Introduction
Methodology
PICO component | Details |
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Participant (P) | Hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD) (or previous diagnoses of EDS-HT or JHS) |
Intervention (I) | Conservative management |
Comparison (C) | No intervention, ‘usual care’ or another intervention (randomised controlled trials); or before-after treatment comparison (cohort studies) |
Outcome (O) | Pain, physical function, psychological well-being and quality of life |
Search number | Search terms |
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Search 1 | hypermobil* OR Ehlers-Danlos type III OR Ehlers-Danlos type 3 |
Search 2 | treatment OR management OR intervention OR therapy |
Inclusion | Exclusion |
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hEDS, HSD, EDS-HT, JHS. | |
Beighton score in isolation. | |
Adults and children. | |
Conservative management. | Pharmacological or surgical interventions. |
Quantitative assessment of pain, physical function, psychological wellbeing or quality of life. | |
RCTs and cohort studies, including feasibility, pilot and preliminary studies. | |
Peer-reviewed academic journal articles. | |
Articles published from 1998 onwards as the international Villefranche (EDS) and Brighton (JHS) criteria were published from 1998. | |
English language. |
Results
Authors Country; setting | Study design | Participants (% female) | Age, years (mean ± SD unless otherwise stated) | Sample size (n recruited, n completed, sample size calculation) | Diagnostic criteria |
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Bale et al. (2019) [27]. UK; paediatric rheumatology clinic. | Randomised controlled trial. | Children aged 5–16 years (55% girls). | Intervention: 9.47 ± 3.18, standard care: 9.35 ± 3.20. | n = 119 recruited (intervention: n = 59, standard care: n = 60). n = 105 completed (intervention n = 54, standard care n = 51) (12% attrition). Prospective sample size calculation n = 100 (n = 50 per arm). | Beighton score ≥ 4 or Bulbena score ≥ 5 (males) or ≥ 6 (females). Plus musculoskeletal pain in ≥ 1 body area for ≥ 3 months. |
Bathen et al. (2013) [28]. Norway; rehabilitation hospital. | Pilot cohort study. | Adults (100% women). | Median, range = 35, 20–51. | n = 12 recruited. n = 12 completed (0% attrition). No prospective sample size calculation (pilot study). | Villefranche criteria (EDS-HT) or Brighton criteria (JHS). |
Celenay & Kaya (2017) [29]. Turkey; university physiotherapy and rehabilitation department. | Randomised controlled trial. | Adults aged 18–30 years (100% women). | Exercise: 20.3 ± 2.2, Control: 21.0 ± 2.2. | n = 46 recruited (exercise n = 23, control n = 23). n = 38 completed (exercise n = 20, control n = 18) (17% attrition). Prospective sample size calculation n = 42 (n = 21 per arm). | Brighton criteria (JHS). |
Daman et al. (2019) [30]. Iran; physiotherapy, orthopaedic knee and rheumatology clinics. | Randomised controlled trial. | Adults aged 18–30 years (100% women). | Exercise: 22.25 ± 1.28, Control: 21.66 ± 1.96. | n = 24 recruited (exercise n = 12, control n = 12). n completed not explicitly reported (% attrition unable to assess). Prospective sample size calculation n = 24. | Brighton criteria (JHS). |
Ferrell et al. (2004) [31]. UK; hypermobility clinic. | Cohort study. | Adults (89% women). | Mean, range = 27.3, 16–49. | n = 20 recruited. n = 18 completed (10% attrition). No prospective sample size calculation. | Brighton criteria (JHS) plus knee pain. |
Kemp et al. (2010) [32]. UK; children’s rheumatology department. | Randomised controlled trial. | Children aged 7–16 years (33% girls). | Targeted physiotherapy: 11.0 ± 2.5, generalised physiotherapy: 10.7 ± 2.5. | n = 57 recruited (targeted n = 30, generalised n = 27). n = 32 completed (targeted n = 17, generalised n = 15) (44% attrition). Prospective sample size calculation n = 96 (n = 48 per arm). | Brighton criteria (JHS) plus arthralgia for > 3 months. |
Pacey et al. (2013) [33]. Australia; children’s hospital clinics. | Randomised controlled trial. | Children aged 7–16 years (66% girls). | Training in hypermobile range (‘hypermobile’): 13.48 ± 3.05, training to neutral (‘neutral’) 11.02 ± 2.51 (p = 0.04). | n = 29 recruited. n = 26 randomised (hypermobile n = 12, neutral n = 14) n = 25 completed (hypermobile n = 11, neutral n = 14) (4% attrition). Prospective sample size calculation n = 26 (n = 13 per arm). | Knee pain, Beighton score ≥ 5, > 10° knee hyperextension. Brighton criteria (JHS). |
Palmer et al. (2016) [34]. UK; two rheumatology physiotherapy services. | Pilot randomised controlled trial. | Adults aged ≥ 16 years (90% women). | Advice and physiotherapy: 37.2 ± 14.13, advice: 33.3 ± 9.71 years. | n = 29 recruited (advice and physiotherapy n = 15, advice n = 14). n = 19 completed (advice and physiotherapy n = 11, advice n = 8) (34% attrition). No prospective sample size calculation (pilot study). | Brighton criteria (JHS). |
Reychler et al. (2019) [35]. Belgium; rheumatology outpatient ward. | Randomised controlled trial. | Adults (100% women). | Intervention: 45.8 ± 5.5, control: 53.1 ± 3.4 (p = 0.011). | n = 20 recruited (intervention n = 10, control n = 10). n = 19 completed (intervention n = 9, control n = 10) (5% attrition). Prospective sample size calculation n = 20 (n = 10 per arm). | Villefranche criteria (EDS-HT) and Brighton criteria (JHS). Reviewed against 2017 criteria to confirm hEDS diagnosis. |
Sahin et al. (2008) [36]. Turkey; physical medicine and rehabilitation department outpatient clinic. | Randomised controlled trial. | Adults aged 20–45 years (85% women). No prospective sample size calculation. n = 40 recruited | Exercise: 25.60 ± 5.98, control: 27.68 ± 7.77. | n = 40 recruited (exercise n = 15, control n = 25). n = 40 completed (exercise n = 15, control n = 25) (0% attrition). No prospective sample size calculation. | Brighton criteria (JHS) plus knee pain. |
To & Alexander (2018) [37]. UK; patient support groups and hospital group; and university, local sports centres, and clubs. | Cohort study. | Adults aged 18–55 years (84% women). | JHS: 34.6 ± 10.6, GJH: 31.8 ± 10.5, Control: 38.2 ± 9.3. | n = 102 recruited (JHS n = 47, GJH n = 29, control n = 26). n = 72 completed (JHS n = 31, GJH n = 20, control n = 21) (29% attrition). Prospective sample size calculation n = 60 (n = 20 per arm). | Brighton criteria with anterior knee pain (JHS group). Beighton score ≥ 4 with anterior knee pain (GJH group). Beighton score ≤ 3 with anterior knee pain (control group). |
Authors | Study design | Intervention details | Outcome measures | Main statistical findings | Authors’ conclusion |
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Bale et al. (2019) [27]. | Randomised controlled trial. | Duration: 8 weeks. Intervention: individual multidisciplinary programme of 3 individualised PT sessions, OT/PT school visit, OT home assessment, equipment provision. Standard care: single paediatric rheumatology appointment, verbal advice, referral to PT/OT if required. | Follow-up time points: 3 months and 12 months following baseline. Child-reported pain: Wong-Baker faces pain scale. Parent-reported pain: VAS. Parent-reported physical function: CHAQ. Child-reported QoL: Child Health Utility. Motor skills and coordination: Movement Assessment Battery for Children. Grip strength: hand-held dynamometer. | Effect of group: No significant differences between groups at 3 months or 12 months for any outcome (all p > 0.05). Effect of time: significant improvements from baseline to 12 months in child-reported pain; parent-reported pain; motor skills and coordination; and grip strength (data from both groups combined) (all p < 0.05). No significant changes from baseline to 12 months in parent-reported physical function or child-reported QoL (data from both groups combined) (both p > 0.05). | “We conclude that… standard care… is sufficient to lead to a sustained improvement in symptoms over a twelve-month period and that a more intensive multidisciplinary approach offers little further benefit.” |
Bathen et al. (2013) [28]. | Pilot cohort study. | Duration: 15 weeks. Intervention: underpinned by a cognitive behavioural approach. In-patient programme (2.5-week duration) included testing, physical training, group discussions and lectures. Home exercise (3-month duration) focused on strength and endurance, core stability, body awareness, posture and physical endurance, facilitated weekly by local PT. Readmission (4 days duration) for retesting and further training advice. | Follow-up time point: 15 weeks. Daily activity limitations: COPM (activity performance and performance satisfaction). Muscle strength and endurance: tandem walking backwards, stair walking up and down, and stepping up on toes. Kinesiophobia: Tampa Scale of Kinesiophobia-13. Pain intensity over last 7 days: Numerical Pain Rating Scale. | Effect of group: N/A. Effect of time: significant improvements from baseline to 15 weeks in activity performance; performance satisfaction; tandem walking backwards; stair walking up; up on toes; and kinesiophobia (all p < 0.05). No significant improvements from baseline to 15 weeks in stair walking down or pain intensity (both p > 0.05). | “…an intensive multidisciplinary rehabilitation program with a cognitive behavioural approach, including intensive muscle strength and –endurance training and pain coping might be feasible and safe for adults with EDS-HT/JHS.” |
Celenay & Kaya (2017) [29]. | Randomised controlled trial. | Duration: 8 weeks. Intervention: 40–45-min group exercise programme (10 min warm-up, 25 min spinal stabilisation exercises, 5–10-min cool-down and stretching). 3 days per week for 8 weeks. Supervised by an experienced physiotherapist. Maximum 5–6 participants per group. Control: no intervention. | Follow-up time point: 8 weeks. Pain intensity: VAS. Trunk endurance: McGill’s trunk muscle endurance tests (× 4 parameters). Postural stability: Biodex Balance System (× 4 parameters). | Effect of group: Significant difference between groups (in favour of intervention) for pain intensity (p = 0.022); all 4 trunk endurance tests (all p < 0.05); and 1 of the postural stability tests (dynamic mode eyes open, p = 0.036). No significant difference between groups in the other 3 postural stability tests (all p > 0.05). Effect of time: Significant improvements in the intervention group from baseline to 8 weeks in pain intensity (p = 0.001); all 4 trunk endurance tests (all p < 0.05); and 2 of 4 postural stability tests (static mode eyes closed, p = 0.028; dynamic mode eyes closed, p = 0.008). No significant improvements in the intervention group from baseline to 8 weeks in the other 2 postural stability tests (both p > 0.05). No significant improvements in the control group from baseline to 8 weeks for any outcome. | “This exercise program can be used for general pain relief, trunk muscle endurance weakness, and postural impairment in women with BJHS.” |
Daman et al. (2019) [30]. | Randomised controlled trial. | Duration: 4 weeks. Intervention: combined exercise therapy. Closed kinetic chain and proprioception exercises with progression. 3 days per week for 4 weeks. Supervised by an expert physiotherapist. Control: no intervention. | Follow-up time point: 4 weeks. Pain intensity: VAS. QoL: SF-36 (physical functioning and mental health). Knee joint position sense: angle error using goniometry (weight-bearing and non-weight-bearing). | Effect of group: Significant difference between groups at 4 weeks (in favour of intervention) for joint position sense in weight-bearing (p = 0.03) and non-weight-bearing (p = 0.009); pain intensity (p < 0.001); and physical functioning (p = 0.01). No significant difference between groups at 4 weeks for mental health (p = 0.42). Effect of time: Significant improvements in the intervention group from baseline to 4 weeks in joint position sense in weight-bearing (p = 0.005) and non-weight-bearing (p = 0.01); pain intensity (p = 0.001); and physical functioning (p = 0.01). No significant improvement in the intervention group from baseline to 4 weeks in mental health (p > 0.05). No significant improvements from baseline to 4 weeks in the control group for any outcome (p > 0.05). | “…combined exercise therapy reduced pain intensity, and improved joint proprioception and quality of life immediately after the intervention.” |
Ferrell et al. (2004) [31]. | Cohort study. | Duration: 8 weeks. Intervention: home exercise programme with progressive, closed kinetic chain exercises for knee proprioception, balance and strength. 4 days per week for 8 weeks. | Follow-up time point: 8 weeks. Knee joint proprioception: threshold detection paradigm. Balance: instrumented balance board. Muscle strength: Kin-Com isokinetic dynamometer. Pain intensity: VAS. QoL: SF-36 (physical functioning and mental health). | Effect of group: N/A. Effect of time: Significant improvements from baseline to 8 weeks in all outcomes (all p < 0.05). | “Appropriate exercises lead not only to symptomatic improvement, but also to demonstrable enhancement of objective parameters such as proprioception.” |
Kemp et al. (2010) [32]. | Randomised controlled trial. | Duration: 6 weeks. Targeted physiotherapy: standardised exercises of symptomatic joints aimed at addressing functional stability. Generalised physiotherapy: standardised general exercises aimed at maximising muscle strengthening and fitness. Both interventions involved 6 individual 30-min weekly sessions provided by a senior physiotherapist. Both groups also received home exercises to be done on a daily basis. | Follow-up time points: Approximately 2 months and 5 months following randomisation. Pain intensity (child-reported): faces scale < 11 years and VAS ≥ 11 years. Pain intensity (parent-reported): VAS. Global evaluation of impact (parent-reported): VAS. Functional impairment: CHAQ. General physical condition: 6-min shuttle test. | Effect of group: no significant differences between groups at 2 months in any outcome (all p > 0.05). Significant difference between groups at 5 months (in favour of targeted physiotherapy) for parental global assessment (p = 0.027). No significant differences between groups at 5 months in any other outcome (all p > 0.05). Effect of time: significant improvements from baseline to 2 months in child-reported pain (p < 0.001); parent-reported pain (p < 0.001); parental global assessment (p = 0.005); and CHAQ (p = 0.024) (data from both groups combined). No improvement from baseline to 2 months in shuttle test (p = 0.42) (data from both groups combined). Significant improvements from baseline to 5 months in child-reported pain (p < 0.001); parent-reported pain (p < 0.001); and CHAQ (p = 0.035) (data from both groups combined). No improvement from baseline to 5 months in parental global assessment (p = 0.13) (data from both groups combined). Shuttle test not assessed at 5 months. | “…significant and sustained reduction in pain when both groups were combined, but did not detect any difference between the groups.” |
Pacey et al. (2013) [33]. | Randomised controlled trial. | Duration: 8 weeks. Both groups received the same knee exercises with the only difference being the range in which the exercises were carried out (hypermobile into full knee hyperextension, Neutral to neutral knee extension only). Exercises included quadriceps and hamstring isometric exercises; theraband resisted and joint exercises in standing; eccentric hamstring strengthening; and gluteus medius and hip abductor strengthening. Exercises were progressed by increasing repetitions, resistance and complexity. 6 physiotherapy sessions over 8 weeks (weekly for 4 weeks and fortnightly for 4 weeks). Each session lasted 30–60 min, provided by an experienced paediatric physiotherapist. Both groups also received home exercises to be performed 5 times per week. | Follow-up time point: 8 weeks. Average and maximum knee pain over the last week (child-reported): VAS. Global impression of change (child-reported): PGIC. Functional ability (child-reported): CHAQ. QoL (parent-reported): CHQ (physical and psychosocial summary scores). Thigh muscle strength: hand-held dynamometer. Stair ascent/descent for 2 min: number of flights completed. | Effect of group: No significant differences between groups at 8 weeks in any child-reported or physical outcome measure (all p > 0.05). Significant difference between groups at 8 weeks (in favour of Neutral) for parent-reported physical CHQ (p = 0.037); and (in favour of Hypermobile) for parent-reported psychosocial CHQ (p = 0.009). Effect of time: Significant improvements from baseline to 8 weeks in average and maximum child-reported pain (p = 0.004 and 0.003); PGIC (p < 0.001); thigh strength (p = 0.004); and parent-reported physical and psychosocial CHQ (p = 0.002 and 0.03) (data from both groups combined). No improvements from baseline to 8 weeks in CHAQ (p = 0.433) or stair ascent/descent (p = 0.11) (data from both groups combined). | “… a physiotherapist-supervised exercise programme is significantly effective in reducing pain, improving health-related quality of life, and increasing muscle strength in children with JHS and knee pain.” |
Palmer et al. (2016) [34]. | Pilot randomised controlled trial. | Duration: 4 months. Advice: tailored information and advice on self-management, including patient organisation booklets. Advice was a one-off session delivered by a trained therapist. Advice and physiotherapy: Advice as above plus comprehensive whole-body physiotherapy intervention. Physiotherapy delivered by a trained therapist via 6 × 30-min sessions across 4 months. | Follow-up time points: 4 months and 7 months following baseline. Impact: BIoH questionnaire. Pain: VAS. Disease activity: MDHAQ (including RAPID3). QoL: EQ-5D-5L. Adverse events. Qualitative interviews with therapists and people with JHS. | Effect of group: no statistical analysis (pilot study). Effect of time: no statistical analysis (pilot study). Mean improvements in both groups from baseline to 4 months in BIoH scores. Continued improvement from 4 months to 7 months in the Advice & Physiotherapy group in BIoH score, whilst the Advice group reverted to baseline. Results support the feasibility of a RCT. | “A comprehensive physiotherapy intervention package was developed which was generally very well received by both patients and physiotherapists, and shows evidence of promise in improving the impact of JHS.” |
Reychler et al. (2019) [35]. | Randomised controlled trial. | Duration: 6 weeks. Intervention: inspiration exercises using a pressure threshold IMT device. 5 unsupervised sessions per week for 6 weeks. Each session included 6 × 10 repetitions. Progressive increase in resistance from 60% to 85% of initial maximal SNIP. Control: not explicitly reported. | Follow-up time point: 7 weeks. Inspiratory muscle strength: maximal SNIP using pressure meter. Cardiopulmonary function: FVC and FEV1. Functional exercise capacity: 6MWD. [Sp02, dyspnoea (VAS) and heart rate assessed before and after 6MWD]. Anxiety & depression: HADS. Physical activity: Baecke questionnaire. | Effect of group: Significant difference between groups at 7 weeks (in favour of intervention) for SNIP (p < 0.001), FEV1 (p = 0.009) and 6MWD (p = 0.003). No significant differences between groups at 7 weeks in any other outcome measure (all p > 0.05). Effect of time: Significant improvements in the intervention group from baseline to 7 weeks in SNIP (p = 0.003), FEV1 (p = 0.010) and 6MWD (p = 0.036). Significant increase in the intervention group from baseline to 7 weeks in pre- to post-6MWD heart rate variation (p = 0.029). Significant decrease in the control group from baseline to 7 weeks in FVC (p = 0.047). No significant changes in either group from baseline to 7 weeks for any other outcome (all p > 0.05). | “The IMT protocol used in this randomized controlled trial achieved clinically significant increases in both respiratory and exercise capacity…” |
Sahin et al. (2008) [36]. | Randomised controlled trial. | Duration: 8 weeks. Intervention: proprioception exercises (including balance and kinaesthesia exercises). Supervised by a doctor in clinic 3 days per week for 8 weeks. Control: no intervention. | Follow-up time point: 8 weeks. Joint position sense: active knee joint reproduction test using isokinetic dynamometer. Pain intensity on movement and at rest: VAS. Function: AIMS-2 | Effect of group: no between-group statistical comparisons reported at 8 weeks. Effect of time: Significant improvements from baseline to 8 weeks in the intervention group in pain on movement (p = 0.010); pain at rest (p = 0.027); joint position sense (left knee p = 0.001, right knee p = 0.000); and the occupational activity subscale of AIMS-2 (p < 0.05). No significant improvement from baseline to 8 weeks in the intervention group in the other AIMS-2 subscales (all p > 0.05). No significant improvement from baseline to 8 weeks in the control group in any outcome (all p > 0.05). | “…proprioception exercises cause decrease in pain and improvement of functional status in BJHS group.” |
To & Alexander (2018) [37]. | Cohort study. | Duration: 16 weeks. Intervention: All participants (JHS, GJH, control) received individualised leg exercises. Exercises were goal-related and functional where possible. American College of Sports Medicine guidelines were followed for progression. Appointment with a senior physiotherapist every 2 weeks for 16 weeks. Home exercises 3 times per week on non-consecutive days. | Follow-up time point: 16 weeks. Intention to treat analysis using multiple imputation to account for missing data. Pain intensity: VAS. Pain medication: diary. Knee function: Lysholm knee scale. Activity: Adjusted Activity Score and Human Activity Profile score. Muscle strength: concentric and eccentric leg press torque using isokinetic dynamometer. | Effect of group: no difference between groups in the rate of change in concentric and eccentric torque from baseline to 16 weeks (p > 0.05). Significant differences between groups in concentric and eccentric torque at baseline (JHS < Control < GJH). Estimated to take 11.6 weeks (concentric torque) and 16.2 weeks (eccentric torque) for JHS to reach the baseline GJH mean. Effect of time: Significant improvements in the JHS group from baseline to 16 weeks in pain (p < 0.00); knee function (p < 0.00); and activity (p < 0.00). All improvements in the JHS group were clinically meaningful. | “People with JHS can strengthen at the same rate as other people in pain… Their increase in strength related to their decrease in pain.” |
CASP Checklist Question | Bale et al. (2019) [17] | Celenay & Kaya (2017) [28] | Daman et al. (2019) [18] | Kemp et al. (2010) [31] | Pacey et al. (2013) [32] | Palmer et al. (2016) [33] | Reychler et al. (2019) [29] | Sahin et al. (2008) [30] |
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1. Did the trial address a clearly focused issue? | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
2. Was the assignment of patients to treatments randomised? | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
3. Were all of the patients who entered the trial properly accounted for at its conclusion? | ✓ | ✓ | ? | ✓ | ✓ | ✓ | ✓ | ✓ |
4. Were patients, health workers and study personnel ‘blind’ to treatment? | ✓ | ✓ | ✓ | ✓ | ✓ | ✗ | ✓ | ✗ |
5. Were the groups similar at the start of the trial? | ✓ | ✓ | ✓ | ✓ | ✗ | ✓ | ✗ | ✓ |
6. Aside from the experimental intervention, were the groups treated equally? | ✗ | ✓ | ? | ✓ | ✓ | ✓ | ? | ? |
7. How large was the treatment effect? | See Table 5 | See Table 5 | See Table 5 | See Table 5 | See Table 5 | See Table 5 | See Table 5 | See Table 5 |
8. How precise was the estimate of the treatment effect? | 95% CIs reported | No CIs reported | No CIs reported | 95% CIs reported | 95% CIs reported | 95% CIs eported | No CIs reported for between group differences | No CIs reported |
9. Can the results be applied to the local population, or in your context? | ✓ | ✗ | ✗ | ✓ | ✓ | ✗ | ✓ | ? |
10. Were all clinically important outcomes considered? | ✓ | ✓ | ✓ | ✗ | ✗ | ✓ | ✓ | ✗ |
11. Are the benefits worth the harms and costs? | ✓ | ✓ | ✓ | ✗ | ✓ | ✓ | ✓ | ✓ |
CASP Checklist Question | Bathen et al. (2013) [34] | Ferrell et al. (2004) [35] | To & Alexander (2018) [19] |
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1. Did the trial address a clearly focused issue? | ✓ | ✓ | ✓ |
2. Was the cohort recruited in an acceptable way? | ? | ? | ✓ |
3. Was the exposure accurately measured to minimise bias? | ✗ | ✗ | ✓ |
4. Was the outcome accurately measured✗to minimise bias? | ✓ | ✓ | ✓ |
5(a) Have the authors identified all important confounding factors? | ? | ? | ✓ |
5(b) Have they taken account of the confounding factors in the design and/or analysis? | ✗ | ✗ | ✓ |
6(a) Was the follow-up of subjects complete enough? | ✗ | ✗ | ✗ |
6(b) Was the follow-up of subjects long enough? | ✗ | ✗ | ✗ |
7. What are the results of this study? | See Table 5 | See Table 5 | See Table 5 |
8. How precise are the results? | No CIs reported | No CIs reported | 95% CIs reported |
9. Do you believe the results? | ✗ | ✗ | ✓ |
10. Can the results be applied to the local population? | ✗ | ✓ | ✓ |
11. Do the results of this study fit with other available evidence? | ✓ | ✗ | ✗ |
12. What are the implications of this study for practice? | See Discussion section | See Discussion section | See Discussion section |