopped, and immediate care will be provided if any significant adverse effects happen during the treatment period, including a substantial increase in the severity of pain or discomfort. | PMC10258964 |
Strategies to improve adherence to interventions {11c} | Participants may choose the time of sessions that suits them the most during working days. The opening hours of the Sports Performance and Biomechanics Laboratory will be extended to cover the evening hours so that participants may come for assessment after work. A record of compliance to eccentric exercise will be made when they come for PEMF treatment. | PMC10258964 |
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Relevant concomitant care permitted or prohibited during the trial {11d} | There are no restrictions on relevant concomitant care. Participants are allowed to continue with their usual care. | PMC10258964 |
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Provisions for post-trial care {30} | Participants may have access to the research clinic at the Prince of Wales Hospital if they suffer from orthopaedic conditions after the trial. | PMC10258964 |
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Outcomes {12} | PMC10258964 |
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Patient-reported outcomes | pain | ACHILLES TENDINOPATHY | The primary outcome is the score of the Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire, which is explicitly designed for Achilles tendinopathy. VISA-A will be used to evaluate pain and symptom severity with activity in participants with AT. Chinese-speaking participants will complete the validated VISA-A HK questionnaire [Short Form-36 questionnaires (SF-36) will be used to evaluate health-related quality of life [ | PMC10258964 |
Functional outcomes | PMC10258964 |
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Ankle range of motion | Weight-bearing lunge test will be used to measure ankle dorsiflexion’s range of motion (ROM). It will be used as an indicator of the flexibility of the gastrocnemius muscle. The participant will maximally dorsiflex the ankle while keeping the knee extended and the heel on the floor [ | PMC10258964 |
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Calf muscle strength | The heel-rise test will be used to measure calf muscle strength. The participant will stand on a pressure mat (Tekscan, USA). The information on the plantar pressure will be collected for analysis [ | PMC10258964 |
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Ultrasonographic outcomes | The ultrasonographic outcomes are measured by a PhD candidate with 2 years of experience performing ultrasound measurements of the Achilles tendon. A standardised imaging procedure is used to ensure repeatability. Ultrasound examinations for this study will be performed during baseline assessment and all follow‐up visits after inclusion in the RCT. No specific instructions will be provided about activities before the consultation. The participants will be placed in a prone position on the examination table, and the ankle will be placed over the table in a relaxed position. All ultrasounds will be bilateral according to a standardised protocol using the Aixplorer machine (SuperSonic Imagine, Aix-En-Provence, France) equipped with a 12-MHz superficial linear transducer. Participants will be placed in a prone position with their legs extended. The examination will start with grayscale B mode, power Doppler ultrasound, and end with shear wave elastography. | PMC10258964 |
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Tendon thickness | All parameters are measured on the left side of the Achilles tendon and then the right side of the Achilles tendon. Greyscale ultrasound is used initially to identify the Achilles tendon. Longitudinal scans are performed medially and laterally across the Achilles tendon until the scan plane shows the Achilles tendon clearly, and maximum tendon thickness is obtained. To minimise the anisotropic effect, the transducer is adjusted so that the ultrasound beam is perpendicular to the tendon fibres. A greyscale sonographic image is taken of the Achilles tendon. Tendon thickness is measured with grayscale and axial ultrasound at the region of interest [ | PMC10258964 |
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Neovascularity | peritendinous, transducer | NEOVASCULARIZATION | The transducer is placed perpendicular to obtain a sagittal view of the Achilles tendon at the most painful part on palpation. The upper limit of the colour box is set on the dorsal side of the tendon. Pressure from the transducer is kept to a minimum to prevent the occlusion of neovascularization. The assessor screens the tendon for the area of maximum Doppler flow during the preparation phase for 1 min. The transducer is gently moved to medial and lateral over where Doppler flow is present. When the location of the maximum Doppler flow is identified, a sonographic image is taken. The modified Öhberg score from 0 to 4 + is determined during the US examination. In this scoring system, scores are determined as 0 (no vessels), 1 + (1 vessel, primarily anterior to the tendon), 2 + (1 or 2 vessels throughout the tendon), 3 + (3 vessels throughout the tendon), or 4 + (more than three vessels throughout the tendon). A higher score indicates more Doppler flow in the peritendinous and intratendinous tissues [ | PMC10258964 |
Tendon elasticity | tendon stiffness, tendinopathy | Shear wave elastography (SWE) quantifies soft tissue stiffness and provides an absolute value of tendon stiffness [The ultrasound normalisation procedure for subjects with bilateral tendinopathy will be done by using the mean values measured in healthy individuals as stated in current evidence. The mean value of a healthy Achilles tendon was reported to be 5.3 mm [ | PMC10258964 |
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Sample size {14} | A minimum clinically significant difference is 16 points on the VISA-A scores based on the pilot study using VISA-A as the primary outcome in treating AT [ | PMC10258964 |
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Recruitment {15} | Achilles tendinopathy, Sports Injury | ACHILLES TENDINOPATHY, RECRUITMENT | Participants will be recruited from the Department of Orthopaedics and Traumatology at the Prince of Wales Hospital in Hong Kong. The orthopaedic surgeons will explain the details of the trial based on the eligibility criteria. They will screen all patients with Achilles tendinopathy coming for consultation in the outpatient department at the Prince of Wales Hospital. In addition, the information of the study will be sent to the coaches of the sports teams at CUHK. Recruitment information for the trial will also be sent through the internal mass mail system at CUHK. Individuals will come for eligibility assessment at the Sports Injury and Biomechanics Laboratory if they are interested to join the trial. | PMC10258964 |
Assignment of interventions: allocation | PMC10258964 |
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Sequence generation {16a} | The randomisation is performed using an online research randomiser ( | PMC10258964 |
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Concealment mechanism {16b} | The randomisation is performed using an online research randomiser by the chief engineer at Quantum TX. He will only share the randomisation results with the biostatistician at the Chinese University of Hong Kong. It will not be disclosed to the participants and assessors of this trial before the end of the treatment period. The participants will be assigned a unique RFID by which the PEMF or sham treatment will be randomly assigned to the RFID. Participants and assessors are blinded as participants will use the RFID to complete the treatment without knowing the treatment they receive. | PMC10258964 |
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Implementation {16c} | The chief engineer from Quantum TX performs the randomisation. The randomisation result is shared with the biostatistician at the Chinese University of Hong Kong. The orthopaedic surgeon and PhD candidate from CUHK recruit participants. The PhD candidate will complete the assessment and assigns participants to interventions. The randomisation results will only be disclosed to the orthopaedic surgeon and PhD candidate after the participants complete all PEMF sessions. | PMC10258964 |
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Assignment of interventions: blinding | PMC10258964 |
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Who will be blinded? {17a} | HEAT | Assessors and participants will be blinded to the interventions. Participants will be blinded to the PEMF given to them as active and sham PEMF will not produce heat or other perceivable sensations. The engineer performs the randomisation from Quantum TX, and it will not be disclosed to the assessors before the end of the PEMF treatment period. | PMC10258964 |
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Procedure for unblinding if needed {17b} | ADVERSE EVENT | There will be unblinding of the participants and assessors if a severe adverse event occurs. The adverse event will be reported to the Joint Clinical Research Ethics Committee of the Chinese University of Hong Kong and the New Territories East Cluster of the Hospital Authority. | PMC10258964 |
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Data collection and management | PMC10258964 |
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Plans for assessment and collection of outcomes {18a} | RECRUITMENT | The collection of demographic data will be done during screening and before recruitment. Participants that fulfil all the inclusion criteria will be randomised into PEMF or sham groups. Follow-up assessments with various outcome parameters will be conducted with data processing details as shown in the section “Outcomes {12}”. | PMC10258964 |
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Plans to promote participant retention and complete follow-up {18b} | Participants will choose the time for each PEMF session during the week. The working hours will be extended to the evenings so that participants may come for assessment and treatment after work. | PMC10258964 |
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Data management {19} | All data collected will be entered into the online database in Excel files and SPSS files. All data will be kept in password-protected computers and destroyed 5 years after publication in PhD thesis and peer-reviewed journals. The PhD candidate will be responsible for data collection, data entry, and data analysis. She will enter the data into the database for screening and randomisation purposes. After data collection, she will enter all data into Excel files and then input them into SPSS files for data analysis. Double data entry and range checks for data values will be used to promote data quality. | PMC10258964 |
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Confidentiality {27} | All personal information and consent forms will be stored in locked cabinets at the Sports Performance and Biomechanics Laboratory. The online electronic database with personal information will be kept on password-protected computers. All data collected will be kept strictly confidential and only accessed by members of the trial team. Participants will not have the right to access the data set. There is no plan to share the data collected with other organisations. | PMC10258964 |
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Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} | Not applicable. This study will not require the use of biological specimens. | PMC10258964 |
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Statistical methods | PMC10258964 |
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Statistical methods for primary and secondary outcomes {20a} | Statistical analysis will be performed using SPSS software (SPSS 26.0) based on the intention-to-treat principle. The normality of the data will be tested using the Kolmogorov–Smirnov test. A repeated-measures two-way analysis of variance (ANOVA) will be used to compare muscle strength, ankle range of motion, and results of questionnaires at baseline, 4 weeks, 8 weeks, and 3-, and 6-month follow-up. A nonparametric Mann–Whitney | PMC10258964 |
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Interim analyses {21b} | ADVERSE EVENT | An interim analysis will be performed on the primary endpoint when 20% of participants have completed the eight weeks of PEMF. The interim analysis ensures that there is no serious adverse event that happened during the study period. | PMC10258964 |
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Methods for additional analyses (e.g. subgroup analyses) {20b} | midportion tendinopathy, tendinopathy | ACHILLES TENDINOPATHY | The heterogeneity in tendinopathy will be addressed by sub-group analysis. AT will be categorised into midportion and insertional tendinopathy. The assessor will make the diagnosis of the type of Achilles tendinopathy. Midportion AT will be diagnosed by local thickening and a colour doppler flow of at least two out of four in the modified Öhberg score 2–6 cm proximal to the insertion of the Achilles tendon. Insertional AT will be diagnosed by local thickening and colour Doppler flow of at least grade two of four in the modified Öhberg score within 2 cm of the insertion of the Achilles tendon. Sub-group analysis will be performed to understand if PEMF has clinical effects on all outcome measures in the midportion tendinopathy and insertional tendinopathy, respectively, since the number of participants will be smaller in the subgroups. A non-parametric test, the Mann–Whitney | PMC10258964 |
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} | The intention-to-treat analysis will be used to include all study participants in the groups to which they are randomised, regardless of any departures from the original assigned group. The missing values will be estimated by multiple imputations with the assumption that values are missing at random. | PMC10258964 |
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Plans to give access to the full protocol, participant-level data, and statistical code {31c} | The protocol has been shown on ClinicalTrials.gov (ID: NCT05316961). The participant-level data and statistical code can be provided upon request. | PMC10258964 |
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Oversight and monitoring | PMC10258964 |
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Composition of the coordinating centre and trial steering committee {5d} | RECRUITMENT | The principal investigator will monitor the progress of the study. The trial steering committee are research team members who will participate in participant recruitment, data collection, and management. | PMC10258964 |
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Composition of the data monitoring committee, its role, and reporting structure {21a} | MUSCULOSKELETAL DISORDERS | The trial steering committee consists of orthopaedic surgeons, a physiotherapist, and a biostatistician. The orthopaedic surgeons and physiotherapists will participate in data collection and analysis. The biostatistician will monitor data collection and perform interim analysis. There is no independent data monitoring committee as this is not required by the ethics committee. This is a low-risk study as PEMF was implemented as a conventional conservative treatment for patients with other musculoskeletal disorders. | PMC10258964 |
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Adverse events reporting and harms {22} | adverse reaction | ADVERSE EFFECTS, EVENT, ADVERSE REACTION | The PhD candidate will have thorough training on the operation of the machine, familiarise herself with the troubleshooting scheme, and closely monitor adverse effects during PEMF. In the event of a severe adverse reaction to the PEMF, it will be reported to the trial steering committee immediately. The participant will be removed from the trial and referred to the outpatient clinic at the Prince of Wales Hospital.An independent auditor from the ethics committee will conduct the trial conduct annually. The trial steering group meet weekly to report research progress to the principal investigator. The principal investigator will complete a standardised progress report form for the ethics committee to review conduct annually during the trial period. | PMC10258964 |
Plans for communicating necessary protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} | The investigators will apply for protocol amendments to the ethics committee and should be approved by the ethics committee before implementation. Trial participants will be informed about the amendments to the protocol. The protocol changes will be published in the Trial Register. | PMC10258964 |
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Dissemination plans {31a} | EVENT | The early findings of the research will be presented at the Hong Kong Orthopaedic Association annual congress, the flagship event attended by all local orthopaedic surgeons. Final results will be presented at regional sports medicine conferences such as the Asia–Pacific Knee Arthroscopy and Sports Medicine (APKASS) Congress and published in a scientific peer-review journal. The funder does not pose any restrictions on the decision of publication. | PMC10258964 |
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Discussion | swelling, inflammation, tendon stiffness, pain, chronic tendon pain, tendinopathy | NEOVASCULARITY, INFLAMMATION, DEGENERATIVE, CLINICAL SYNDROME, PATHOGENESIS | AT is a clinical syndrome characterised by pain, swelling, and functional impairment, indicating a degenerative inflammatory process in the Achilles tendon. The overall incidence rate of AT was 2.45 per 1000 in the adult population between 21 and 60 years in their lifetime. It can affect athletes and non-athletes. Patients with AT commonly refer to persistent pain that may result in loss of function and activity cessation. The pathogenesis of tendinopathy can be described as failed healing of the diseased tendon. Failed recovery mainly refers to prolonged inflammation and failed resolution of the normal healing process. Furthermore, increased focal vascularity contributes to the clinical presentations of chronic tendon pain, stiffness, and weakness.An increase in tendon thickness is often found in patients with AT. It could happen in either midportion or insertion of the Achilles tendon, which is caused by swelling of the affected area. Moreover, the ingrowth of new blood vessels into tendinopathic regions is often seen in ultrasound imaging. PEMF may reduce tendon inflammation, thus reducing tendon thickness and neovascularity. Tendon elasticity is measured by shear wave elastography (SWE). SWE could quantify soft tissue stiffness and provide an absolute value of the stiffness of the soft tissue. There may be an increase in tendon stiffness in patients with AT. This is because patients may reduce the level of activities because of pain associated with AT. PEMF may minimise tendon pain and facilitate the performance of the eccentric exercise. Thus, there may be a reduction in tendon elasticity.This trial may demonstrate the effectiveness of PEMF in relieving pain, improving function, and restoring mechanical changes of the tendon in patients with AT. AT is a common clinical condition affecting both athletes and sedentary populations. Exercise prescription is used as a non-invasive therapy for patients with AT. However, some participants do not respond well to exercise therapy and conventional treatments. It is essential to investigate treatment adjuncts to improve rehabilitation outcomes for this group of patients. | PMC10258964 |
Trial status | RECRUITMENT | Enrolment in the study started on 1 July 2021. Recruitment is expected to be completed by the end of September 2023. | PMC10258964 |
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Acknowledgements | Not applicable. | PMC10258964 |
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Author contributions {31b} | VMCK, XH, SCF, PSHY, and SKKL participate in study design, data collection, and management. VMCK and SKKL wrote this manuscript. All authors read and approved this manuscript before publication. | PMC10258964 |
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Funding {4} | This trial is fully funded by the Health and Medical Research Fund (HMRF), Food and Health Bureau of the government of HKSAR (Ref: 10210186). The study funder does not take on the legal responsibility and management of the research study. It only provides financial support to this research study. | PMC10258964 |
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Availability of data and materials {29} | All investigators will have access to the final trial dataset upon request. Any data required to support the protocol can be supplied on request. | PMC10258964 |
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Declarations | PMC10258964 |
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Ethics approval and consent to participate {24} | Clinical research ethics approval is obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Reference number: 2021.150). Written, informed consent to participate will be obtained from all participants. | PMC10258964 |
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Consent for publication {32} | Not applicable. This manuscript does not include details, images, or videos relating to a person. A model consent form will be provided on request. | PMC10258964 |
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Competing interests {28} | The authors declare that they have no competing interests. | PMC10258964 |
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