Credibility at stake: only two-thirds of randomized trials of nutrition interventions are registered and lack transparency in outcome and treatment effect definitions.

OBJECTIVES: This study aimed to investigate the adherence of randomized controlled trials of nutrition interventions to transparency practices informing assessments of selective reporting biases, including the availability of a trial registration entry, protocol and statistical analysis plan (SAP). STUDY DESIGN AND SETTING: Retrospective observational study with cross-sectional design. We systematically searched for trials published from 1 July 2019, to 30 June 2020, and included a randomly selected sample of 400 studies. We searched for registry entries, protocols, and SAPs for all included studies. We extracted data to characterize the disclosure of sufficient information in the available materials to inform assessments of selective reporting biases, considering the definition of outcome domain, measure, metric, method of aggregation, time point, analysis population, methods to handle missing data and method of adjustment. RESULTS: Most trials (69%) were registered, but these often lacked sufficient specification of outcomes and intended treatment effects. Protocols and SAPs provided more details but were less often available (14% and 3%, respectively), and even then, almost all studies presented limited information to inform the assessments of risk of bias due to the selection of the reported result. CONCLUSION: Lack of full specification of outcomes and intended treatment effects hinder a full adherence of randomized controlled trials of nutrition interventions to transparency practices and may affect their credibility.

Improving adherence to acute low back pain guideline recommendations with chiropractors and physiotherapists: the ALIGN cluster randomised controlled trial.

BACKGROUND: Acute low back pain is a common condition, has high burden, and there are evidence-to-practice gaps in the chiropractic and physiotherapy setting for imaging and giving advice to stay active. The aim of this cluster randomised trial was to estimate the effects of a theory- and evidence-based implementation intervention to increase chiropractors' and physiotherapists' adherence to a guideline for acute low back pain compared with the comparator (passive dissemination of the guideline). In particular, the primary aim of the intervention was to reduce inappropriate imaging referral and improve patient low back pain outcomes, and to determine whether this intervention was cost-effective. METHODS: Physiotherapy and chiropractic practices in the state of Victoria, Australia, comprising at least one practising clinician who provided care to patients with acute low back pain, were invited to participate. Patients attending these practices were included if they had acute non-specific low back pain (duration less than 3 months), were 18 years of age or older, and were able to understand and read English. Practices were randomly assigned either to a tailored, multi-faceted intervention based on the guideline (interactive educational symposium plus academic detailing) or passive dissemination of the guideline (comparator). A statistician independent of the study team undertook stratified randomisation using computer-generated random numbers; four strata were defined by professional group and the rural or metropolitan location of the practice. Investigators not involved in intervention delivery were blinded to allocation. Primary outcomes were X-ray referral self-reported by clinicians using a checklist and patient low back pain-specific disability (at 3 months). RESULTS: A total of 104 practices (43 chiropractors, 85 physiotherapists; 755 patients) were assigned to the intervention and 106 practices (45 chiropractors, 97 physiotherapists; 603 patients) to the comparator; 449 patients were available for the patient-level primary outcome. There was no important difference in the odds of patients being referred for X-ray (adjusted (Adj) OR: 1.40; 95% CI 0.51, 3.87; Adj risk difference (RD): 0.01; 95% CI - 0.02, 0.04) or patient low back pain-specific disability (Adj mean difference: 0.37; 95% CI - 0.48, 1.21, scale 0-24). The intervention did lead to improvement for some key secondary outcomes, including giving advice to stay active (Adj OR: 1.96; 95% CI 1.20, 3.22; Adj RD: 0.10; 95% CI 0.01, 0.19) and intending to adhere to the guideline recommendations (e.g. intention to refer for X-ray: Adj OR: 0.27; 95% CI 0.17, 0.44; intention to give advice to stay active: Adj OR: 2.37; 95% CI 1.51, 3.74). CONCLUSIONS: Intervention group clinicians were more likely to give advice to stay active and to intend to adhere to the guideline recommendations about X-ray referral. The intervention did not change the primary study outcomes, with no important differences in X-ray referral and patient disability between groups, implying that hypothesised reductions in health service utilisation and/or productivity gains are unlikely to offset the direct costs of the intervention. We report these results with the caveat that we enrolled less patients into the trial than our determined sample size. We cannot recommend this intervention as a cost-effective use of resources. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609001022257 . Retrospectively registered on 25 November 2009.

Assessment of the Methods Used to Develop Vitamin D and Calcium Recommendations-A Systematic Review of Bone Health Guidelines.

BACKGROUND: There are numerous guidelines developed for bone health. Yet, it is unclear whether the differences in guideline development methods explain the variability in the recommendations for vitamin D and calcium intake. The objective of this systematic review was to collate and compare recommendations for vitamin D and calcium across bone health guidelines, assess the methods used to form the recommendations, and explore which methodological factors were associated with these guideline recommendations. METHODS: We searched MEDLINE, EMBASE, CINAHL, and other databases indexing guidelines to identify records in English between 2009 and 2019. Guidelines or policy statements on bone health or osteoporosis prevention for generally healthy adults aged ≥40 years were eligible for inclusion. Two reviewers independently extracted recommendations on daily vitamin D and calcium intake, supplement use, serum 25 hydroxyvitamin D [25(OH)D] level, and sunlight exposure; assessed guideline development methods against 25 recommended criteria in the World Health Organization (WHO) handbook for guideline development; and, identified types identified types of evidence underpinning the recommendations. RESULTS: we included 47 eligible guidelines from 733 records: 74% of the guidelines provided vitamin D (200~600-4000 IU/day) and 70% provided calcium (600-1200 mg/day) recommendations, 96% and 88% recommended vitamin D and calcium supplements, respectively, and 70% recommended a specific 25(OH)D concentration. On average, each guideline met 10 (95% CI: 9-12) of the total of 25 methodological criteria for guideline development recommended by the WHO Handbook. There was uncertainty in the association between the methodological criteria and the proportion of guidelines that provided recommendations on daily vitamin D or calcium. Various types of evidence, including previous bone guidelines, nutrient reference reports, systematic reviews, observational studies, and perspectives/editorials were used to underpin the recommendations. CONCLUSIONS: There is considerable variability in vitamin D and calcium recommendations and in guideline development methods in bone health guidelines. Effort is required to strengthen the methodological rigor of guideline development and utilize the best available evidence to underpin nutrition recommendations in evidence-based guidelines on bone health.

Epidemiology and reporting characteristics of preclinical systematic reviews.

In an effort to better utilize published evidence obtained from animal experiments, systematic reviews of preclinical studies are increasingly more common-along with the methods and tools to appraise them (e.g., SYstematic Review Center for Laboratory animal Experimentation [SYRCLE's] risk of bias tool). We performed a cross-sectional study of a sample of recent preclinical systematic reviews (2015-2018) and examined a range of epidemiological characteristics and used a 46-item checklist to assess reporting details. We identified 442 reviews published across 43 countries in 23 different disease domains that used 26 animal species. Reporting of key details to ensure transparency and reproducibility was inconsistent across reviews and within article sections. Items were most completely reported in the title, introduction, and results sections of the reviews, while least reported in the methods and discussion sections. Less than half of reviews reported that a risk of bias assessment for internal and external validity was undertaken, and none reported methods for evaluating construct validity. Our results demonstrate that a considerable number of preclinical systematic reviews investigating diverse topics have been conducted; however, their quality of reporting is inconsistent. Our study provides the justification and evidence to inform the development of guidelines for conducting and reporting preclinical systematic reviews.

Evaluation of Reproducible Research Practices in Oncology Systematic Reviews With Meta-analyses Referenced by National Comprehensive Cancer Network Guidelines.

IMPORTANCE: Reproducible research practices are essential to biomedical research because these practices promote trustworthy evidence. In systematic reviews and meta-analyses, reproducible research practices ensure that summary effects used to guide patient care are stable and trustworthy. OBJECTIVE: To evaluate the reproducibility in theory of meta-analyses in oncology systematic reviews cited by the 49 National Comprehensive Cancer Network (NCCN) guidelines for the treatment of cancer by site and evaluate whether Cochrane reviews or systematic reviews that report adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines use more reproducible research practices. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional investigation of all systematic reviews with at least 1 meta-analysis and at least 1 included randomized clinical trial (RCT) that are cited by NCCN guidelines for treatment of cancer by site. We scanned the reference list of all NCCN guidelines (n = 49) for potential systematic reviews and meta-analyses. All retrieved studies were screened, and data were extracted, independently and in duplicate. The analysis was carried out between May 6, 2018, and January 28, 2019. MAIN OUTCOMES AND MEASURES: The frequency of reproducible research practices, defined as (1) effect estimate and measure of precision (eg, hazard ratio with 95% confidence interval); (2) clear list of studies included for each analysis; and (3) for subgroup and sensitivity analyses, it must be clear which studies were included in each group or level. RESULTS: We identified 1124 potential systematic reviews, and 154 meta-analyses comprising 3696 meta-analytic effect size estimates were included. Only 2375 of the 3696 meta-analytic estimates (64.3%), including subgroup and sensitivity analyses, were reproducible in theory. Forest plots appear to improve the reproducibility of meta-analyses. All meta-analytic estimates were reproducible in theory in 100 systematic reviews (64.9%), and in 15 systematic reviews (9.7%), no meta-analytic estimates could potentially be reproduced. Data were said to be imputed in 29 meta-analyses, but none specified which data. Only 1 meta-analysis included a link to an online data set. CONCLUSIONS AND RELEVANCE: More reproducible research practices are needed in oncology meta-analyses, as suggested by those that are cited by the NCCN. Reporting meta-analyses in forest plots and requirements for full data sharing are recommended.

The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents. METHODS AND FINDINGS: We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016). Interventions of interest were pharmacological (stimulants, non-stimulants, antidepressants, antipsychotics, and other unlicensed drugs), psychological (behavioural, cognitive training and neurofeedback) and complementary and alternative medicine (dietary therapy, fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity). The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation). Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy (alone or in combination with stimulants), stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms (anorexia, weight loss and insomnia), but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution. CONCLUSIONS: Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008.

Electrotherapy modalities for rotator cuff disease.

BACKGROUND: Management of rotator cuff disease may include use of electrotherapy modalities (also known as electrophysical agents), which aim to reduce pain and improve function via an increase in energy (electrical, sound, light, or thermal) into the body. Examples include therapeutic ultrasound, low-level laser therapy (LLLT), transcutaneous electrical nerve stimulation (TENS), and pulsed electromagnetic field therapy (PEMF). These modalities are usually delivered as components of a physical therapy intervention. This review is one of a series of reviews that form an update of the Cochrane review, 'Physiotherapy interventions for shoulder pain'. OBJECTIVES: To synthesise available evidence regarding the benefits and harms of electrotherapy modalities for the treatment of people with rotator cuff disease. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), Ovid MEDLINE (January 1966 to March 2015), Ovid EMBASE (January 1980 to March 2015), CINAHL Plus (EBSCOhost, January 1937 to March 2015), ClinicalTrials.gov and the WHO ICTRP clinical trials registries up to March 2015, unrestricted by language, and reviewed the reference lists of review articles and retrieved trials, to identify potentially relevant trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised trials, including adults with rotator cuff disease (e.g. subacromial impingement syndrome, rotator cuff tendinitis, calcific tendinitis), and comparing any electrotherapy modality with placebo, no intervention, a different electrotherapy modality or any other intervention (e.g. glucocorticoid injection). Trials investigating whether electrotherapy modalities were more effective than placebo or no treatment, or were an effective addition to another physical therapy intervention (e.g. manual therapy or exercise) were the main comparisons of interest. Main outcomes of interest were overall pain, function, pain on motion, patient-reported global assessment of treatment success, quality of life and the number of participants experiencing adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted the data, performed a risk of bias assessment and assessed the quality of the body of evidence for the main outcomes using the GRADE approach. MAIN RESULTS: We included 47 trials (2388 participants). Most trials (n = 43) included participants with rotator cuff disease without calcification (four trials included people with calcific tendinitis). Sixteen (34%) trials investigated the effect of an electrotherapy modality delivered in isolation. Only 23% were rated at low risk of allocation bias, and 49% were rated at low risk of both performance and detection bias (for self-reported outcomes). The trials were heterogeneous in terms of population, intervention and comparator, so none of the data could be combined in a meta-analysis.In one trial (61 participants; low quality evidence), pulsed therapeutic ultrasound (three to five times a week for six weeks) was compared with placebo (inactive ultrasound therapy) for calcific tendinitis. At six weeks, the mean reduction in overall pain with placebo was -6.3 points on a 52-point scale, and -14.9 points with ultrasound (MD -8.60 points, 95% CI -13.48 to -3.72 points; absolute risk difference 17%, 7% to 26% more). Mean improvement in function with placebo was 3.7 points on a 100-point scale, and 17.8 points with ultrasound (mean difference (MD) 14.10 points, 95% confidence interval (CI) 5.39 to 22.81 points; absolute risk difference 14%, 5% to 23% more). Ninety-one per cent (29/32) of participants reported treatment success with ultrasound compared with 52% (15/29) of participants receiving placebo (risk ratio (RR) 1.75, 95% CI 1.21 to 2.53; absolute risk difference 39%, 18% to 60% more). Mean improvement in quality of life with placebo was 0.40 points on a 10-point scale, and 2.60 points with ultrasound (MD 2.20 points, 95% CI 0.91 points to 3.49 points; absolute risk difference 22%, 9% to 35% more). Between-group differences were not important at nine months. No participant reported adverse events.Therapeutic ultrasound produced no clinically important additional benefits when combined with other physical therapy interventions (eight clinically heterogeneous trials, low quality evidence). We are uncertain whether there are differences in patient-important outcomes between ultrasound and other active interventions (manual therapy, acupuncture, glucocorticoid injection, glucocorticoid injection plus oral tolmetin sodium, or exercise) because the quality of evidence is very low. Two placebo-controlled trials reported results favouring LLLT up to three weeks (low quality evidence), however combining LLLT with other physical therapy interventions produced few additional benefits (10 clinically heterogeneous trials, low quality evidence). We are uncertain whether transcutaneous electrical nerve stimulation (TENS) is more or less effective than glucocorticoid injection with respect to pain, function, global treatment success and active range of motion because of the very low quality evidence from a single trial. In other single, small trials, no clinically important benefits of pulsed electromagnetic field therapy (PEMF), microcurrent electrical stimulation (MENS), acetic acid iontophoresis and microwave diathermy were observed (low or very low quality evidence).No adverse events of therapeutic ultrasound, LLLT, TENS or microwave diathermy were reported by any participants. Adverse events were not measured in any trials investigating the effects of PEMF, MENS or acetic acid iontophoresis. AUTHORS' CONCLUSIONS: Based on low quality evidence, therapeutic ultrasound may have short-term benefits over placebo in people with calcific tendinitis, and LLLT may have short-term benefits over placebo in people with rotator cuff disease. Further high quality placebo-controlled trials are needed to confirm these results. In contrast, based on low quality evidence, PEMF may not provide clinically relevant benefits over placebo, and therapeutic ultrasound, LLLT and PEMF may not provide additional benefits when combined with other physical therapy interventions. We are uncertain whether TENS is superior to placebo, and whether any electrotherapy modality provides benefits over other active interventions (e.g. glucocorticoid injection) because of the very low quality of the evidence. Practitioners should communicate the uncertainty of these effects and consider other approaches or combinations of treatment. Further trials of electrotherapy modalities for rotator cuff disease should be based upon a strong rationale and consideration of whether or not they would alter the conclusions of this review.

Manual therapy and exercise for rotator cuff disease.

BACKGROUND: Management of rotator cuff disease often includes manual therapy and exercise, usually delivered together as components of a physical therapy intervention. This review is one of a series of reviews that form an update of the Cochrane review, 'Physiotherapy interventions for shoulder pain'. OBJECTIVES: To synthesise available evidence regarding the benefits and harms of manual therapy and exercise, alone or in combination, for the treatment of people with rotator cuff disease. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), Ovid MEDLINE (January 1966 to March 2015), Ovid EMBASE (January 1980 to March 2015), CINAHL Plus (EBSCO, January 1937 to March 2015), ClinicalTrials.gov and the WHO ICTRP clinical trials registries up to March 2015, unrestricted by language, and reviewed the reference lists of review articles and retrieved trials, to identify potentially relevant trials. SELECTION CRITERIA: We included randomised and quasi-randomised trials, including adults with rotator cuff disease, and comparing any manual therapy or exercise intervention with placebo, no intervention, a different type of manual therapy or exercise or any other intervention (e.g. glucocorticoid injection). Interventions included mobilisation, manipulation and supervised or home exercises. Trials investigating the primary or add-on effect of manual therapy and exercise were the main comparisons of interest. Main outcomes of interest were overall pain, function, pain on motion, patient-reported global assessment of treatment success, quality of life and the number of participants experiencing adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted the data, performed a risk of bias assessment and assessed the quality of the body of evidence for the main outcomes using the GRADE approach. MAIN RESULTS: We included 60 trials (3620 participants), although only 10 addressed the main comparisons of interest. Overall risk of bias was low in three, unclear in 14 and high in 43 trials. We were unable to perform any meta-analyses because of clinical heterogeneity or incomplete outcome reporting. One trial compared manual therapy and exercise with placebo (inactive ultrasound therapy) in 120 participants with chronic rotator cuff disease (high quality evidence). At 22 weeks, the mean change in overall pain with placebo was 17.3 points on a 100-point scale, and 24.8 points with manual therapy and exercise (adjusted mean difference (MD) 6.8 points, 95% confidence interval (CI) -0.70 to 14.30 points; absolute risk difference 7%, 1% fewer to 14% more). Mean change in function with placebo was 15.6 points on a 100-point scale, and 22.4 points with manual therapy and exercise (adjusted MD 7.1 points, 95% CI 0.30 to 13.90 points; absolute risk difference 7%, 1% to 14% more). Fifty-seven per cent (31/54) of participants reported treatment success with manual therapy and exercise compared with 41% (24/58) of participants receiving placebo (risk ratio (RR) 1.39, 95% CI 0.94 to 2.03; absolute risk difference 16% (2% fewer to 34% more). Thirty-one per cent (17/55) of participants reported adverse events with manual therapy and exercise compared with 8% (5/61) of participants receiving placebo (RR 3.77, 95% CI 1.49 to 9.54; absolute risk difference 23% (9% to 37% more). However adverse events were mild (short-term pain following treatment).Five trials (low quality evidence) found no important differences between manual therapy and exercise compared with glucocorticoid injection with respect to overall pain, function, active shoulder abduction and quality of life from four weeks up to 12 months. However, global treatment success was more common up to 11 weeks in people receiving glucocorticoid injection (low quality evidence). One trial (low quality evidence) showed no important differences between manual therapy and exercise and arthroscopic subacromial decompression with respect to overall pain, function, active range of motion and strength at six and 12 months, or global treatment success at four to eight years. One trial (low quality evidence) found that manual therapy and exercise may not be as effective as acupuncture plus dietary counselling and Phlogenzym supplement with respect to overall pain, function, active shoulder abduction and quality life at 12 weeks. We are uncertain whether manual therapy and exercise improves function more than oral non-steroidal anti-inflammatory drugs (NSAID), or whether combining manual therapy and exercise with glucocorticoid injection provides additional benefit in function over glucocorticoid injection alone, because of the very low quality evidence in these two trials.Fifty-two trials investigated effects of manual therapy alone or exercise alone, and the evidence was mostly very low quality. There was little or no difference in patient-important outcomes between manual therapy alone and placebo, no treatment, therapeutic ultrasound and kinesiotaping, although manual therapy alone was less effective than glucocorticoid injection. Exercise alone led to less improvement in overall pain, but not function, when compared with surgical repair for rotator cuff tear. There was little or no difference in patient-important outcomes between exercise alone and placebo, radial extracorporeal shockwave treatment, glucocorticoid injection, arthroscopic subacromial decompression and functional brace. Further, manual therapy or exercise provided few or no additional benefits when combined with other physical therapy interventions, and one type of manual therapy or exercise was rarely more effective than another. AUTHORS' CONCLUSIONS: Despite identifying 60 eligible trials, only one trial compared a combination of manual therapy and exercise reflective of common current practice to placebo. We judged it to be of high quality and found no clinically important differences between groups in any outcome. Effects of manual therapy and exercise may be similar to those of glucocorticoid injection and arthroscopic subacromial decompression, but this is based on low quality evidence. Adverse events associated with manual therapy and exercise are relatively more frequent than placebo but mild in nature. Novel combinations of manual therapy and exercise should be compared with a realistic placebo in future trials. Further trials of manual therapy alone or exercise alone for rotator cuff disease should be based upon a strong rationale and consideration of whether or not they would alter the conclusions of this review.

The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: protocol for a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of children and adolescents, with a significant impact on health services and the community in terms of economic and social burdens. The objective of this systematic review will be to evaluate the comparative efficacy and safety of pharmacological and non-pharmacological treatments in children and adolescents with ADHD. METHODS: Searches involving PubMed/MEDLINE and the Cochrane Database of Systematic Reviews will be used to identify related systematic reviews and relevant randomized trials. Search results will be supplemented by reports from the regulatory and health technology agencies, clinical trials registers and by data requested from trialists and/or pharmaceutical companies. We will consider studies evaluating pharmacological interventions (e.g. stimulants, non-stimulants, antidepressants), psychological interventions (e.g. behavioural interventions, cognitive training and neurofeedback) and complementary and alternative medicine interventions (e.g. dietary interventions, supplement with fatty acids, vitamins, minerals, aminoacids, herbal treatment, homeopathy, and mind-body interventions including massage, chiropractic, acupuncture, yoga, meditation, Tai chi). Eligible control conditions will be placebo, waitlist, no treatment and usual care. Randomized controlled trials of a minimum of 3 weeks duration will be included. The primary outcomes of interest will be the proportion of patients who responded to treatment and who dropped out of the allocated treatment, respectively. Secondary outcomes will include treatment discontinuation due to adverse events, as well as the occurrences of serious adverse events and specific adverse events (decreased weight, anorexia, insomnia and sleep disturbances, anxiety, syncope and cardiovascular events). Two reviewers will independently screen references identified by the literature search, as well as potentially relevant full-text articles in duplicate. Data will be abstracted and risk of bias will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through discussion. Random-effects pairwise meta-analyses and Bayesian network meta-analyses will be conducted where appropriate. DISCUSSION: This systematic review and network meta-analysis will compare the efficacy and safety of treatments used for ADHD in children and adolescents. The findings will assist patients, clinicians and healthcare providers to make evidence-based decisions regarding treatment selection. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014015008 .

Electrotherapy modalities for adhesive capsulitis (frozen shoulder).

BACKGROUND: Adhesive capsulitis (also termed frozen shoulder) is a common condition characterised by spontaneous onset of pain, progressive restriction of movement of the shoulder and disability that restricts activities of daily living, work and leisure. Electrotherapy modalities, which aim to reduce pain and improve function via an increase in energy (electrical, sound, light, thermal) into the body, are often delivered as components of a physical therapy intervention. This review is one in a series of reviews which form an update of the Cochrane review 'Physiotherapy interventions for shoulder pain'. OBJECTIVES: To synthesise the available evidence regarding the benefits and harms of electrotherapy modalities, delivered alone or in combination with other interventions, for the treatment of adhesive capsulitis. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE, CINAHL Plus and the ClinicalTrials.gov and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) clinical trials registries up to May 2014, unrestricted by language, and reviewed the reference lists of review articles and retrieved trials to identify any other potentially relevant trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials using a quasi-randomised method of allocation that included adults with adhesive capsulitis and compared any electrotherapy modality to placebo, no treatment, a different electrotherapy modality, or any other intervention. The two main questions of the review focused on whether electrotherapy modalities are effective compared to placebo or no treatment, or if they are an effective adjunct to manual therapy or exercise (or both). The main outcomes of interest were participant-reported pain relief of 30% or greater, overall pain, function, global assessment of treatment success, active shoulder abduction, quality of life, and the number of participants experiencing any adverse event. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted the data, performed a risk of bias assessment, and assessed the quality of the body of evidence for the main outcomes using the GRADE approach. MAIN RESULTS: Nineteen trials (1249 participants) were included in the review. Four trials reported using an adequate method of allocation concealment and six trials blinded participants and personnel. Only two electrotherapy modalities (low-level laser therapy (LLLT) and pulsed electromagnetic field therapy (PEMF)) have been compared to placebo. No trial has compared an electrotherapy modality plus manual therapy and exercise to manual therapy and exercise alone. The two main questions of the review were investigated in nine trials.Low quality evidence from one trial (40 participants) indicated that LLLT for six days may result in improvement at six days. Eighty per cent (16/20) of participants reported treatment success with LLLT compared with 10% (2/20) of participants receiving placebo (risk ratio (RR) 8.00, 95% confidence interval (CI) 2.11 to 30.34; absolute risk difference 70%, 95% CI 48% to 92%). No participants in either group reported adverse events.We were uncertain whether PEMF for two weeks improved pain or function more than placebo at two weeks because of the very low quality evidence from one trial (32 participants). Seventy-five per cent (15/20) of participants reported pain relief of 30% or more with PEMF compared with 0% (0/12) of participants receiving placebo (RR 19.19, 95% CI 1.25 to 294.21; absolute risk difference 75%, 95% CI 53% to 97%). Fifty-five per cent (11/20) of participants reported total recovery of joint function with PEMF compared with 0% (0/12) of participants receiving placebo (RR 14.24, 95% CI 0.91 to 221.75; absolute risk difference 55%, 95% CI 31 to 79).Moderate quality evidence from one trial (63 participants) indicated that LLLT plus exercise for eight weeks probably results in greater improvement when measured at the fourth week of treatment, but a similar number of adverse events, compared with placebo plus exercise. The mean pain score at four weeks was 51 points with placebo plus exercise, while with LLLT plus exercise the mean pain score was 32 points on a 100 point scale (mean difference (MD) 19 points, 95% CI 15 to 23; absolute risk difference 19%, 95% CI 15% to 23%). The mean function impairment score was 48 points with placebo plus exercise, while with LLLT plus exercise the mean function impairment score was 36 points on a 100 point scale (MD 12 points, 95% CI 6 to 18; absolute risk difference 12%, 95% CI 6 to 18). Mean active abduction was 70 degrees with placebo plus exercise, while with LLLT plus exercise mean active abduction was 79 degrees (MD 9 degrees, 95% CI 2 to 16; absolute risk difference 5%, 95% CI 1% to 9%). No participants in either group reported adverse events. LLLT's benefits on function were maintained at four months.Based on very low quality evidence from six trials, we were uncertain whether therapeutic ultrasound, PEMF, continuous short wave diathermy, Iodex phonophoresis, a combination of Iodex iontophoresis with continuous short wave diathermy, or a combination of therapeutic ultrasound with transcutaneous electrical nerve stimulation (TENS) were effective adjuncts to exercise. Based on low or very low quality evidence from 12 trials, we were uncertain whether a diverse range of electrotherapy modalities (delivered alone or in combination with manual therapy, exercise, or other active interventions) were more or less effective than other active interventions (for example glucocorticoid injection). AUTHORS' CONCLUSIONS: Based upon low quality evidence from one trial, LLLT for six days may be more effective than placebo in terms of global treatment success at six days. Based upon moderate quality evidence from one trial, LLLT plus exercise for eight weeks may be more effective than exercise alone in terms of pain up to four weeks, and function up to four months. It is unclear whether PEMF is more or less effective than placebo, or whether other electrotherapy modalities are an effective adjunct to exercise. Further high quality randomised controlled trials are needed to establish the benefits and harms of physical therapy interventions (that comprise electrotherapy modalities, manual therapy and exercise, and are reflective of clinical practice) compared to interventions with evidence of benefit (for example glucocorticoid injection or arthrographic joint distension).

Manual therapy and exercise for adhesive capsulitis (frozen shoulder).

BACKGROUND: Adhesive capsulitis (also termed frozen shoulder) is commonly treated by manual therapy and exercise, usually delivered together as components of a physical therapy intervention. This review is one of a series of reviews that form an update of the Cochrane review, 'Physiotherapy interventions for shoulder pain.' OBJECTIVES: To synthesise available evidence regarding the benefits and harms of manual therapy and exercise, alone or in combination, for the treatment of patients with adhesive capsulitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL Plus, ClinicalTrials.gov and the WHO ICTRP clinical trials registries up to May 2013, unrestricted by language, and reviewed the reference lists of review articles and retrieved trials, to identify potentially relevant trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised trials, including adults with adhesive capsulitis, and comparing any manual therapy or exercise intervention versus placebo, no intervention, a different type of manual therapy or exercise or any other intervention. Interventions included mobilisation, manipulation and supervised or home exercise, delivered alone or in combination. Trials investigating the primary or adjunct effect of a combination of manual therapy and exercise were the main comparisons of interest. Main outcomes of interest were participant-reported pain relief of 30% or greater, overall pain (mean or mean change), function, global assessment of treatment success, active shoulder abduction, quality of life and the number of participants experiencing adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted the data, performed a risk of bias assessment and assessed the quality of the body of evidence for the main outcomes using the GRADE approach. MAIN RESULTS: We included 32 trials (1836 participants). No trial compared a combination of manual therapy and exercise versus placebo or no intervention. Seven trials compared a combination of manual therapy and exercise versus other interventions but were clinically heterogeneous, so opportunities for meta-analysis were limited. The overall impression gained from these trials is that the few outcome differences between interventions that were clinically important were detected only up to seven weeks. Evidence of moderate quality shows that a combination of manual therapy and exercise for six weeks probably results in less improvement at seven weeks but a similar number of adverse events compared with glucocorticoid injection. The mean change in pain with glucocorticoid injection was 58 points on a 100-point scale, and 32 points with manual therapy and exercise (mean difference (MD) 26 points, 95% confidence interval (CI) 15 points to 37 points; one RCT, 107 participants), for an absolute difference of 26% (15% to 37%). Mean change in function with glucocorticoid injection was 39 points on a 100-point scale, and 14 points with manual therapy and exercise (MD 25 points, 95% CI 35 points to 15 points; one RCT, 107 participants), for an absolute difference of 25% (15% to 35%). Forty-six per cent (26/56) of participants reported treatment success with manual therapy and exercise compared with 77% (40/52) of participants receiving glucocorticoid injection (risk ratio (RR) 0.6, 95% CI 0.44 to 0.83; one RCT, 108 participants), with an absolute risk difference of 30% (13% to 48%). The number reporting adverse events did not differ between groups: 56% (32/57) reported events with manual therapy and exercise, and 53% (30/57) with glucocorticoid injection (RR 1.07, 95% CI 0.76 to 1.49; one RCT, 114 participants), with an absolute risk difference of 4% (-15% to 22%). Group differences in improvement in overall pain and function at six months and 12 months were not clinically important.We are uncertain of the effect of other combinations of manual therapy and exercise, as most evidence is of low quality. Meta-analysis of two trials (86 participants) suggested no clinically important differences between a combination of manual therapy, exercise, and electrotherapy for four weeks and placebo injection compared with glucocorticoid injection alone or placebo injection alone in terms of overall pain, function, active range of motion and quality of life at six weeks, six months and 12 months (though the 95% CI suggested function may be better with glucocorticoid injection at six weeks). The same two trials found that adding a combination of manual therapy, exercise and electrotherapy for four weeks to glucocorticoid injection did not confer clinically important benefits over glucocorticoid injection alone at each time point. Based on one high quality trial (148 participants), following arthrographic joint distension with glucocorticoid and saline, a combination of manual therapy and supervised exercise for six weeks conferred similar effects to those of sham ultrasound in terms of overall pain, function and quality of life at six weeks and at six months, but provided greater patient-reported treatment success and active shoulder abduction at six weeks. One trial (119 participants) found that a combination of manual therapy, exercise, electrotherapy and oral non-steroidal anti-inflammatory drug (NSAID) for three weeks did not confer clinically important benefits over oral NSAID alone in terms of function and patient-reported treatment success at three weeks.On the basis of 25 clinically heterogeneous trials, we are uncertain of the effect of manual therapy or exercise when not delivered together, or one type of manual therapy or exercise versus another, as most reported differences between groups were not clinically or statistically significant, and the evidence is mostly of low quality. AUTHORS' CONCLUSIONS: The best available data show that a combination of manual therapy and exercise may not be as effective as glucocorticoid injection in the short-term. It is unclear whether a combination of manual therapy, exercise and electrotherapy is an effective adjunct to glucocorticoid injection or oral NSAID. Following arthrographic joint distension with glucocorticoid and saline, manual therapy and exercise may confer effects similar to those of sham ultrasound in terms of overall pain, function and quality of life, but may provide greater patient-reported treatment success and active range of motion. High-quality RCTs are needed to establish the benefits and harms of manual therapy and exercise interventions that reflect actual practice, compared with placebo, no intervention and active interventions with evidence of benefit (e.g. glucocorticoid injection).

Exercise and mobilisation interventions for carpal tunnel syndrome.

BACKGROUND: Non-surgical treatment, including exercises and mobilisation, has been offered to people experiencing mild to moderate symptoms arising from carpal tunnel syndrome (CTS). However, the effectiveness and duration of benefit from exercises and mobilisation for this condition remain unknown. OBJECTIVES: To review the efficacy and safety of exercise and mobilisation interventions compared with no treatment, a placebo or another non-surgical intervention in people with CTS. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialised Register (10 January 2012), CENTRAL (2011, Issue 4), MEDLINE (January 1966 to December 2011), EMBASE (January 1980 to January 2012), CINAHL Plus (January 1937 to January 2012), and AMED (January 1985 to January 2012). SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing exercise or mobilisation interventions with no treatment, placebo or another non-surgical intervention in people with CTS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed searches and selected trials for inclusion, extracted data and assessed risk of bias of the included studies. We calculated risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CIs) for primary and secondary outcomes of the review. We collected data on adverse events from included studies. MAIN RESULTS: Sixteen studies randomising 741 participants with CTS were included in the review. Two compared a mobilisation regimen to a no treatment control, three compared one mobilisation intervention (for example carpal bone mobilisation) to another (for example soft tissue mobilisation), nine compared nerve mobilisation delivered as part of a multi-component intervention to another non-surgical intervention (for example splint or therapeutic ultrasound), and three compared a mobilisation intervention other than nerve mobilisation (for example yoga or chiropractic treatment) to another non-surgical intervention. The risk of bias of the included studies was low in some studies and unclear or high in other studies, with only three explicitly reporting that the allocation sequence was concealed, and four reporting blinding of participants. The studies were heterogeneous in terms of the interventions delivered, outcomes measured and timing of outcome assessment, therefore, we were unable to pool results across studies. Only four studies reported the primary outcome of interest, short-term overall improvement (any measure in which patients indicate the intensity of their complaints compared to baseline, for example, global rating of improvement, satisfaction with treatment, within three months post-treatment). However, of these, only three fully reported outcome data sufficient for inclusion in the review. One very low quality trial with 14 participants found that all participants receiving either neurodynamic mobilisation or carpal bone mobilisation and none in the no treatment group reported overall improvement (RR 15.00, 95% CI 1.02 to 220.92), though the precision of this effect estimate is very low. One low quality trial with 22 participants found that the chance of being 'satisfied' or 'very satisfied' with treatment was 24% higher for participants receiving instrument-assisted soft tissue mobilisation compared to standard soft tissue mobilisation (RR 1.24, 95% CI 0.89 to 1.75), though participants were not blinded and it was unclear if the allocation sequence was concealed. Another very low-quality trial with 26 participants found that more CTS-affected wrists receiving nerve gliding exercises plus splint plus activity modification had no pathologic finding on median and ulnar nerve distal sensory latency assessment at the end of treatment than wrists receiving splint plus activity modification alone (RR 1.26, 95% CI 0.69 to 2.30). However, a unit of analysis error occurred in this trial, as the correlation between wrists in participants with bilateral CTS was not accounted for. Only two studies measured adverse effects, so more data are required before any firm conclusions on the safety of exercise and mobilisation interventions can be made. In general, the results of secondary outcomes of the review (short- and long-term improvement in CTS symptoms, functional ability, health-related quality of life, neurophysiologic parameters, and the need for surgery) for most comparisons had 95% CIs which incorporated effects in either direction. AUTHORS' CONCLUSIONS: There is limited and very low quality evidence of benefit for all of a diverse collection of exercise and mobilisation interventions for CTS. People with CTS who indicate a preference for exercise or mobilisation interventions should be informed of the limited evidence of effectiveness and safety of this intervention by their treatment provider. Until more high quality randomised controlled trials assessing the effectiveness and safety of various exercise and mobilisation interventions compared to other non-surgical interventions are undertaken, the decision to provide this type of non-surgical intervention to people with CTS should be based on the clinician's expertise in being able to deliver these treatments and patient's preferences.